DD151170A5 - PROCESS FOR THE PREPARATION OF NEW 3-THIOVINYL-CEPHALOSPORINES - Google Patents

Abstract

The invention relates to a process for the preparation of novel cephalosporins of general formula I in which R is alkyl, L-2-amino, 2-carboxyethyl, phenyl, optionally N-oxidized pyridyl, 2-pyrimidinyl, 3-pyridazinyl substituted, 5,6- Dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl substituted in the 4-position, 1,3,4-triazol-5-yl or 2-alkyloxycarbonyl-1, 3, 4-triazol-5-yl substituted at the 1-position, 1,4-dialkyl-5,6, -dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl , 1-alkyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl, 2-alkyl-5,6-dioxo-1,2,5,6 tetrahydro-1,2,4-triazin-3-yl, 5-triazolyl, substituted or unsubstituted 1,3,4-thiadiazol-5-yl, substituted or unsubstituted 1,2,4-thiadiazol-5-yl, substituted or unsubstituted 1,3,4-oxadiazol-5-yl, substituted or unsubstituted 2-oxazolYL or substituted in the 1-position or unsubstituted 5-tetrazolyl, R 'is a hydrogen atom or a radical of general formula II, R & expo! Hydrogen, alkyl, vinyl or cyanomethyl, and their salts, which can be used as an active ingredient in pharmaceutical compositions.

Description

Field of application of the invention

The invention relates to a process for the preparation of novel 3-thiovinyl-cephalosporins which can be used as active ingredient in pharmaceutical compositions.

Characteristic of the known technical solutions

As the closest prior art, FR-PS 2 081 451 and 2 137 899 can be given.

aim the invention

The aim of the invention is the enrichment of the prior art by hitherto unknown pharmacological agents.

Explanation of the essence of the invention

The invention relates to novel 3-thiovinyl-cephalosporins of the general formula

N * -C-CONH- ^ S \

ii

-CH = CH-SR

(I)

COOR ¹

their salts, processes for their preparation and pharmaceutical compositions containing them.

In the general formula I, the symbol R is selected from the following meanings:

1-alkyl, L-2-amino-2-carboxyethyl, phenyl,

2. 2-pyridyl, 3-pyridyl or 4-pyridyl and their N-oxides _f

29.9.1980 AP C 07 D / 221 271 22127 U -2- 57 466/11

3. 2-pyrimidinyl; 3-pyridazinyl substituted at the 6-position (by an alkyl, methoxy, amino or acylamino radical) and optionally N-oxidized, or tetrazolo-4,5-b! 6-pyridazinyl,

4. B ^ -dioxo-1'-bis-tetrahydro-1'-triazine-S-yl substituted in 4-stellurig; 1,3,4-triazol-5-yl or 2-alkyloxycarbonyl-l-3,4-triazol-5-yl which are substituted in the 1-position,

a) by an alkyl radical, unsubstituted or substituted by an alkyloxy, alkylthio, phenyl-formyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, acyl, alkyloxycarbonyl or 2-thiazolidinyl radical _f

b) by an allyl; 2,3-dihydroxypropyl; 1,3-dihydroxy-2-propyl; 2-formyl-2-hydroxyethyl ~; 3-formyloxy-2-hydroxypropyl; 2,3-bis-formyloxy-propyl or 1,3-bis-formyloxy-2-propyl radical;

c) by an alkyl radical having 2 to 4 carbon atoms, substituted by a hydroxy, carbamoyloxy, acyloxy (whose acyl moiety may be substituted by an amino, alkylamino or dialkylamino radical), alkylsulfinyl, alkylsulfonyl, amino, alkylamino , Dialkylamino, sulfamino, alkylsulfonylamino, sulfamoylamino, acylamino (whose acyl part is optionally substituted by hydroxy, amino, alkylamino or dialkylamino), alkyloxycarbonylamino, ureido, alkylureido, dialkylureido, dj by a radical having one of the following formulas corresponds to: ·

2Θ.9.1980 AP C 07 D / 221 271 12 7 1, - 3 - 57 466/11

- ALk - C

or - CH ₂ -CHOH-CH III

^ \ jCi. D

or - AIk-CH IV,

OR *

wherein Alk is an alkylene radical having 1 to 4 carbon atoms, X ^ and Y ^ are the same and are oxygen or sulfur atoms, and R ^ is an alkyl radical, or wherein X * ^ and Y ^ are the same or different and represent oxygen or sulfur atoms and the Radicals R ⁴ * together form an alkylene radical having 2 or 3 carbon atoms, and R represents a hydrogen atom or an alkyl radical having 1 to 3 carbon atoms,

e) by an alkyl radical having 1 to 5 carbon atoms, substituted by an alkyloxyimino or hydroxyimino radical,

5x1,4-dialkyl-5,6-dibenzo-1,4,5,6-1-tetrahydro-1, 2,4-triazin-3-yl; l-alkyl-Sio-dioxo-l ^^ ie-tetrahydro-l ^^ - triazin-3-yl; 2-alkyl-5,6-dioxo-l, 2,5,6-tetrahydro-l, 2,4-triazin-3-yl,

6. 1, 3,4-triazol-5-yl; ! ^, is-triazol-o-yl or 1-alkyl, 2,4-triazol-5-yl, unsubstituted or substituted in the 3-position by alkyloxycarbonyl,

Ί 27

7. a) 1,3,4-ThIaCUaZOl-S-Yl, unsubstituted or substituted by an alkyl, trifluoromethyl, alkyloxy, alkylthio, hydroxyalkylthio, the alkyl part of which contains from 2 to 4 carbon atoms, alkylsulfonyl, hydroxy, Hydroxyalkyl, carboxy, carboxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, acylamino or acylaminoalkyl radical,

b) l, 2,4-thiadiazol-5-yl, substituted by an alkyl or alkyloxy radical,

8. a) l, 3,4 ~ 0xadiazol-5-yl, unsubstituted or substituted

by an alkyl, trifluoromethyl, phenyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or acylaminoalkyl radical, b) 2-oxazolyl or 4-alkyl-2-oxazolyl,

9. 5-tetrazolyl, unsubstituted or substituted in the 1-position

a) an alkyl radical, unsubstituted or substituted by alkyloxy, sulfo, carboxy, formyl or sulfamoyl,

b) an alkyl radical having 2 to 4 carbon atoms, substituted by hydroxy, amino, alkylamino, dialkylamino, acylamino, carboxyalkylamino, sulfamoylamino, sulfamino, ureido, alkylureido or dialkylureido,

c) an alkyl radical having 1 to 5 carbon atoms, substituted by hydroxyimino or alkyloxyimino,

d) a phenyl; 2,3-dihydroxypropyl; l, 3-dihydroxy-2-propyl; 2-formyl-2-hydroxy-ethyl; 3-formyloxy-2-hydroxy-propyl-; 2,3-bis-formyloxy-propyl or

- l _f 3-bis-formyloxy-2-propyl or e) is a radical of the general formula II wherein R is a hydrogen atom, or a radical of the general formula III;

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wherein the symbol R represents a hydrogen atom or an alkyl, vinyl or cyanomethyl radical;

and the symbol R ^{1 represents} a hydrogen atom or an enzymatically easily eliminable radical of the general formula

- CH - OCOR "'V

R "

wherein R "represents a hydrogen atom or an alkyl radical and R" 'represents an alkyl radical or the cyclohexyl radical.

It is understood that. the aforesaid (or hereinafter referred to) alkyl or acyl moieties or moieties (unless otherwise specified) are straight or branched and contain from 1 to 4 carbon atoms.

It is also understood that the substituent in the (3) -position of the compounds of the general formula I can be in the cis- or trans-form or in a mixture of the cis and trans forms. «

In the following, the trans stereoisomerism is denoted by E and the cis stereoisomerism by Z «

It is also understood that the group OR ⁰ can be in one of the syn or anti positions and that these isomers and their mixtures are within the scope of the invention.

The syn-form can be represented by the following formula:

221271

* * O **

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• C-CONH-N-OR ^r

O = d

(Ia)

-CH = CH-SR

COOR ¹

The anti-form can be represented by the following formula:

H ₂ N-yy "

(Ib)

R ⁰ ON

CH = CH-SR

COOR ¹

Similarly, when the group R contains a hydroxyaminoalkyl or alkyloxyiminoalkyl substituent, this group may represent the syn and anti isomers and these isomers and their mixtures are also within the scope of the invention.

When the radical R is a 1,4,5,6-tetrahydro-triazinyl radical which is substituted in the 1- or 4-position, or the 1,2,5,6-tetrahydro-triazinyl radical which is in the 2-position it can be represented by the tautomeric forms:

22127 1

(Via)

or

noun ·

- OH

noun

I

Ν-Ν

OH

(VIb)

(VIc)

When the radical R contains a formylalkyl radical, it may be in the form of the free aldehyde or the aldehyde hydrate. In particular, these forms are determined under the conditions described below.

In particular, nuclear magnetic resonance studies show that when R is 5,6-dioxo-4-formylmethyl-1,4,5,6-tetrahydro-1, 2,4-triazin-3-yl:

in acidic solvent, such as formic acid or trifluoroacetic acid (which are deuterated), in the presence or absence of (heavy) water, the product is mainly in the form of the free aldehyde;

22 1 27 1

in basic solvent, such as (heavy) water, mixed with sodium bicarbonate, mainly in the form of the aldehyde hydrate;

in neutral solvent such as dimethylsulfoxide (d _fi ), the forms of the free aldehyde and the aldehyde hydrate, the addition of water progressively bringing about the conversion of the free aldehyde form to the aldehyde hydrate form.

In general, the products of general formula Ia are preferred.

In particular, among the above meanings of the symbol R:

Methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec, butyl, t-butyl

l, 3,4-thiadiazol-5-yl

2-methyl-l, 3,4-thiadiazol-5-yl

2-ethyl-l, 3,4-thiadiazol-5-yl

2-propyl-l, 3,4-thiadiazol-5-yl

2-isopropyl-1,3,4-thiadiazol-5-yl

2-butyl-l, 3,4-thiadiazol-5-yl

2-isobutyl-1,3,4-thiadiazol-5-yl

2-sec-Buty1-1,3,4-thiadiazol-5-yl

2-t-butyl-1,3,4-thiadiazol-5-yl

2-hydroxymethyl-l, 3,4-thiadiazol-5-yl 2-t 2-hydroxyethyl] J -1,3,4-thiadiazol-5-yl 2-aminomethyl-1,3,4-thiadiazol-5-yl 2 -Methylaminomethyl-l, 3,4-thiadiazol-5-yl 2-Dimethylaminomet hy1-1,3,4-thiadiazol-5-yl

2 - / "2-aminoethyl" -1,1,4-thiadiazol-5-yl 2- = £ 2-methylaminoethyl J-1,3,4-thiadiazol-5-yl 2-C2-dimethylaminoethyl J.sub.1-l , 4-thiadiazol -5-yl

221 271

29.9.1980 AP C 07 D / 221 - 9 - 57 466/11

2-Carboxymethyl-1 _J 3 _/ 4-thiadiazol-5-yl 2- (2-carboxyethyl) -1,3,4-thiadiazol-5-yl 2-methoxy-1,3,4-thiadiazol-5-yl 2 methylthio-l, 3 _f 4-thiadiazol-5-yl 2R-methylsulfonyl-l, 3 _J 4-thiadiazol-5-yl 2-amino-1,3,4-thiadiazol-5-yl ~ 2-methylamino-l, 3,4-thiadiazol-5-yl

2-Acetylamino-l, 3,4-thiadiazol-5-yl 2-hydroxy-l _/ 3,4-thiadiazol-5-yl 2-acetamidomethyl-l, 3,4-thiadiazol-5-yl 2 ~ (2- Acetamidoethyl) -l, 3 _l 4-thiadiazol-5-yl 3-methyl-l, 2,4-thiadiazol-5-yl

l, 2,3-triazol-5-yl

l _f 3,4-triazol-5-yl

l-methyl-3-methoxycarbonyl-l, 2,4-triazol-5-yl 3-methoxycarbonyl-l-ethyl-l, 2,4-t-riazol-5-yl l-methyl-S-ethoxycarbonyl-l ^^ -t riazol-5-yl 1-ethyl-3-ethoxycarbonyl-1 _f Z, 4-triazol-5-yl 5-flHj-tetrazolyl

l-Methyl-5-tetrazolyl l-ethyl-5-tetrazolyl l -propyl-5-tet razolyl l-isopropyl-5-tetrazolyl 1-butyl-5-tatrazolyl 1- (2-hydroxyethyl) -5-tet razolyl l (3-Hydroxypropyl) -5-tetrazolyl 1-methoxymethyl-5-tetrazolyl 1-carboxymethyl-5-tetrazolyl 1-sulfomethyl-5-tetrazolyl

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22 127 1

1- (2-Methylamino-ethyl) -5-tetrazole-1- (2-dimethylamino-ethyl) -5-tetrazolyl-1- (2-diethylamino-ethyl) -5-tetrazolyl-1- (3-dimethylaminopropyl) -5-tetrazolyl

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1- (2-sulfamoylaminoethyl) -5-tetrazolyl 1- (2-acetamidoethyl) -5-tetrazolyl 2-pyridyl 3-pyridyl 4-pyridyl 2-pyridyl-1-oxide 6-methyl-3-pyridazinyl 6-methyl-3 -pyridazinyl-1-oxide 6-ethyl-3-pyridazinyl 6-ethyl-3-pyridazinyl-1-oxide 6-methoxy-3-pyridazinyl 6-amino-3-pyridazinyl 6-acetamido-3-pyridazinyl tetrazolo-4,5-b-pyridazine -6-yl

5,6-dioxo-4-methyl-1, 4,5,6-tetrahydro-1,2,4-triazine-3-yl-5,6-dioxo-4-ethyl-1, 4,5,6-tetrahydro -l, 2,4-triazin-3-yl 5,6-dioxo-4-propyl-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl 5, ö-dioxo ^ - isopropyl-1,4,5,6-1 et rahydro-1,2, A- 1-riazin-3-yl 4-allyl-5,6-dioxo-l, 4,5,6-tetrahydro-1,2, 4-triazin-3-yl 5,6-dioxo-4 - (2-hydroxy et hy I) -1,4,5,6-1 et rahydro-1,2,4-triazin-3-yl

5,6-dioxo-4- (3-hydroxypropyl) -1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl

5,6-dioxo-4-methoxymethy1-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl

5,6-dioxo-4- (2-methoxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl

5,6-dioxo-4-ethoxymethyl-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl. 5,6-dioxo-4- (2-ethoxyethyl) -l, 4, 5,6-tetrahydro-1,2,4-triazine

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4- (2 ~ acetamidoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl

4-Benzyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4-phenethyl-1, 4,5,6-tetrahydro -i, 2,4-t-riazin-3-yl-di-dioxo-methylthiomethyl-1-yl-tetrahydro-1'-triazin-3-yl

Fe-dioxo ^ -methylthioethyl-l ^^ ie-tetrahydro-l ^^ -

triazin-3-yl _;

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4-carbamoylmethyl-5,6-dioxo-l, 4 _f 5,6-tetrahydro-l, 2,4-t riazin-

4- (2-Carbamoylethyl) -5,6-dioxo-1, 4,5,6-tetrahydro-1, 2,4-triazin-3-yl 4 ~ (3-carbamidylpropyl) -5 _, 6 ^ 10X0 -1,4,5,6-tetrahydro-l, 2,4-t riazin-3-yl 4- (2-carbamoyloxyethyl) -5,6-dioxo-l, 4 _l 5,6-tetrahydro-1, 2,4-triazin-3-yl 4- (3-carbamoyloxypropyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl-5,6-dioxo 4-methylsulfinylethyl-1,4,5,6-tetrahydro-l, 2,4-triazin-3-yl 5,6-dioxo-4- (2-sulfyloxyethyl) -1,4,5,6-tetrahydro-1 , 2,4-triazin-3-yl 5,6-dioxo-4- (3-formyloxypropyl) -1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl 4- (2- Acetoxyethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl 4- (3-acetoxypropyl) -5,6-dioxo-l, 4,5, 6-tetrahydro-l, 2,4-triazin-3-yl 5,6-dioxo-4- (2-glycyl-1-yl) -l, 4,5,6-tetrahydro-l, 2,4-triazine-3 -yl 5,6-dioxo-4- (3-glycyloxypropyl) -l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl 5,6-dioxo-4-bis (2-propanoyloxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl 4- (2,2-dimethoxyethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1, 2,4-triazin-3-yl 4- (3,3-dimethoxypropyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-

triazin-3-yl. ·

4- (2,2-diethoxyethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl

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4- (3,3-diethoxypropyl) -5,6-010X0-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl

4- (2,2-Bismethylthioethyl) -5,6-dioxo-l, 4,5,6-tetrahydrol, 2,4-triazin-3-yl

29.9.1980 g. AP C 07 D / 221

2 212 7 1st - ta - 57 4β6 / ιι

4- (3,3-bismethylthiopropyl) -5,6 ^ 10X0-1,4,5,6-tetrahydrol, 2,4-triazin-3-yl 4- (2,2-bisethylthoethyl) -5.6- dioxo-l, 4,5,6-tet rah yd ro l, 2,4-triazin-3-yl 4- (3,3-Bisethylthiopropyl) -5,6-dioxo-l, 4,5,6-tetrahydrol , 2,4-triazin-3-yl-5,6-dioxo-1,3-dioxolan-2-yl-4-methyl-1,4,5,6-tetrahydrol, 2,4-triazine-3 yl 5,6-0x0X0-4- [Z- (1,3-dioxolan-2-yl) -ethyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6 Dioxo (1,3-dithiolan-2-yl) -4-methyl-1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl-5,6-dioxo-4-one - (1,3-dithiolan-2-yl) ethyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl-5,6-dioxo (1, 3) oxathiolan-2-yl) -4 (1,3-dioxan-2-yl) -methyl-1,4,5,6-tetrahydro-l, 2,4,1-riazin-3-yl-5,6-dioxo 4- (2- (1,3-oxathiolan-2-yl) -ethyl "] - 1,4,5,6-tetrahydahydro-i, 2,4,1-riazin-3-yl-5,6-dioxo - (l, 3-dioxan-2-yl) -4 (1,3-dioxan-2-yl) -methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl 5 , 6-DX0X0-4- [2- (1/3-dioxan-2-yl) -ethyl} -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6 -Dioxo- (l, 3-dithian-2-yl) -4 (l, 3-dioxan-2-yl) methyl-1,4,5,6-tetrahydro-1,2,4-triazin-3- yl 5,6-dioxo-4-pi-2- (i, 3-dithian-2-yl) -ethyl] -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl 2 -pyrimidinyl _{5,6-dioxo-4-methyl->} lcarbamoylmethyl-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl 5,6-dioxo-4- (2-methylcarbamoylethyl) -l , 4,5,6-tetrahydro-1, 2, 4-triazin-3-yl

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5,6-dioxo-4-ethylcarbamoylmethyl-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl

4-dimethylcarbamoylmethyl-5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl

4- (2-dimethylcarbamoylethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl

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4-diethylcarbamoylmethyl-5,6-dioxo-1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl-4-acylmony 1-5, 6 ^ x0X0-1, 4, 5, 6-1 et rahydro-1,2,4-1-riazin-3-yl 5,6-dioxo-4- (2-oxobutyl) -1,4,5,6-tetrahydro-1,2,4-triazine -3-yl

5,6 ~ dioxo-4- (3-oxo-butyl) -l, 4,5,6-tetrahydro-1, 2,4-triazin-3-yl

5,6-dioxo-4- (methoxycarbonylmethyl) -1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (2-methoxycarbonylethyl) -1, 4 , 5,6-tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (ethoxycarbonylmethyl) -1, 4,5,6-tetrahydro-1,2,4-triazine-3 -yl 5,6-dioxo-l, 4,5,6-tetrahydro-4 (2-thiazolidinyl) -methyl-1,2,4-triazin-3-yl 4- (2,3-dihydroxypropyl) -5, 6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl ·

4- (1,3-dihydroxy-2-propyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl-5,6-dioxo-4- 2-formyl-2-hydroxyethyl) -1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl 4- (2-aminoethyl) -5,6-dioxo-l, 4,5, 6-tetrahydro-1,2,4-triazin-3-yl

4- (3-aminopropyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl-5,6-dioxo-4- (2-methylaminoethyl) - l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (3-methylaminopropyl) -l, 4,5,6-tetrahydro-1,2,4 ~ triazin-3-yl 5,6-dioxo-4- (2-ethylaminoethyl) -1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl

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5.6 ~ dioxo-4- (3-ethylamino-ropyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl 4- (2-dimethylaminoethyl) -5,6- dioxo-l, 4,5,6-tetrahydro-1,2,4-trxazin-3-yl 4 ~ (3-dimethylaminopropyl) -5 _f 6-dioxo-l, 4,5,6-tetrahydro-l, 2 , 4-triazin-3-yl 4 ~ (2-diethylaminoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl

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4- (3-diethylaminopropyl) ~ 5,5-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl

5,6-dioxo-4- (2-sulfaminoethyl) -I, 4,5,6-tetrahydro-I ₁ 2,4-triazin-3-yl

5,6-dioxo-4- (2-methylsulfonylaminoethyl) -1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (3-methylsulfonylaminopropyl) -1 , 4,5,6-tetrahydro-1,2,4-triazin-3-yl-5,6-dioxo-4- (2-sulfamoyl-aminoethyl) -l, 4,5,6-tetrahydro-n-triazine 3-yl 5,6-dioxo-4- (3-sulfamoylaminopropyl) -l, 4,5,6-tetahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (2- glycoloylaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4-2- (2-hydroxypropionamido) -ethyl 3-l, 4,5,6 tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (2-glycylaminoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl

4 ~~~ (L) -2 ~ alanylaminoethyl-3,5-dioxo-l, 4,5,6-tetahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (3 -gIycylaminopropy1) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl

5,6-dioxo-4- (2-methylaminoacetarnidoethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl 4- (2-dimethylaminoacetamidoethyl) -5,6-dioxo-1 , 4,5,6-tetrahydro-1,2,4-triazin-3-yl 4- (2-diethylaminoacetamidoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4- triazin-3-yl 5,6-dioxo-4- (2-methoxycarbonylaminoethyl) -1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (2 -ethoxycarbonylaminoethyl) -l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl

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5,6-dioxo-1,4,6,6-etaahydro-4- (2-ureidoethyl) -1,2,4-triazin-3-yl 5.6-010X0-1.4, 5,6 tetrahydro-4- (3-ureidopropyl) -1,2,4-triazin-3-yl

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5,6-dioxo-4 - / '2 - (3-methylureido) -et-hy IJ-1,4,5,6-1 et rahydrol, 2,4-triazin-3-yl 5,6 ~ dioxo 4- £ 3- (3-methylureido) -propyr] -l, 4,5,6-tetrahydrol, _2-f 4 tria2in-3-yl 5,6-dioxo-4 - / 2- (3-ethylureido) ethyl-1- _i 4,5,6-tetrahydro-

4- ^ 2- (3,3-Dimethyl) ethyl] -5 _# 6-dioxo-l _f 4,5,5-tetrahydro-l, 2,4-triazin-3-yl 4-F3- (3, 3-Dimethyl-ureido) -propylü-5,6-dioxo-1,4,5,6 ~ tetrahydro-1,2, 4-triazin-3-yl 4-C2- (3,3-diethylureido) -ethylJ-5, 6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazih-3-yl 4- (2,2-dimethoxypropyl) -5,6-dioxo-l, 4,5,6-tetrahydro -l, 2,4-triazin-3-yl 4- (3,3-dinethoxy-2-hydroxypropyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazine 3-yl 5,6 ~ dioxo-4- / 3- (2-dioxolanyl) -2-hydroxypropyl-1,10,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6- Dioxo-4- (2-hydroxy-2-methoxyethyl) -1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (3-hydroxy-3- methoxypropyl) -1, A, 5,6-tetrahydro-1,2,4-triazin-3-yl 5,6 ~ dioxo-4- (2-ethoxy-2-hydroxyethyl) -l _f 4,5,6- tetrahydro-1,2,4-triazin-3-yl 5,6-dioxo-4- (3-ethoxy-3-hydroxypropyl) -1,4,5,6-tetrahydro-1,2,4-triazine-3 -yl 5,6-dioxo-4- (2-hydroxy-2-propoxy-ethyl) -l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl-5,6-dioxo-4 ( 2-hydroxy-iminoethyl) -l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl, 5,6-dioxo-4- (2-hydroxyiminopropyl) -1,4,5,6- tet ahydro-1,2,4-triazin-3-yl

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5 _# 6-dioxo-4- (2-methoxyiminoethyl) -1, 4,5,6-tetrahydro-1,2,4-triazine-3-yl

5,6-dioxo-4- (3-methoxyiminopropyl) -l, 4 _f 5,6-tetrahydro-l _f 2,4-triazin-3-yl

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5,6-dioxo-4- (2-ethoxyiminoethyl) -1,4,5,6-tetrahydro ~ l, 2,4-triazin-3-yl

1- (formylmethyl) -1,3,4-triazol-5-yl 1- (2-formylethyl) -1,3,4-triazol-5-yl 1-carbamoylmethyl-1,3,4-triazole-5- yl 1- (2-Hydroxyethyl) - -, 3,4-triazol-5-yl 1- (2-Carbamoyloxyethyl) -1,3,4-triazol-5-yl 1- (2-Glycyloxyethyl) -1,3 , 4-triazol-5-yl 1- (2-acetamidoethyl) -1,3,4-triazol-5-yl 1- (2,2-dimethoxyethyl) -1,3,4-triazol-5-yl 1 Methylcarbamoylmethyl-1-methyl-1,3,4-triazol-5-yl 1- (2-dimethylcarbamoyl-ethyl) -1,3,4-triazol-5-yl-1 Acetony1-1,3,4-triazol-5-yl 1- (2-thiazolidinylmethyl) -1,3,4-triazol-5-yl 1- (2,3-dihydroxy-propyl) -1,3,4-triazole 5-yl 1- (1,3-dihydroxy-2-propyl) -1,3,4-triazol-5-yl 1- (2-formyl-2-hydroxyethyl) -1,3,4-triazole-5- yl 1- (2-aminoethyl) -1,3,4-triazol-5-yl 1- (2-methylaminoethyl) -1,3,4-triazol-5-yl 1- (2-dimethylaminoeth 1) -1, 3,4-triazol-5-yl 1- (2-methylsulfonylaminoethyl) -I, 3,4-triazol-5-yl 1- (2-sulfamoylaminoethyl) -1,3,4-triazol-5-yl 1- (2-methylsulfonylaminoethyl) -I, 3,4-triazol-5-yl 2-glycoloylaminoethyl) -1,3,4-triazol-5-yl 1- (2-glycylaminoethyl) -1,3,4-triazol-5-yl 1- (2-methoxycarbonylaminoethyl) -1 , 3,4-triazol-5-yl 1- (2-ureidoethyl) -1,3,4-triazol-5-yl 1-f2- (3-methylureido) -ethyl-1,3,3,4-triazole-5 -yl 1- t 2- (3,3-dimethylureido) -ethyl] -1,3,4-triazol-5-yl 1- (3,3-dimethoxy-2-hydroxy-propyl) -I, 3,4 -triazol-5-yl 1- (2-hydroxy-2-methoxyethyl) -1,3,4-triazol-5-yl 1- (2-hydroxyiminoethyl) -1,3,4-triazol-5-yl

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1- (2-methoxyiminoethyl) -1,3,4-triazol-5-yl-1-formylmethyl-2-methoxycarbony1-1,3,4-triazol-5-yl 2-ethoxycarbonyl-1-methylmethyl , 4-1riazol-5-yl 1- (2-formylethyl) -2-methoxycarbonyl-l, 3,4-triazol-5-yl

29.9.1980 AP C 07 D / 221 2 2 1271 - & -., 57 456/11

1- (2-hydroxyethyl) -2-methoxycarbonyl-1,3,4-triazol-5-yl 1-carbamoylmethyl-2-methoxycarbonyl-1,3,4-triazol-5-yl 1- (2-carbamoylethyl) - 2-methoxycarbonyl-1,3,4-triazol-5-yl 1- (2-acetamidoethyl) -2-methoxycarbony1-1,3,4-triazol-5-yl 1- (2,2-dimethoxyethyl) -2- methoxycarbonyl-1,3,4-triazol-5-yl 1- (dimethylcarbamoylmethyl) -2-methoxycarbony1-1,3,4-triazol-5-yl

1-acetonyl-2-methoxycarbonyl-1,3,4-triazol-5-yl. 1- (2,3-Dihydroxypropyl) -2-methoxycarbony1-1,3,4-triazol-5-yl 1- (1,3-dihydroxy-2-propyl) -2-methoxycarbonyl-1,3,4-triazole -5-yl

1- (3-formyl-2-hydroxyethyl) -2-methoxycarbonyl-1,3,4-triazol-5-yl

l- (2-dimethylaminoethyl) -2-methoxycarbonyl-1,3,4-triazol-5-yl

2-Methoxycarbony1-1- (2-methylsulfonylaminoethyl) -1,3,4-triazol-5-yl 2-methoxycarbonyl-1- (2-sulfamoylaminoethyl) -1,3,4-triazol-5-yl

2-Methoxycarbony1-1- (2-methoxycarbonylaminoethyl) -1,3,4-triazol-5-yl 2-methoxycarbony1-1- (2-ureidoethyl) -1,3,4-triazol-5-yl 2-methoxycarbony1- 1- ^ 2- (3-Methylureido) -ethyl J-I, 3,4-triazol-5-yl 1-Γ2- (3,3-dimethylureido) -ethyl-2-methoxycarbonyl-1,3,4-triazole-5 -yl 1- (3,3-dimethoxy-2-hydroxypropyl) -2-methoxycarbonyl-l, 3,4-triazol-5-yl 1- (2-hydroxy-2-methoxyethyl) -2-methoxycarbonyl-1,3 , 4-triazol-5-yl 1, 4-dimethyl-5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl

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1-ethyl-4-methyl-5,6-dioxo-l, 4 _# 5,6-tetra.hydro-l _/ 2,4-triazine

4-ethyl-1-methyl-5,6-dioxo-l, 4 _# 5,6-tetrahydro-l, 2,4-triazine

l-methyl-5,6-dioxo ~ l, 4,5,6-tetrahydro - _l, 2,4-Triaz: in - 3-yl

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.221271 -SS _{1 -;} 57 466/11

2 ~ ethyl 5,6-dioxo-l, 2,5,6-tetrahydro-l, 2,4-triazin-3-yl l-methyl-l, 2,4-triazol-5-yl 2- (2 -Hydroxyethylthio) -1,3,4-thiadiazol-5-yl 1 _# 3,4-oxadiazol-5-yl

2-methyl ~ l _/ 3,4-oxadiazol-5-yl 2-phenyl-l, 3,4-oxadiazol-5-yl 2 ~ aminomethyl-l, 3 _f 4-oxadiazol-5-yl ~ 2-Acetamidomethyl l , 3 _# 4-oxadiazol-5-yl 2-dimethylaminomethyl-l _/ 3,4-oxadiazol-5-yl-2-oxazolyl

4-methyl-2-oxazolyl

1- Formylmethy1-5-tetrazolyl l ~ (2 ~ formylethyl) -5-tetrazolyl-1-tetrazolyl Sulfamoylmethy1-5 l ~ (2 ~ Carboxymethylaminoethyl) -5-tetrazolyi 1- (2-SuIfaminodhyl) -5-tetrazolyl l- ( 2-ureidoethyl) -5-tetrazolyl '. ·, 1- (2- (3-Methylureido) -ethyl) -5-tetrazolyl 1-6-2- (3,3-dimethylureido) -ethyrl-5-tetrazolyl-1- (2-hydroxyiminoethyl) -5-tetrazolyl. (3-Hydroxyiminopropyl) -5-tetrazolyl 1- (2-methoxyiminoethyl) -5-tetrazolyl 1 - (3-Methoxyiminopropyl) ~ 5-tetrazolyl 1- ( _2f- 3-dihydroxypropyl) -5-tetrazolyl 1- (1,3 dihydroxy-2 ~ propyl) -5-tetrazolyl l ~ (2-formyl-2-hydroxyethyl) -5-tetrazolyl l- (2 _i 2-dimethoxyethyl) -5-tetrazolyl l- (3,3-dimethoxypropyl) -5 tetrazolyl 1- (2-hydroxy-2-methoxyethyl) -5-tetrazolyl 1- (2-ethoxy-2-hydroxyethyl) -5-tetrazolyl 2-hydroxy-1- (2-propoxyethyl) -5-tetrazolyl ( 3-hydroxy-3-methoxypropyl-5-tetrazolyl

1- (3-ethoxy-3-hydroxypropyl) -5-tetrazolyl 1- (2-dioxolanylethyl) -5-tetrazolyl

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38 AP.C 07 D / 221 271

2 21271 - £ 9- 57 466/11

Particular mention may be made of the above meanings for the symbol R: hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, vinyl, cyanomethyl.

Among the above meanings for the symbol R "may be mentioned in particular: hydrogen, pivaloyloxymethyl and acetoxymethyl.

A) According to the invention, the compounds of the general formula I in which R is different from a triazinyl or triazolyl radical which is substituted by a group of the general formula IV can be prepared by the action of an acid of the general formula

(VII)

-C-COOH

wherein R is as defined above, and whose amine function has been previously protected (and the oxime when R represents hydrogen) or a reactive derivative of this acid to a 7-amino-cephalosporin of the general formula

(VIII), -CH = CH-SR

wherein R is as defined above, with the exception of a triazolyl radical or a triazinyl radical substituted by

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2 2 1 2 7 Ij _ SB - 57 466/11

a group.der general formula IV, R represents a hydrogen atom, a radical of general formula V or an easily cleavable protecting group, for example methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl, p-methoxybenzyl and η has the meaning of O or 1 , whereupon the resulting sulfoxide, if η = 1, reduced and then cleaved the protecting groups.

It is understood that the acid of general formula VII in syn- or anti-form or in the form of their mixtures in each case to products of general formula I in syn- or anti-form or in the form of mixtures thereof.

a) If one uses a compound of general formula VII in the form of the acid, the protection of its amino group is carried out by any known or conventional method for blocking an amine function, without attacking the rest of the molecule. It is necessary to use an easily eliminable group such as t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl ₇ · chloroacetyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, formyl or trifluoroacetyl group.

When R represents a hydrogen atom, the protection of the oxime can be effected by any known method which does not alter the rest of the molecule. In particular, a trityl, tetrahydropyranyl or 2-methoxy-2-propyl group is used.

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In general, condensation of the product of general formula VII, the acid function of which is free and whose amine function has been previously protected, is effected with the 7-amino-cephalosporin of general formula VIII, wherein R and η are as defined above, R.sup.1 is a radical of the general formula V or an easily removable protection · »

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I Ä / I. "^. 57 466/11

group, such as methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl, or p-methoxybenzyl, working in an organic solvent, such as dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride or chloroform, in the presence of a condensing agent, such as a carbodiimide (e.g. dicyclohexylcarbodiimide), N, N ¹ -Carbonyldiimidazpl or 2-ethoxy ~ l-ethoxycarbonyl-l, 2-dihydroquinoline, at a temperature of -20 to 40 C, followed by reducing the oxide obtained when a 7-amino-cephalosporin of wherein η = 1, and the protecting groups from the amine function and optionally from the acid function and the oxime cleaved.

It will be understood that the amino, alkylamino, carboxy and hydroxy groups present in various R groups are or may be protected by any of the groups commonly used to protect amines, carboxylic acids or alcohols, the use of which moreover Remainder of the molecule not changed.

For example

the amino and alkylamino groups are protected by residues such as t-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, trichloroacetyl, trityl, benzyl, dibenzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, chloroacetyl, formyl or trifluoroacetyl;

29.9.1980 2.2 / AP C. 07 D / 221

2OI97I - 2φ & - 57 466/11

§Β§ ·mim W I

the carboxyl groups may be protected by radicals such as methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl or p-methoxybenzyl;

the hydroxyl groups can be protected by means of radicals such as trityl, tetrahydropyranyl or 2-methoxy

22 1 27 1,

29.9.1980 £ 2 AP C 07 D / 221 271

- ** 57 466/11

2-propyl or else in the form of a 2,2-dimethyl-4-dioxolanylmethyl radical or 2,2-dimethyl-5-dioxanyl radical _f when it concerns the protection of 2,3-dihydroxypropyl or 1,3-dihydroxy-2- propyl radicals.

It is understood that when in the general formula VIII the radical R contains a hydroxy, sulfo, sulfinyl or sulfonyl group, it is preferred to use a product in which η = 0,

If it is desired to obtain a product of general formula I in which R contains a formylalkyl or acylalkyl radical, this radical may optionally be protected in the acetal state in the form of a radical of general formula II or III as defined above.

Deprotection of * R is carried out after reduction of the oxide, before, simultaneously or after removal of the other protecting groups.

The reduction of the S-oxide is carried out, for example, according to the conditions described in DE-OS 26 37 176. The removal of the various protecting groups may be simultaneous or sequential.

1 " For example, removal of the amine protecting groups is as follows:

if it is a t-butoxycarbonyl, trityl, p-methoxybenzyloxycarbonyl or formyl radical: by treatment in an acidic medium. Preferably, trifluoroacetic acid is used, which is carried out at a

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Temperature of from 0 to 20 ^° C., or anhydrous or aqueous formic acid or p-toluenesulfonic acid or methanesulfonic acid in acetone or acetonitrile can also be used at a temperature of from 20 ° C. to the reflux temperature of the reaction mixture.

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turn. Under these conditions, the compound of general formula I in the form of trifluoroacetate, ... of the acetate of methanesulfonate or of p-toluenesulfonate obtained from which the amine function by any known or usual way to obtain an amine from a of its salts, without attacking the rest of the molecule. In particular, it works by contact with an ion exchange resin or by the action of an organic base;

when it is a 2,2,2-trichloroethoxycarbonyl or p-nitrobenzyloxycarbonyl radical: by reduction (especially by treatment with zinc in acetic acid);

if it is a chloroacetyl or Trichloracetylrest: through application of the "in the FR-PS described 2,243,199 method;

when it is a benzyl, dibenzyl or Benzyloxycarbonylrest: by catalytic hydrogenation;

if it is a Trifluoracetylrest: by treatment in a basic medium.

2 » The removal of the protective groups of the carboxyl radical takes place, for example:

in the case of a t-butyl, p-methoxybenzyl or benzhydryl group: by treatment in an acidic medium, other than those mentioned above for the removal of

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In the case of the benzhydryl group one can work in the presence of anisole;

if it is a methoxymethyl group: by treatment in dilute acid medium;

if it is a p-nitrobenzyl group: by reduction (in particular by treatment with zinc in

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Acetic acid or by hydrogenolysis).

3. The removal of the protective groups from the oxime and / or the hydroxy radicals can be carried out, for example, as follows:

if it is a trityl or tetrahydropyranyl or 2 _/ 2-dimethyl-4-dioxolanylmethyl or 2,2-dimethyl-5-dioxanyl radicals: by acidolysis, for example by means of trifluoroacetic acid, aqueous or non-aqueous formic acid or p-toluenesulfonic acid , If one uses aqueous or non-aqueous formic acid, the release of the protected as cyclic acetal hydroxyl radicals may at least partially lead to corresponding mono- or diesters, which may optionally be separated by chromatography;

if it is a 2-methoxy-2-propyl group: according to the method described in BE-PS 875,379.

4. The removal of the groups of the general formula II or III (if it is desired to obtain a product of the general formula I in which R represents a formylalkyl or acylalkyl radical) can be carried out, for example;

in the presence of a sulphonic acid (for example methanesulphonic acid or p-toluenesulphonic acid) in an organic solvent (for example acetonitrile or acetone), if appropriate in the presence of water and, if appropriate, in the presence of a

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acetalisierbaren reagent, such as acetone, glyoxylic acid, benzaldehyde or pyruvic acid, at a temperature of 20 C to the reflux temperature of the reaction mixture;

or when the radical R is a 5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl radical, by the action of aqueous formic acid (which preferably contains less than 10 % water ) either in the presence or absence of silica, or by transacetalization in the presence of an acetalizable reagent as defined above.

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b) If one uses a reactive derivative of the acid of the general formula VII ₁ , it is possible, the anhydride, a mixed anhydride or a reactive ester of the general formula

N Ii-C-COOZ

wherein R is as defined above and Z is a succinimido, 1-benzotriazolyl, 4-nitrophenyl, 2,4-dinitrophenyl, pentachlorophenyl or phthalimido radical, the amine function of such derivatives having been previously protected (for example as defined above a) described).

It is also possible to use reactive derivatives such as a thiol ester of general formula XIV defined below or an acid halide. In the latter case, for example, the hydrochloride of the acid chloride with the 7-amino-cephalosporin in the general formula VIII bring to reaction.

When the anhydride, mixed anhydride or acid halide (which can be prepared in situ) is employed, condensation in an inert organic solvent such as an ether (e.g. tetrahydrofuran or dioxane), a chlorinated solvent (e.g. chloroform or methylene chloride ), an amide (for example dimethylformamide or dimethylacetamide) or a ketone (for example acetone), or in the mixtures of the above solvents, in the presence of an acid acceptor such as an epoxide (for example

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Propylene oxide) or a nitrogenous organic base such as pyridine, dimethylaminopyridine, N-methylmorpholine or a trialkylamine (eg triethylamine) or in an aqueous-organic medium in the presence of an alkaline condensing agent such as sodium bicarbonate and operating at a temperature of ~40 to +40 C and then optionally reduces the resulting S-oxide and optionally replaced the protecting groups by hydrogen atoms.

If a reactive ester of the general formula IX or a thiol ester is used, the reaction is generally carried out in the presence of a trialkylamine (for example triethylamine) in an organic solvent such as dimethylformamide at a temperature of 0 to 40 ° C. Reduced oxide and the protecting groups replaced by hydrogen atoms.

B) According to the invention, the compounds of the general formula I in which R is different from a triazinyl radical or triazolyl radical substituted by a group of the general formula IV can also be prepared by the action of a thiol of the general formula:

R-SH (X)

(or one of its alkali salts or alkaline earth metal salts) in which R, as defined above, is protected in the acetal state as defined by the general formulas II and III, if a cephalosporin of the general formula I is to be obtained, where R is a formyl or acylalkyl radical, to a cephalosporin derivative (or optionally to a mixture of the isomers of this derivative) of the general formula

29.9.1980 AP C 07 D / 221 271 221271. -22- 57 466/11

Y ^ On

N- '- C - CONH -,

ι ι

N "- ~ OR ° O

(XI)

-CH = CH-R.

COOR ₁ wherein R ⁰ , R and η are as defined above,

when η = O, the compound is in the form of 2- or 3-bicyclooctene

and when η = 1, the product is in the form of 2-bicyclooctene (according to the Chemical Abstracts nomenclature),

wherein the substituent on the carbon atom in the 3-position of the bicyclooctene has the E or Z stereoisomerism,

R _{2 represents} a hydrogen atom or a protective group for the amino group as defined above under A), and

R _{3 is} a radical of the general formula - 0 - SO ₉ - R '

Cm O

or - 0 - CO - R ",

in which R 'is an alkyl, trifluoromethyl, trichloromethyl radical or a phenyl radical, optionally substituted by a halogen atom or by an alkyl or nitro radical, and R ", as defined for R ¹ , or an acylmethyl radical, Acylethyl, 2-acylpropyl,

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Alkyloxycarbonylmethyl-, 2-Alkyloxycarbonylethyl- or 2-Alkyloxycarbonylpropylrest, whereupon reducing the resulting oxide (when η = 1)

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and then optionally splits off protecting groups.

It is understood that when R in the compound of general formula X is suitable for interfering with the reaction, it is preferred to protect this group under the conditions described above (in particular when R is an amino, alkylamino, hydroxy) or contains carboxy radical).

It is also understood that when R ° is hydrogen, it is possible to protect the oxime under the conditions described above.

It will also be understood that if there is a risk that the R group may participate in the reduction reaction, it is preferable to use a compound of the general formula XI in which η = O, (especially when R is a hydroxy, sulfo, , Sulfinyl or sulfonyl group).

The reaction is generally carried out in the presence of an organic base, such as a pyridine or a tertiary organic base of the type

(XIII).

^Z l

wherein X., Y. and Z are alkyl or phenyl radicals, or optionally two thereof form a ring with the nitrogen atom to which they are attached. For example, diisopropylethylamine or diethylphenylamine is used «

If an alkali salt or alkaline earth metal salts of the thiol of the general formula X is allowed to react, it is not necessary to react in the presence of an organic base as described above.

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2 2 1 2 7 1. - ** - ⁵⁷ 466/11

to work.

The reaction proceeds advantageously in an organic solvent such as dimethylformamide, tetrahydrofuran or acetonitrile or in a mixture of the abovementioned solvents.

It is also possible, in the presence of alkali metal bicarbonate _t in a solvent such as defined above, to work if appropriate in the presence of water.

It works at a temperature of -20 C to the reflux temperature of the reaction mixture, wherein the selected temperature varies with the thiol used. In the same way, depending on the thiol used, the reaction time can vary from 5 minutes to 48 hours.

Optionally, working under nitrogen.

Preferably, if one wants to use a 3-bicyclooctene of the general formula XI, one uses such a product for which R. is different from hydrogen.

The reduction of the oxide and the removal of the protective groups are carried out according to the methods described above.

C) According to the invention, the compounds of the general formula I ₁ in which R _{1 is} different from a triazinyl radical or triazolyl radical substituted by a group of the general formula IV, can also be prepared by the action of a thiol ester of the general formula

μ 1 _e-co-:

(XIV)

_N 1 -C-CO-SR

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wherein R and R _{2 are} as defined above and R is as defined above. "It is understood that when it contains an amino or alkylamino substituent, it is protected; when it contains a hydroxy or carboxy substituent, it is free or protected and if it contains a formyl or acylalkyl radical, this is protected in the acetal state of the general formula II or HIJ on a 7-amino-cephalosporin of the general formula

.0

 η

N ·

-CH = CH-R

COOR.

wherein R., R, and η are as defined above, and having the stereoisomerism defined above for the compound of general formula XI, followed by reducing the resulting sulfoxide, if η = 1, and optionally removing protective groups.

As for process A), it will be understood that the thiol esters of the syn- or anti-form or mixtures thereof will each lead to products of general formulas I in the syn or anti-form or in the form of their mixtures.

It is also understood that the radicals R which contain a group which can interfere with the reaction, previously

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to be protected. This also applies to the oxime, when R represents the hydrogen radical.

Likewise, as described for the processes described above, when R contains a hydroxy, sulfo, sulfinyl or sulfonyl substituent it is preferred to use © a compound of general formula XV in which η = O,

• 29.9.1980

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2 2 1 2 7 1 - 53. - 57 466/11

The protection and removal of the protecting groups are carried out under the conditions described above.

The reaction of the thiol ester with the 7-amino-cephalosporin of the general formula XV is generally carried out in the presence of an acid acceptor, such as an organic base, in particular in the presence of a pyridine or a tertiary organic base of the general formula XIII, in particular triethylamine, N, N- Diisopropyl-N-ethylamine, diethylphenylamine or N-methylmorpholine.

The reaction is advantageously carried out in an organic solvent such as an amide (for example dimethylformamide, dimethylacetamide), an ether (for example tetrahydrofuran, dioxane), a chlorinated solvent (for example chloroform, methylene chloride), a ketone (for example acetone) or a nitrile (eg. As acetonitrile), or in a mixture of these solvents. It is also possible in the presence of one

Alkalibicarbonats in one of the above solvents, optionally in the presence of water to work.

At a temperature of -20 ⁰ C the reaction is carried to the reflux temperature of the reaction mixture "Optionally If the reaction under nitrogen.

The reduction of the S-oxide takes place under the conditions described above.

D) According to the invention, the compounds of general formula I wherein R and R ^{1 are} as defined above and

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R are as defined above, with the exception of a triazinyl or triazolyl substituted by a group of the general formula IV _{t be} prepared by the action of a thiourea of the general formula

09/29/1980

^ AP C 07 D / 221 271

2 2 1 2 7..L _ sow .. 57 466/11

R ₂ NH - CS - NH ₂ (XVI),

(wherein Rp is as defined under B) above, with the exception of chloroacetyl or trichloroacetyl), to a compound of the general formula

Hal-CH ₀ CO C - CONH- ² 11

N

OR ⁰

COOR ₁

wherein R, R, R ₁ and η are as defined above, and Hai represents a chlorine or bromine, followed by reducing, if necessary, the sulfoxide and removing protective groups.

It generally works in an aqueous, organic or aqueous-organic medium ", for example in solvents or mixtures of solvents such as alcohols (methanol, ethanol, ketones (acetone), chlorinated solvents (chloroform, ethylene chloride), nitriles (acetonitrile), amides (Dimethylformamide, dimethylacetamide), ethers (tetrahydrofuran, dioxane), esters (ethyl acetate) or acids (acetic acid, formic acid) in the presence or absence of a base such as sodium hydroxide, potassium hydroxide, carbonates, hydrogencarbonates of the alkali metals, salts of carboxylic acids and alkali metals (sodium formate , Sodium acetate) or tertiary amines

29.9.1980 ': 5Q AP C 07 D / 221 271

2 2 12 7 1 - 33 »-. 57 466/11

(Triethylamine, trimethylamine or pyridine) at a temperature of -30 to 60 C. '

If you work in the presence of a base, you do not isolate or isolate, depending on the nature of the base and the

09/29/1980

_SA AP C 07 D / 221 271

2 2 1 2 7. t <'-. 3 = F - 57 466/11

brought amount, an intermediate of the general formula

NH Il

R NH-CS-CHCO C-CONH- ₁ f (XVIIA),

Il

N O = J Nv ^ * -CH = CH-SR

COOR ₁

wherein R, R, R and η are as defined above, which can then be cyclized in an acidic medium.

If it is desired to obtain a compound of the general formula I in which R is a formylalkyl or acylalkyl radical, this radical may be protected in the state of the acetal, in the form of a radical of the general formula II or III, as defined above.

The reduction of the sulfoxide and the deprotection are carried out under the conditions described above.

E) According to the invention, the compounds of the general formula I in which R and R 'are as defined above, R a 5,6-dioxo-l, 4,5r6-tetrahydro ~ l, 2,4 ~ triazin-3 ~ ylrest substituted in the 4-position or also 1,3,4-triazol-5-yl or 2-alkyloxycarbonyl-l, 3,4-triazol-5-yl radical, which are substituted in the 1-position, by an alkyl radical having 2- 4 carbon atoms represented by a carbamoyloxy or acyloxy group, their acyl part

09/29/1980

_S 2j AP C 07 D / 221

221271. -3 £ a- 57 466/11

optionally substituted by an amino, alkylamino or dialkylamino radical, which are functional derivatives of the corresponding compound of general formula I wherein R and R ^{1 are} as defined above and R is a radical - (R) - Alk'-OH is selected from 5,6-dioxo ~ 4-hydroxyalkyl-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl or 1-hydroxy

09/29/1980

52 AP C 07 E / 221

2 2 12 7 Ij - 54 - 57 466/11

alkyl-l, 3,4-triazol-5-yl or 2-alkyloxycarbonyl-l-hydroxy-l _f 3,4-triazol-5-yl, starting from a compound of the general formula

R ' ₂ -NH

-CH = CH-S- ©

COOR ₁ Alk ^ OH

A is% -

wherein R, R ₁ , (ra-Alk'-OH and η are as defined above and R 'is defined as Rp, with the exception of hydrogen, by any known or conventional method

 jr.

to obtain an ester or a carbamate starting from an alcohol without attacking the rest of the molecule followed, if necessary, by reduction of the resulting sulfoxide and deprotection.

The esterification is carried out at a temperature of -50 ⁰ C to the reflux temperature of the reaction mixture, in particular by condensation of the acid anhydride (or other reactive derivative, for. Example, the halide) in an inert organic solvent such as an ether (e.g. tetrahydrofuran), a chlorinated solvent (for example methylene chloride) or a mixture of these solvents, in the presence of a nitrogenous base such as pyridine, 4-dimethylaminopyridine, or a trialkylamine (triethylamine) or

29.9.1980 54 AP C 07 D / 221 271

2 2 12 7 1 "" ^32pa ~ ^{57 456/11}

an alkaline condensing agent (for example, sodium bicarbonate), followed where appropriate by reduction of the resulting S-oxide and removal of the protective groups by the methods described above.

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92127 1 "^" ^{57 465/11}

The preparation of the carbamate is carried out by any known or conventional method that does not change the rest of the molecule. It works in particular by the action of chlorosulfonyl isocyanate or trichloroacetyl isocyanate in an organic inert solvent such as tetrahydrofuran or acetonitrile, at a temperature of -80 to 20 fernung the protecting groups.

Temperature from -80 to 20 C with subsequent discharge

The compounds of general formula I 'can be prepared by any of the methods described above.

f ) According to the invention, the compounds of general formula I, wherein R ⁰ and R 'are as defined above.

R a SiS

radical, substituted in the 4-position, or a 1,3,4-triazol-5-yl radical or 2-alkyloxycarbonyl-l, 3,4-triazol-5-yl radical, substituted in the 1-position an alkyl group having 2-4 carbon atoms substituted by a sulfamino, alkylsulfonylamino, sulfamoylamino, acylamino (whose acyl group is optionally substituted by hydroxy, amino, alkylamino or dialkylamino) _# alkyloxycarbonylamino, ureido, alkylureido or dialkylureido group or a 1,3,4-thiadiazole. 5-yl radical substituted by an acylamino or acylaminoalkyl radical, represents an l, 3,4-oxadiazol-5-yl radical substituted by an acylaminoalkyl radical, or a 5-tetrazolyl radical substituted in the 1-position by a Alkyl radical having 2-4 carbon atoms, substituted by an acylamino, sulfamoylamino, sulfamino, ureido, alkylureido or dialkyl

29.9.1980 ^ AP C 07 D / 221 271

2 2 Ί 2 7 ¹ L ~ ⁵ ^ " ⁵⁷ 466/1 ^{: L}

ureido group, which are each functional derivatives of the corresponding amine, are prepared starting from a compound of general formula I "

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ψψ AP C 07 D / 221 271

22127 \. - 5 & - 57 466/11

-CH = CH-S-A-NH,

COOR

wherein R °, R ₁ , R ' ₂ and η are as defined above, and - ^ - NH_ a 5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl radical substituted in the 4-position, or a 1,3,4-triazol-5-yl ~ or 2-alkyloxycarbonyl-l, 3,4-triazol-5-yl radical substituted in the 1-position are represented by an aminoalkyl radical _f whose alkyl moiety contains 2-4 Kphltstoffatome, or represents a 1,3,4-thiadiazol-5 ~ ylrest substituted by an amino or aminoalkyl radical, or a 1,3,4-oxadiazole-5 -yl-radical substituted by an aminoalkyl radical, or a 5-tetrazolyl radical substituted in the 1-position by an aminoalkyl radical whose alkyl moiety contains 2-4 carbon atoms,

according to any known or customary method for producing an amide or sulfamide, carbamate or urea function, without attacking the remainder of the molecule, optionally followed by reduction of the sulfoxides and removal of the protective groups.

It is understood that the compounds containing a sulfenyl, sulfonyl or sulfamoyl group are preferably prepared starting from a compound of the general formula I "in which η = 0

29.9.1980 S3 AP C 07 D / 221

2 2 1 2 7 1: - ³ ^ ~ ^{57 455/1 : L}

In addition, to produce a compound whose radical R contains an amino or hydroxy group, it is necessary to protect these residues in the reagents used. Similarly, it is ₀ when R represents a hydrogen atom, it is necessary to protect the oxime

22 127 1

29.9,1980

AP C 07 D / 221

57 466/11

If it is desired to prepare a compound of general formula I wherein R is an alkylsulfonylamino, sulfamoylamino, acylamino (substituted or unsubstituted), alkyloxycarbonylamino or dialkylureido radical, the reaction is preferably carried out by the action of a corresponding chlorosulfonyl, acid chloride, chloroformate or dialkylcarbamoyl chloride derivative under the conditions described above for the reaction of the acid chloride of general formula VII with the 7-amino-cephalosporin of general formula VIII.

to prepare a compound of the general formula I in which the radical R contains a sulfamino, alkylsulfonylamino or acylamino (substituted or not) radical, the reaction can be carried out by means of a corresponding acid anhydride, as described above for the reaction of the compound of the general formula Formula VII in the form of the anhydride described conditions.

If it is desired to prepare a compound of general formula I in which R contains an acylamino (substituted or not) radical, it is also possible to react the corresponding acid under the process conditions described above for the use of the acid of general formula VII ,

If it is desired to prepare a compound of the general formula I in which R contains a ureido or alkylureido radical, then alkali isocyanate or an alkyl isocyanate with the corresponding compound of the general formula I "in an aqueous-organic or organic

29 »9.1980

QQ AP C 07 D / 221

'221271- 3? E- - 57 466/11

Medium (for example in tetrahydrofuran) at a temperature of -20 to 60 C react.

The reduction and removal of the protecting groups are carried out under the conditions described above.

G) According to the invention, the compounds of the general formula and R can

Formula I, wherein R ° and R ^{1 are} as defined above,

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2 2 1 27. V-SB - 57 466/11

a 5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl radical _f substituted in the 4-position, or a 1,3,4-triazol-5-yl radical or 2-Alkyloxycarbonyl-l, 3,4-triazol-5-yl radical which are substituted in the 1-position by a 2-Thiazolidinylalkylrest, by a radical of the general formula IV or by a Hydroxyiminoalkyl- or Alkyloxyiminoalkylrest, whose Iminoalkylteil Contains 1-5 carbon atoms, or represents a 5-tetrazolyl radical substituted at 1-position by a hydroxyaminoalkyl or alkyloxyiminoalkyl radical whose iminoalkyl moiety contains 1-5 carbon atoms, which are addition derivatives of the compound of the general formula I in which R ⁰ and R 'are as defined above, and R is one of the aforementioned heterocycles substituted by a formylalkyl radical (or its hydrate form), starting from a compound of general formula I " ¹

R ₂ -NH

-CH = CH-S-R-Alk · CHO

wherein R °, R and R _{2 are} as defined above, and []

- [R] -Alk ¹ CHO a 5,6-dioxo-4-hydro-l, 2,4-triazin-3-yl or l-formylalkyl-1,3,4-triazol-5-yl, 2 Alkyloxycarbonyl-1-formylalkyl-1,3,4-triazol-5-yl or 1-formylalkyl-5-tetrazolyl radical.

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Q ₁ AP C 07 E / 221

221271 - 3SB -. 57 466/11

by addition of cysteamine, an alcohol, hydroxylamine or an alkyloxyamine according to bekannt'bzw. customary methods for the preparation of addition derivatives of carbonylated functions, whereupon optionally protecting groups are removed.

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"221271 -» - 57 466/11

The reaction is generally carried out in an organic solvent at a temperature of 20 ⁰ C to the reflux temperature of the reaction mixture.

The organic solvents are selected as a function of the solubility of the compounds. If a compound of the general formula I " ^{1 is used} in which R ₁ and R ₂ are different from hydrogen, then it is preferable to use solvents such as tetrahydrofuran, acetonitrile, alcohols and ketones If a compound of the general formula I '" is used in which R ₁ and Rp are hydrogen atoms, it is preferable to work in solvents such as pyridine, dimethyl sulfoxide or dimethylformamide.

If you want to produce a compound of general formula I, wherein the radical R contains a substituent of the general formula IV, it works in an acidic medium.

H) According to the invention, the compounds of general formula I, wherein. R * represents a group of the general formula V, wherein R "and R '" are as defined above, also prepared by esterification of a compound of general formula I, wherein R' represents a hydrogen atom, and whose amine function has been previously protected, after each a known or conventional method of preparing an ester starting from an acid without attacking the remainder of the molecule.

In general, an alkali metal salt or a tertiary amine salt of the compound of general formula I, as defined above, whose amine function has been previously protected and in which optionally the radical R and the oxime are also protected, is allowed to react with a compound of the general formula

09/29/1980

y. AP C 07 D / 221

221271.-43- 57 466/11

Z _p -CH- OCO - R ¹ "^ J (XVIII)

R "

in which R "and R" ^{1 are} as defined above and Z _? is a halogen atom, in an inert solvent, such as dimethylformamide, at a temperature of 0 to 30 ^° C.

The compounds of general formula XVIII can be prepared by the method described in DE-PS 2 350 230.

The compounds of general formula VII may be prepared by the method described in the BE-PS 850 662 method or by the method described in Belgian Patent No. 877,884.

The compounds of general formula VII, wherein R ° is a vinyl radical, can be prepared by the method described in the BE-PS 869 method.

The compounds of general formula VII wherein R ° is a cyanomethyl radical can be prepared by the method described in DE-OS 2,812,625.

The compounds of general formula VIII can be obtained starting from a compound of general formula

R ₄ -NH-

0-

N v ^^ - CH = CH- SR

COOR ¹

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2 2 1 2 7 1 - 45 - - 57 466/11

(wherein R and η are as defined above, but wherein R is not triazinyl or triazolyl substituted by a radical of the general formula IV, R 'is as defined for R _1, with the exception of hydrogen, and R ₄ is an easily eliminable radical group) by eliminating a remainder R. or optionally consecutive or simultaneous elimination of residues R and R ¹ _1, if one wishes to obtain a compound of the all-common formula VIII, wherein represents R represents a hydrogen atom.

An easily eliminable radical R. is understood to mean a benzydryl or trityl radical, a 2,2,2-trichloroethyl radical, an acyl radical of the general formula

R ₅ -CO- (XX) av

(wherein R _{1 is} a hydrogen atom or an alkyl radical f optionally substituted by one or more halogen atoms or by a phenyl or phenoxy radical or phenyl radical) or else a radical of the general formula

R ₆ O CO - · (XX) b,

Cworin R _{fi is} a branched unsubstituted allyl radical

straight or branched alkyl group containing one or more substituents selected from the halogen atoms, a cyano, trialkylsilyl, phenyl, phenyl substituted (by one or more alkoxy, nitro or phenyl), vinyl, allyl or quinolyl istj or nitrophenylthio. In addition, the radical R.NH- can be replaced by a methyleneimino radical in which the methylene radical is substituted by a dialkylamino or aryl group (the latter optionally substituted by

09/29/1980

₁ CJb AP C 07 D / 221

'* - 4§ - 57 466/11

one or more methoxy or nitro radicals).

As examples of radicals R - which can be used, the following may be mentioned:

Formyl, acetyl, chloroacetyl, trichloroacetyl, phenylacetyl, phenoxyacetyl, benzoyl, t-butoxycarbonyl, 2-chloro-1, 1-dimethylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-1, dimethylethoxycarbonyl, 2-cyano-1, 1-dimethylethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyl, p -methoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl., diphenylmethoxycarbonyl, 2- (4-biphenylyl) - isopropyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 8-quinolyloxycarbonyl, o-nitrophenylthio, p-nitrophenylthio.

As examples of Methyleniminoreste one can call:

Dimethylaminomethyleneimino, 3,4-dimethoxybenzylidenimino, 4-nitrobenzylidenimino.

The elimination of the protecting group R is carried out by any known or customary method for releasing an amine function, without attacking the rest of the molecule.

For example, you can name the following methods:

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Q. AP C 07 D / 221

221271 -43- 57 466/11

- When R _{4 is} trityl, benzhydryl, trichloroacetyl, chloroacetyl, t-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-methoxy-benzyloxycarbonyl and p-nitrobenzyioxycarbonyl, according to the above-mentioned methods for releasing the amino group of the compound of general formula I; it is advantageous to use p-toluenesulfonic acid in acetonitrile at a temperature of from 0 to 50 ^° C.,

when R _{4 is} formyl, 2-chloro-1, 1-dimethylethoxycarbonyl, 2-cyano-1-yl-dimethylethoxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, 2- (4-biphenylyl) isopropyloxycarbonyl, vinyloxycarbonyl, allyloxycarbonyl, 8-quinolyloxycarbonyl, o-Nitrophenylthio, p-Nitrophenylthio, and when R ₄ NH- is replaced by Dimethylaminomethylenimino, 3,4-Dimethoxybenzylidenimino or 4-Nitrobenzylidenimino, by hydrolysis in an acidic medium,

when R _{4 is} 2,2,2-trichloroethyl or 2,2,2-trichloro-1, 1-dimethylethoxycarbonyl, by treatment with zinc in acetic acid,

when R _{4 represents} acetyl, benzoyl, phenylacetyl or phenoxyacetyl, according to the method described in Belgian Pat. No. 758,800, '' t

- when R ₄ trimethylsilylethoxycarbonyl, according to the method described by H, Gerlach, Helv. Chim. Acta 60 (8), 3039 (1977),

when R _{4 represents} p-nitrobenzyloxycarbonyl, by hydrogenolysis or hydrogenation in the presence of palladium.

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2 9 19 7 1 ^ ^ '* - 43® - ^ 57 466/11

The compounds of the general formula XIX can be prepared by the action of a thiol of the general formula X, the radical R of which is optionally protected, or one of its alkali metal or alkaline earth metal salts

a cephalosporin derivative or optionally a mixture of isomers of a derivative of the general formula

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2 O 1 O 7 1 w έ I ^ '»- 44 - 57 466/11

R ₄ -NH-

»-CH = CH - R

wherein R '- # Rz / R ₄ and η are as defined above,

when, if η = O, the compound is in the 2- or 3-bicyclooctene form,

if η = 1, the compound is in the 2-bicyclooctene form and

the substituent of the carbon atom in the 3-position of the bicyclooctene has E or Z stereoisomerism.

The reaction is generally carried out under the conditions described above for the achievement of a 3-thiovinyl cephalosporin of the general formula I, starting from a thiol of the general formula X and a compound of the general formula XI »

The thiols of general formula X ("which can be used in their tautomeric form) can be prepared by using one of the following methods, depending on the meaning of the radical R:

when R is a 3-pyridyl radical: by the method described by H. M. Wuest and E. H. Sakai, "Am. Chem. Soc., 73, 1210 (1951),

when R is an 1-oxyd-3-pyridyl radical: according to the method described by B. Blank et al., J, Med. Chem. 17, 1065 (1974),

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221271 - * 5- 57 466/11

"~ if R is 1-oxide-4-pyridyl: by the method described by R. A, Y. Oones et al., D, Chem. Soc., 2937 (1960),

if R is a 3-pyridazinyl radical substituted by alkyl or methoxy and optionally N-oxidized: by the method described in Belgian Patent No. 787,635,

if R is a 3-pyridazinyl radical substituted by amino and optionally N-oxidized: by the method described in Belgian Pat. No. 579,291,

if R is a 3-pyridazinyl radical substituted by acylamino and optionally N-oxidated, by the methods described by M. Kumagai and M, Bando, Nippon Kagaku Zasshi, 84, 995 (1963) and by T, Horie and T. Ueda, , Chem. Pharm. Bull., 11, 114 (1963),

if R is a tetrazolo f4,5-bispyridazin-6-yl radical: according to the method described in Belgian Pat. No. 804,251,

if R is a 5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl radical, substituted in the 4-position, or 2-alkyloxycarbonyl-l, 3, 4-triazol-5-yl radical substituted in the 1-position by a radical R, selected from:

a) allyl, alkyl (m.it 1-4 carbon atoms, optionally substituted by an alkoxy, alkylthio, phenyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, acyl, alkyl-oxycarbonyl or 2-Thiazolidinylrest )rest,

b) a 2,3-dihydroxypropyl.l or l, 3-dihydroxy-2-propyl radical, (gei acetals),

rest, (possibly protected in the form of the c

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^ AP C 07 D / 221 271

221271--4Sa-. 57 466/11

c) an alkyl radical having from 2 to 4 carbon atoms, itself substituted by hydroxy, carbamoyloxy, dialkylamino, alkylsulfinyl, alkylsulfonyl, alkylsulfonylamino, sulfamoylamino, acylamino (corresponding to

09/29/1980

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2 21271 -46-. 57 466/11

optionally substituted), alkyloxycarbonylamino, ureido, alkylureido, dialkylureido ^ J,

d) a radical of the general formula II or III,

e) a hydroxyaminoalkyl or alkyloxyiminoalkyl radical:

by the action of an alkyloxalate on a thiosemicarbazide of the general formula

R 1 NH CS NH-NH ₂ (X) a,

wherein R 'is as defined above in the presence of an alkali metal alkoxide, for example, sodium ethylate or methylate or potassium t-butylate, by the method described by M. Pesson and M. Antoine in Bull. Soc. Chim. .France (1970), 1590.

It is not absolutely necessary to purify the product obtained (nor to release the protective groups) in order to carry out the preparation of the compounds of general formula I.

The thiosemicarbazide of general formula Xa may be prepared by one of the methods described by K-A, Oensen et al., Acta Chim. Scand., 22, 1 (1968), or using the method described by Y. Kazarov and 3. Y. Potovskii, Doklady Acad. Nauk. SSSR 134, 824 (1966), it being understood that if R ^ * contains an amino group, it is protected.

The protection of the amino group and the deprotection are carried out by the usual methods that do not alter the rest of the molecule. In particular, the t-butoxycarbonyl

29.9.1980 ^ j AP C 07 D / 221 271

.22127 t ¹ - ⁴ * - ⁵⁷ 466/11

group which can be removed by acid hydrolysis.

When R is a 1,3,4-triazol-5-yl radical substituted in the 1-position by an alkyl, allyl or alkyloxyalkyl radical,

is itself substituted by an alkyl radical (1-4 carbon atoms), as defined above under a), with the exception of a 2-thiazolidinyl radical,

by a radical as defined above under c) or by an alkyloxyiminoalkyl radical:

by using one of the methods described by M. Pesson and M. Antoine, Bull. Soc. Chim. France 1590 (1970);

when R is a 1, 3,4-triazol-5-yl radical substituted in the 1-position by 2-thiazolidinylalkyl or hydroxyaminoalkyl:

by the action of cysteamine or hydroxylamine on an 1-dialkyloxyalkyl-5-mercapto-1,3,4-triazole which can be obtained by the method described by M ₀ Kanaoka, D, Pharm. Soc. Dapan, 75, 1149 (1955), starting from a 4-dialkyloxyalkyl thiosemicarbazide;

when R is a l, 3,4-triazol-5-yl radical substituted in the 1-position by 2,3-dihydroxypropyl or l, 3-dihydroxy-2-propyl (which are optionally protected in the form of the cyclic acetal) or represents a radical of the general formula II or III, by applying the method of M. Kanaoka,

3. Pharm. Soc. Japan, 75, 1149 (1955);

29.9.1980 pi AP C 07 D / 221 271

2 2 12 7 1 ~ ^ * ⁷ ® " ^{57 466} Z ¹ I

when R is a 5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl radical substituted in 4-position _f or 2-alkyloxycarbonyl-l ^^ -triazole -S-yl or -l, 3,4-triazol-5-yl radicals which are in the!-Position substituted by acyloxyalkyl (optionally substituted) by acylating the 5,6-dioxo-4-hydroxyalkyl ~ 3 -

09/29/1980

^ AP C 07 D / 221 271

22 1 27 1, _ 4Q _. 57 466/11

ol, 2,4-triazine, of 2-alkyloxycarbonyl-l-hydroxyalkyl-S-mercapto-lS ^ -triazole or of l-hydroxy-alkyl-S-mercapto-l ^^ - triazole, whose mercapto radical has been previously protected ( for example, according to CG Kruse et al., Tet. Lett. 1725 (1976), by any known or conventional method for the acylation of an alcohol without attacking the remainder of the molecule, and subsequent liberation of the mercapto group in an acidic medium;

when R is a 5,6-dioxo-l, 4,5,6-tetrahydro-1, 2,4-triazin-3-yl radical substituted in the 4-position, or 2-alkyloxy-carbonyl-1, 3,4-triazol-5-yl or l, 3,4-triazol-5-yl radical which are substituted in the 1-position by aminoalkyl or alkylaminoalkyl is protected, for example, by liberation of the amine function of the corresponding product a t-butoxycarbonyl group;

when R is a 5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl radical, substituted in the 4-position, 2-alkyloxycarbonyl, 3,4-triazole 5-yl or l, 3,4-triazol-5-yl radical, which are substituted in the 1-position by SuIfaminoalkyl, starting from a corresponding compound substituted by a t-Butoxycarbonylaminoalkylrest, in analogy to the method described in the BE-PS 847 237;

when R is a 1, 4-dialkyl-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl or l-alkyl-5,6-dioxo-l, 4,5,6 tetrahydro-1,2,4-triazin-3-yl-rest is, according to the method described in BE-PS 830 455;

when R is a 2-alkyl-5,6-dioxo-1, 2,5,6-tetrahydro-1,2,4-triazin-3-yl or 1-alkyl-3-alkyloxycarbonyl-1, 2,4 -triazol-

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method described in French Patent Application 2 215 942;

when R is 1, 3,4-triazol-5-yl, according to the procedure described by M- »Kanaoka, O, Pharm. Soc. Oapan, 75, 1149 (1955);

when R is a 1,3,4,7-thiadiazol-5-yl radical, optionally substituted by alkyl, alkyloxy, alkylthio, alkylsulfonyl, amino, alkylamino, dialkylamino or acylamino, according to the method described in BE-PS 830 821;

- When R is a 1,3,4-thiadiazol-5-yl ~ radical, substituted by hydroxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl, by the method described in DE-OS 24 46 254;

- if R is a l, 3,4 ~ Thiadiazol ~ 5-yl radical, substituted by a carboxyalkyl radical, by applying the method described in DE-PS 19 53 861;

- if R is a l, 3,4-thiadiazol-5-yl radical, substituted by a trifluoromethyl radical, according to the method described in DE-OS 21 62 575;

- if R is a l, 3,4-thiadiazol-5-yl radical, substituted by a carboxy radical, according to the method described in OP-PS 77 48 666;

- if R is a l, 3,4-thiadiazol-5-yl radical, substituted by an acylaminoalkyl radical, according to the method described in the OP patent application 76 80857;

- if R is a l, 3,4-thiadiazol-5-yl radical, substituted by a hydroxyalkylthio radical, by application of the method;

5-yl-residue is, according to the method described by M. Pesson and M. Antoine, C.R. Acad. Sci., Ser C, 267, 25, 1726 (1968);

- if R is a 1.2.

29.9.1980 AP C 07 D / 221 2 2 1 2 7 I / - ⁴ ^ - · 57 466/11

described by G. Nannini, Arz. Forsch. 27 (2), 343 (1977);

- if R is a l, 2,4-thiadiazol-5-yl radical, substituted by alkyl or alkyloxy, by the method described in

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DE-OS 28 06 226 or Chem. Ber. 90, 184 (1957);

if R is a 1,3,4-oxadiazol-5-yl radical as defined above under 8a), using the method described by E. Hoggarth, Ό. Chem. Soc. 4811 (1952);

when R is a 2-oxazolyl or 4-alkyl-2-oxazolyl radical, according to the method of C. Bradsher, 3, Org, Chem. 32, 2079 (1967) described above;

if R is a 5-tetrazolyl radical, optionally substituted in the 1-position by alkyl, hydroxyalkyl or phenyl, according to the method described in BE-PS 830 821;

if R is a 5-tetrazolyl radical substituted in the 1-position by alkyloxyalkyl, by addition of sodium azide to an isothiocyanatoalkyloxyalkyl, working in an organic solvent such as ethanol at the reflux temperature of the reaction mixture.

The isothiocyanatoalkyloxyalkyl can be prepared using the method described by E. Schmidt et al., Chem. Ber. 73, 286 (1940).

When R is a 5-tetrazolyl radical substituted in the 1-position by a carboxyalkyl radical, by the method described in Belgian Patent 858,112.

When R is a 5-tetrazolyl radical substituted at the 1-position by a sulfoalkyl radical, by the method described in BE-PS 856 498 or described by DA Berges et al., In 0 Het, Chern 15, 981 (1978). - If R is a 5-tetrazdyl radical substituted in 1-position by an aminoalkyl- .. Alkylaminoalkyl, "dialkylaminoalkyl radical, is, by applying the method described in

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DE-OS 27 38 711.

- If R is a 5 ^ -Tet razolylrest substituted in! -Position by a SuIfamoylalkylrest, SuIfamoylaminoalkylrest or SuIfaminoalkylrest, by the method described in the BE-PS 856 636th

If R is a 5-tetrazolyl radical substituted by an acylaminoalkyl radical or 1, 3,4-thiadiazol-5-yl radical substituted by hydroxy, by the method described in US Pat. No. 4,117,123.

If R is a 5-tetrazolyl radical substituted in the 1-position by a ureidoalkyl, alkylureidoalkyl or dialkylureidoalkyl radical, starting from a corresponding compound which is substituted by aminoalkyl (whose mercapto radical has been previously protected) by treatment with an alkali isothiocyanate, with an alkyl isocyanate or with a Dialkylcerbamoylhalogenid'und subsequent release of the mercapto group under the conditions described in Belgian Patent No. 847,237.

- When R is a 5-tetrazolyl substituted in 1-position by a carboxyalkylaminoalkyl radical, by the method described in DE-OS 27 15 597.

When R is a 5-tetrazolyl radical substituted at the 1-position by a 2,3-dihydroxypropyl radical, by the method described in US Pat. No. 4,064,242.

When R is a 5-tetrazolyl radical substituted in the 1-position by a 1,3-dihydroxy-2-propyl radical, by addition

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of sodium azide to a 2,2-dimethyl-1,3-dioxolan-5-yl isothiocyanate (optionally followed by the release of the hydroxy groups).

- If R is a 5-tetrazolyl radical, substituted in the position by a radical of the general formula II, defined v / ie above under 9e) or the general formula III, or a!

29.9.1980 § _A AP C 07 D / 221

2 2 1 2 7 I '" ⁵ ^ -' ^{57 46} 6 / ii

Radical as defined above under 9c) is, by the action of sodium azide on the corresponding isothiocyanate in analogy to the method described by R, E. Orth, O.

 Pharm. 52 (9), 909 (1963), it being understood that when R contains a hydroxy or hydroxyiminoalkyl substituent, the alcohol or oxime is optionally protected, for example by a tetrahydropyranyl group.

The compounds of the general formulas XI and XXI can be prepared by the action of an active derivative of the acids R 'SO ₃ H and R "COOH /" see the formulas XIIa and XIIbJ of the type:

(XXII)

R "CO Hai

wherein R ', and R "in these formulas are defined as described above, and Hal is a halogen atom on a compound (or mixture of isomers) of the general formula:

(T) n

R ·, -NH-

(XXIII)

O -i N ^.> I ^ s- CH - CHO

COOR ¹

(wherein η and R * are as defined above,

when η = 0, the compound is in the 2- or 3-bicyclooctene or S-oxoethylidene-bicyclooctan form, and

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if η = 1, the compound is in the 2-bicyclooctene or S-oxoethylidene-bicyclooctane form,

and R * is a radical of the general formula

(XXIV) -C-CO-

wherein R is as defined above and R 'is defined as R ₂ except for the hydrogen atom, or R' is R as defined above), optionally followed by reduction of the resulting sulfoxide and optionally removal the protective groups of the amine function and the acidic function (if one wants to obtain a compound of general formula XI, wherein R. and / or R "is hydrogen) ₀

It is understood that when R '. is a radical of general formula XXIV, in which R ° is hydrogen, it is necessary to protect the oxime. The protection and release are carried out according to the methods described above.

It also operates in the presence of a tertiary base as defined for general formula XIII, for example triethylamine or N, N-dimethylaniline, in an organic chlorinated solvent (for example methylene chloride), in an ester (ethyl acetate), an ether (for example dioxane, tetrahydrofuran ), an amide (for example dimethylacetamide, dimethylformamide), in acetonitrile or N-methylpyrrolidone, or directly in a basic solvent, such as pyridine, or else in an aqueous-organic medium, in the presence of a

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alkaline condensation agent (for example, ~ Alkalibi carbonate, sodium hydroxide or potassium hydroxide) 'at a temperature of -78 ⁰ C to the reflux temperature of the reaction mixture.

Optionally, working under nitrogen.

It is not absolutely necessary to purify the intermediate of general formula XXIII to carry out this reaction,.

If appropriate, the removal of the protective groups from the amine function and the acidic function takes place according to the methods described above for obtaining the compound of general formula I.

The compounds of general formula XI can also be obtained by the action of an acid of general formula VII whose amine function has been previously protected or by the action of one of its reactive derivatives on a compound of general formula XV wherein R ₁ , R ₃ and η as defined above, wherein,.

when η = 0, the compound is in the 2- or 3-bicyclooctene form, and

when η = 1, the compound is in the 2-bicyclooctene form and

the substituent on the carbon atom in the 3-position of the bicyclooctene occupies the E or Z stereoisomerism or optionally on an isomer mixture of these compounds

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2 2 1 2 7 1r ⁵⁴ ^ ^- " ^{57 466} Z ¹¹

optionally followed by the reduction of the resulting oxide and optionally subsequent removal of the protective groups.

The reaction is carried out under the conditions described above for the action of an acid of general formula VII on a 7-aminocephalus

29.9.1980 AP C 07 D / 221 271 221271 -β? - 57 466/11

sporin of general formula VIII,

Optionally, the reduction of the oxide as well as the removal of the protecting groups can be achieved under the conditions described for obtaining the compound of general formula I.

The compound of the general formula XV can be obtained by eliminating the protecting group R from a compound of the general formula XXI or optionally by simultaneously eliminating the radicals R ₄ and R "-» if one wishes to obtain a compound of the general formula XV wherein R ₁ Hydrogen means.

It is generally carried out under the conditions described above to obtain a compound of general formula VIII, starting from a compound of general formula XIX.

The compounds of general formula XXIII, wherein η is O, can be obtained by hydrolysis of the enamine (or the mixture of enamine isomers) of the general formula

4 I I Π

O = I N. J-CH = CH-N ^ ⁷

wherein R 'and R' are as defined above, wherein the compound is in the 2- or 3-bicyclooctene form, and the substituent on the carbon atom is in the 3-position of the bicyclooctene in E or Z stereoisomerism, and

29.9.1980 AP C 07 D / 221 271 22 127 1 - & - 57 466/11

R ₇ and R ", which may be identical or different, represent alkyl (optionally substituted by a hydroxy, alkyloxy, amino, alkylamino or dialkylamino radical) or phenyl radicals or together with the nitrogen atom to which they are attached, a form a saturated 5- or 6-membered heterocycle which optionally contains a further heteroatom selected from nitrogen, oxygen or sulfur, and is optionally substituted by an alkyl radical.

Preferably, an enamine of the general formula XXV in which R ₇ and R are each a methyl radical is hydrolyzed.

The reaction is generally carried out in an organic acid (for example formic acid, acetic acid) or inorganic acids (for example hydrochloric acid, sulfuric acid) in the presence or absence of a solvent, in an aqueous or organic medium at a temperature from -20 ° C to the reflux temperature of reaction mixtures. When operating in an organic medium, the hydrolysis is carried out by adding water to the reaction mixture and then optionally treated with an inorganic base (for example alkali bicarbonate) or organic base (for example tertiary amine or pyridine),

When operating in the presence of a solvent, it is not necessary that this solvent be miscible with the aqueous acidic phase. The contact is then effected by vigorous stirring.

29.9.1980 AP C 07 D / 221 2 2 12 7 1 - »: - 57 466/11

Among the usable solvents may be mentioned chlorinated solvents, ethyl acetate, tetrahydrofuran, acetonitrile, dimethylformamide and the alcohols. It is not absolutely necessary to purify the intermediate of general formula XXV to carry out this reaction.

The compounds of the general formula XXIII, in which

29.9.1980 AP C 07 D / 221 2 2 Ί 2 7 1 _ 88. 57 466/11

1 can be obtained by oxidation of the compounds of general formula XXIII, wherein η has the meaning of O, by applying the method described in DE-OS 26 37 176.

In the same way, the compounds of the general formulas VIII, XI, XV, XVII, XIX or XXI, in which η is 1, can be obtained by oxidation of compounds of general formulas VIII, XI, XV, XVII, XIX and XXI, respectively in which η has the meaning of O, by applying the method described in DE-OS 26 37 176.

The compounds of general formula XXV, wherein R ₇ and R ₈ are as defined above, except for alkyl substituted by hydroxy, amino or alkylamino, can be prepared by the action of a compound of the general formula

^CH - V (XXVI),

^R IcT

optionally prepared in situ, Tworin R ₇ and R _{β are} as defined above and R _g and R ₁₀ * may be the same or different

either groups of the general formula

-X ₂ R ₁₁ (XXVII) a,

wherein X _{2 is} an oxygen atom and R represents an alkyl or phenyl radical, or

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one is a radical of general formula XXVII a (wherein X "is a

Oxygen or sulfur atom and R is alkyl or

Phenyl) and the other is an amino group of the general formula

- N (XXVII) b

where R _1? and R. as defined for R ₇ and R, or

Rq and R ₀ each represent a radical of general formula XXVII b} to a cephalosporin derivative of the general formula

R ' ₄ -NH-

(XXVIII), 0

COOR ¹

wherein R 'and R' are as defined above, wherein the compound is in the 3-methyl-2- or 3-bicyclooctene form or the 3-methylenebicyclooctane form.

If one chooses a compound of general formula XXVI in which the radical XXVIIb is different from -NR_R _O, it is

/ 0

it is preferred to choose such a compound that the amine HNR ₄₀ R ,, is more volatile than HNR_, R _O.

It is generally carried out in an organic solvent,

29.9.1980 AP C 07 D / 221 271 2 2 1271 - ^ao - '57 466/11

such as dimethylformamide or hexamethylphosphoric triamide or in a mixed solvent (for example, dimethylformamide-tetrahydrofuran, dimethylformamide-dimethylacetamide, dimethylformamide-ether or dimethylformamide-dioxane) at a temperature of the reaction mixture.

a temperature of 20 ⁰ C to the reflux temperature of

It will be understood that when R 'is a group of general formula XXIV wherein R ^{0 is} hydrogen, it is preferred that the oxime be protected under the conditions described above.

The compounds of general formula XXV, wherein R 'and R' are as defined above, and R ₇ and R "are alkyl radicals substituted by hydroxy, amino or alkylamino can be obtained by transaminating, starting from a compound of general formula XXV ₁ where R ₇ and R "represent alkyl radicals, preferably methyl.

The reaction proceeds by the action of an amine of the general formula

^ ^R1 7 HN "^ ' (XXIX),

^K 8

wherein R "and R ', which may be the same or different, represent alkyl radicals substituted by hydroxy, amino or alkylamine Q, to a compound of general formula XXV, and those of the foregoing are employed for the action of a compound of general formula XXVI Derivative of the general formula XXVIII described conditions.

The compounds of general formula XXVII can be prepared

29.9.1980 34 AP C 07 D / 221 271

221271 - e © - 57 466 / ii

are prepared by the methods described by H, Bredereck et al, Chem. Ber. 101, 41 (1968), Chem. Ber. 101, 3058 (1968) and Chem. Ber. 106, 3725 (1973).

The cephalosporin derivatives of general formula XXVIII, wherein R '. represents a radical of the general formula XXIV, can be prepared, starting from compounds of the general formula

COOR ¹

wherein R ',. as defined above, working under the action of an acid of general formula VII or one of its derivatives under the conditions described above for the achievement of compounds of general formula I.

The cephalosporin derivatives of the general formulas XXVIII and XXX, wherein R 'represents a radical of the general formula V, can be obtained by esterification of the corresponding acids according to the method described above for the preparation of a compound of the general formula I, wherein R is a radical of the general formula V is, starting from a compound of general formula I, wherein R is a hydrogen atom.

The introduction of protecting groups R 'and R' into the compound of general formula XXVIII [or XXX for R ¹ ..] can be effected on a 7-amino-cephalosporin of the general formula

29.9.1980 AP C 07 D / 221 221271 - 6 * - 57 466/11

(XXXI) ₁

0 =

COOH

wherein the position of the double bond is as defined above, by known or literature methods;

- if R ¹ . a formyl radical is, according to 3. C. Sheehan et al., 3rd Arner. Chem. Soc. 80, 1156 (1958),

when R 'is acetyl, chloroacetyl, trichloroacetyl, phenylacetyl, phenoxyacetyl or benzoyl, according to E, H. Flynn, cephalosporin and penicillins, Ac. Press (1972),

when R ^{1 is} a t-butoxycarbonyl radical, according to L. Moroder et al., Hoppe Seyler's 2 nd Physiol. Chem. 357, 1651 (1976),

when R 'is 2,2,2-trichloro-1,1-dimethylethoxycarbonyl, according to CJ, Ugi et al., Angew. Chem. Int. Ed. Engl. 17 (5), 361 (1978),

when R ' _{4 is} 2,2,2-trichloroethoxycarbonyl, 2-chloro-1, ldimethylethoxycarbonyl, 2-cyano-1, 1-dime'thylethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, benzyloxycarbonyloxy, p-methoxybenzyloxycarbonyl, 3.5 Dimethoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, vinyloxycarbonyl, by the action of a chloroformate in an aqueous-organic medium in the presence of an alkali bicarbonate or according to Belgian Pat. No. 788,885,

- when R 'is diphenylmethoxycarbonyl, by the action of the

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acidating azido formate in aqueous-organic medium in the presence of an alkali bicarbonate,

when R 'is 2- (4-biphenylyl) -isopropyloxycarbonyl, in analogy to the method described in HeIv. Chim. Acta, 51, 924 (1968),

when R 'is 8-quinolyloxycarbonyl or allyloxycarbonyl, by the action of the corresponding carbonates in a basic aqueous-organic medium,

when R 'is o-nitrophenylthio or p-nitrophenylthio, in analogy to the method described by L. Zervas et al.,

0. Amer. Chem. Soc., 85, 3660 (1963),

- if R ¹ . NH- is replaced by Dimethylaminomethylenimino, in analogy to the method described by 0. F, Fitt, 0, Org. Chem. 42 (15), 2639 (1977),

when R *> NH- is replaced by 4-nitrobenzylidenimino or 3,4-dimethoxy-benzilidenimino, by the method described by R.A. Sirestone, Tetrahedron Lett., 33, 2915 (1977),

when R 'is methoxymethyl, according to S. Seki et al., Tetrahedron Lett., 33, 2915 (1977),

when R 'is t-butyl, according to R. 0, Stedman, D. Med. Chem., 9, 444 (1966),

when R 'is benzhydryl, according to NL patent application 73 03 263,

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when R 'is p-nitrobenzyl or p-methoxybenzyl, according to R, R, Chauvette et al., 0. Org. Chem. 38 (17), 2994 (1973),

The compounds of the general formula XI can also be prepared starting from a compound of the general formula

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Hal-CH ₂ COC-CONH-τ ₍ -η "(XXXII

OR ⁰ COOR

wherein R °, R ₁ ^ R, and η are as defined above, and Hai as defined for the general formula XVII, in analogy to the method which has been described for the preparation of the compounds of general formula I in the process D.

The compounds of general formula XXXII can be prepared starting from a compound of general formula XV, by using the methods described above for the preparation of the compounds of general formula XVII.

The thiol esters of general formula XIV can be prepared by the action of an acid or a reactive derivative of an acid of the general formula

R 'HN S

'N J-C-COOH

II N

\ R °

In which R ° represents an alkyl, vinyl or cyanomethyl radical , or a protective group, and wherein R 'is as defined for R ₂ , with the exception of the hydrogen atom (or the hydrogen atom

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when the reactive derivative is the acid chloride) J to a thiol of general formula X (wherein R is as defined above for the compound of general formula XIV) or to one of its alkali or alkaline earth metal salts, followed by deprotection of R 'of the amino group, if one wants to obtain a compound in which Rp is a hydrogen atom, and optionally the other protecting groups.

If one wishes to obtain a compound of the general formula XIV in which R is a hydrogen atom, the protection of the oxime can be carried out by any known or customary method which does not alter the rest of the molecule. In particular, the trityl group is used.

Moreover, if one wishes to obtain a compound of the general formula XIV in which R contains a carboxy or sulforest, it is preferred to allow a reactive derivative of the acid of the general formula VII to act on the corresponding thiol.

If a compound is obtained in which R contains a hydroxy radical, it is preferred to protect this radical beforehand, for example with a trityl group.

It is advantageous to remove these protective groups only after the reaction of the thiol esters of the general formula XIV with the compounds of the general formula XV or VIII.

a) When using the compound of general formula VIIa in the form of the acid, the condensation is generally carried out in an organic solvent, such as

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Dimethylformamide, acetonitrile, tetrahydrofuran, methylene chloride, chloroform or ethyl acetate, in the presence of a condensing agent such as a carbodiimide (e.g. dicyclohexylcarbodiimide), Ν, Ν'-carbonyldiimidazole or 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, at a temperature of -20 to

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40 C, whereupon optionally cleaved off the protecting groups.

b) When using a reactive derivative of the acid of general formula VIIa, it is possible to use the anhydride, a mixed anhydride, an acid halide or a reactive ester of the general formula

R ¹ ^ -HN-

l | |] (IX) a

N * - C COOZ

Il N

wherein R ⁰ and R ' _{2 are} as defined above, Z is a residue such as succinimido, 1-benzotriazolyl, 4-nitrophenyl, 2,4-dinitrophenyl * pentachlorophenyl or phthalimido.

c) If it is desired to obtain a compound of the general formula XIV in which R _{2 is} a hydrogen atom, it is also possible to use an acid halide, for example the acid chloride, where the hydrochloride of the acid chloride of the general formula VII is the thiol or one of its salts allow to act.

Using the anhydride, a mixed anhydride or an acid halide (which can be prepared in situ), condensation in an inert organic solvent (e.g. tetrahydrofuran or dioxane), a chlorinated solvent (e.g.

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1271-6 = 53-57 466/11

Chloroform or methylene chloride), an amide (for example dimethylformamide or dimethylacetamide) or a ketone (for example acetone), as well as in the mixtures of the above solvents, in

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Presence of an acid acceptor such as an epoxide (e.g. propylene oxide) or an organic nitrogen containing base such as pyridine, N-methylmorpholine or a trialkylamine (eg triethylamine) or in an aqueous-organic medium, in the presence of an alkaline condensing agent such as sodium bicarbonate, and one works at a temperature of -40 to +40 C, whereupon, if necessary, cleaves off the protective group or the protective groups.

If a reactive ester of the general formula IXa is employed, the reaction is generally carried out in the presence of a trialkylamine (for example triethylamine) in an organic solvent such as dimethylformamide at a temperature of from 0 to 60 ^° C., whereupon the protective group or the Removed protective groups.

For example, the release of various protected residues can be carried out under the following conditions:

If it is desired to obtain a compound of the general formula XIV in which Rp is hydrogen, the t-butoxycarbonyl protecting group of the aminothiazole is removed by treatment in anhydrous acidic medium. In this case, the product is obtained either in the state of the salt or in the state of the solvate with the acid used. Preferably trifluoroacetic acid is used, working at 0 to 20 C. It is also possible to cleave the benzyl protecting group of the aminothiazole by catalytic hydrogenation.

If you want to obtain a compound of general formula XIV, wherein the radical R contains a hydroxy group and / or

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2 2 12 7 1 * ⁶ ^ * "· ^{57 466} Z ¹¹

where R ° is a hydrogen atom, the trityl protecting group or protecting groups are eliminated by acidolysis with anhydrous trifluoroacetic acid. The elimination occurs before, simultaneously with or after the removal of the protective group of the aminothiazole,

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In the present invention, the thiolesters of the general formula XIV wherein R is a carbamoyl-oxyalkyl or acyloxyalkyl group (whose acyl portion is optionally substituted by an amino or alkylamino group protected or by dialkylamino) can also be prepared starting from the corresponding thiolester of the general formula XIV in which R contains a hydroxyalkyl radical wherein the radical Rp and the radical R are different from the hydrogen atom, employing any known method for obtaining a carbamate or an ester starting from an alcohol without attacking the remainder of the molecule, served.

In general, the methods described for obtaining compounds for general formula I which contain such substituents are described starting from a compound of general formula I '.

The compounds of general formula XVII, wherein R is different from the hydrogen atom, can be prepared by the action of an acid halide of the general formula

Hal-CH CO-C-CO Hai ¹

¹ | i (XXXIII),

wherein Hal is as defined above, R ' ⁰ is defined as R °, with the exception of the hydrogen atom, and Hai ^{1 represents} chlorine or bromine, to a 7-amino-cephalosporin of the general formula VIII, optionally followed by an obtained sulfoxide (if η = 1) and cleaves off protective groups.

The reaction is generally carried out in aqueous-organic solvent.

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127 1 -Iss- 57 466/11

agent, for example IVasser ether. (Tetrahydrofuran, dioxane) water-ketone (acetone) or IVasser-chlorinated solvent (chloroform, methylene chloride) in the presence of an alkaline condensing agent such as alkali metal bicarbonate (e.g. sodium bicarbonate), at a temperature of -40 to +40 ⁰ C.

It is also possible to work analogously to the method described in FR patent application 2 399 418.

It will be understood that when the R of the 7-amino-cephalosporin contains an amino or alkylamino radical, it is protected and, if the radical R contains a hydroxy, carboxy, formyl or acylalkyl radical, the latter in free form or protected.

The protection and removal of the protective groups are carried out under the above conditions.

The compounds of general formula XXXIII can be prepared by halogenating a compound of the general formula. ,

CH ₃ CO-C-CO Hai '

Yy (XXXIV),

wherein R '° and Hai ^{1 are} as defined above after each

per se known procedure for the production of halo

genated derivatives that does not alter the rest of the molecule.

09/29/1980

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If a compound of the general formula XXXIII is to be obtained, in which Hal is a bromine atom, the bromine is allowed to react in the presence of a catalyst, either an acidic catalyst.

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tor, such as hydrobromic acid, hydrochloric acid, the sulfonic acids (methanesulfonic acid, anhydrous p-toluenesulfonic acid or benzenesulfonic acid), or in the presence of ultraviolet light.

To obtain a compound of the general formula XXXIII wherein Hal is a chlorine atom, the chlorine is allowed to act in the presence of a catalyst as described above or sulfuryl chloride.

The halogenation takes place in an organic solvent, such as the chlorinated solvents (for example methylene chloride, chloroform, carbon tetrachloride, dichloroethane or trichloroethane) or the ethers (for example ethyl ether or dioxane) or in a mixture of these solvents, at a temperature of temperature of the reaction mixture,

medium, at a temperature of -40 C to the reflux

The compounds of general formula XXXIV can be prepared by the action of a halogenating agent on, the acid, a salt or a silyl ester of the acid of the general formula

CH_ CO COOH ^C-3 K

N (XXXV),

wherein R ¹ ° is as defined above, in the presence of a compound of the general formula

N - C

29.9.1980 AP C 07 D / 221 22127 V -.?& - 57 466/11

wherein X, Y_ and Z ₁ which may be the same or different, represent alkyl or phenyl radicals, or two of which together with the atoms to which they are attached form a heterocycle having 5 or 6 ring members optionally containing a further heteroatom selected from oxygen, nitrogen or sulfur, or wherein X_ and Y represent alkyl radicals as defined above, and Z represents a hydrogen atom or a dialkylamino radical.

The halogenating agent may be selected from phosphorus pentachloride, phosphorus oxychloride, oxalyl chloride or phosgene if one wants to obtain the acid chloride or phosphorus pentabromide, phosphorus oxybromide or thionyl bromide if one wants to obtain the acid bromide.

Among the compounds of general formula XIIIa are advantageously used dimethylacetamide, diethylacetamide, dimethylpropionamide, diethylpropionamide, dimethylformamide, N-Aeetylmorpholin, N-acetylpiperidine, N-acetyl-N-methylaniline, N-methylpyrrolidone or tetramethylurea.

If it is desired to react a salt of the acid of the general formula XXXV, preference is given to using an alkali salt or a tertiary amine salt (for example, triethylamine).

If it is desired to react a silyl ester, it is advantageous to use a trimethylsilyl ester or t-butyldimethylsilyl ester. Optionally, this ester may be prepared using the method described by A. IVissner et al., CJ. Org. Chem., 43 (20), 3972 (1978), or formed in situ.

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The halogenation of the acid of general formula XXXV is generally carried out in an organic solvent such as a chlorinated solvent (for example methylene chloride, chloroform), in an ester (for example ethyl acetate), an aromatic hydrocarbon (for example toluene, xylene),

29.9.1980 AP C 07 D / 221 271 22 127 V-IS-57 466/11

or an ether (e.g. ethyl ether, isopropyl ether or tetrahydrofuran), at a temperature of -70 to +30 ⁰ C.

It is understood that the acids of general formula XXXV in syn form lead to acid halides of the syn form and that the acids of general formula XXXV in anti-form lead to acid halides of general formula XXXIV in the anti-form.

The acids of the general formula XXXV can be prepared by acid hydrolysis or by saponification of an ester of the general formula

CH-CO C-COOAlk

J] (XXXVI) ₁

J]

wherein R ' ^{0 is} as defined above and Alk represents an alkyl radical.

The reaction is generally carried out in the presence of sodium hydroxide in ethanol at the reflux temperature of the reaction mixture.

The esters of general formula XXXVI can be prepared by the use of R. Bucourt et al. in Tetrahedron 34, 2233 (1978).

The compounds of general formula XVII, wherein R represents a hydrogen atom, can be prepared starting from a compound of the general formula

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Hal CH ₂ CO CH ₂ CONH-. J (XXXVII),

-CH = CH-SR

wherein R, R ₁ , Hal and η are as defined above, in analogy to the method described in FR patent application 2 399 418, and then optionally reduction of the sulfoxide and elimination of the protective groups.

It will be understood that when R of the compound of general formula XXXVII contains an amino, alkylamino or formyl radical, it is protected, and if R contains a hydroxy, carboxy or acylalkyl substituent, it is free or protected.

Optionally, reduction of the sulfoxide and elimination of protecting groups occur under the conditions described above.

The compounds of the general formula XXXVII can be prepared starting from a 7-afnino-cephalosporin of the general formula VIII by the action of a compound of the general formula

Hal CH ₂ COCH ₂ -CO Hal (XXXVIII),

wherein Hai is as defined above (which is formed in situ

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using the method described above for the condensation of the compound of general formula XXXIII with a compound of general formula VIII or in analogy to the method described in FR patent application 2 399 418.

The compounds of general formula XXXVIII ₁ which can be prepared in situ are prepared as described in the French patent application mentioned above.

The isomers of the compounds of the general formulas I, VIII, XI, XIV, XV, XVII, XIX, XXI, XXIII, XXV, XXVIII, XXXII or XXXVII can be separated by chromatography or crystallization.

The novel compounds according to the invention can be converted into the acid addition salts. The compounds according to the invention can be obtained in the form of the trifluoroacetate, the solvate with formic acid or water or p-toluenesulfonate. The compounds of general formula I, wherein R is defined according to the invention, which are obtained in the form of the salts can be released by conventional methods or converted into salts with other acids.

The compounds according to the invention can also be converted into metal salts or addition salts with nitrogen-containing bases by methods known per se. These salts can be obtained by the action of a metal base (for example, alkali or alkaline earth metal), ammonia or an amine on a compound according to the invention, in

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a suitable solvent such as an alcohol, an ether or water, or by exchange reaction with a salt of an organic acid. The formed salt precipitates optionally after concentration of the solution, and is separated by filtration, decantation or freeze-drying.

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⁵⁷

As examples of pharmaceutically acceptable salts may be mentioned the addition salts with the inorganic acids (hydrochlorides, hydrobromides, sulfates, nitrates, phosphates) or the organic acids (succinates, fumarates, maleates, p-toluenesulfonates), the salts with the alkali metals (sodium, Potassium, lithium) or the alkaline earth metals (magnesium, calcium), the ammonium salt, the salts with nitrogenous bases (ethanolamine, diethanolamine, trimethylamine, triethylamine, methylamine, propylamine, diisopropylamine, Ν, Ν-dimethylethanolamine, benzylamine, dicyclohexylamine, N-benzyl β-phenethylamine, N, N'-dibenzylethylenediamine, diphenylenediamine, benzhydrylamine, quinine, choline, arginine, lysine, leucine, dibenzylamine).

Optionally, the novel compounds of the invention may be purified by physical methods such as crystallization or chromatography.

The novel cephalosporin derivatives according to the invention and their pharmaceutically acceptable salts have particularly interesting antibacterial properties. They develop considerable in vitro and in vivo efficacy against gram-positive and gram-negative strains,

In vitro, the compounds of general formula I have been shown to be active at a concentration of 0.5 to 15 g / cm against strains of staphylococci susceptible to penicillin G (Staphylococcus aureus Smith) at a concentration of 1 to 30 pg / cm against strains of penicillin G-resistant staphylococci (Staphylococcus aureus MB 9) at a concentration of 0.001 to 1 μg / cm against Escherichia coli

29.9.1980 AP C 07 D / 221-271 221 271.- A- 57 466/11

Strain Monod and at a concentration of 0.06 to 30 μg / cm against Klebsiella pneumoniae. In addition, certain have been found to be active at a concentration of 0.01 to 30 μg / cm against Proteus organism and at a concentration of O ₁ I to 30 μg / cm against Enterobacter aerogenes.

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 / * [- 57 466/11

In vivo, compounds of general formula I have been shown to be active against experimental murine infections by Staphylococcus aureus Smith (sensitive to penicillin G) at a dose of 0.2 to 15 mg / kg per day by subcutaneous route and to Escherichia coli (strain Monod) at doses of 0.001 to 10 mg / kg per day by subcutaneous route.

Furthermore, the DL _{Q of} the compounds of general formula I is subcutaneous in the mouse at 1.5 g / kg to dosages above 2.5 g / kg.

Of particular interest are the compounds of general formula Ia wherein:

the symbol R is selected under the following meanings: 1 »methyl, L-2-amino-2-carboxyethyl or phenyl, 2, 2-pyridyl, optionally N-oxidized,

3 "2-pyrimidinyl or 3-pyridazinyl substituted in the 6-position by a methyl or acetamido radical and optionally N-oxidized,

4. 5,6-Dioxo ~ l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl, substituted in the 4-position

a) an alkyl radical having 1-3 carbon atoms, an alkyl radical having 1 or 2 carbon atoms, substituted by an alkyloxy, alkylthio, phenyl, formyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkyloxycarbonyl or 2-thiazolidinyl radical,

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b) an allyl or 2,3-dihydroxypropyl radical,

c) an alkyl radical having 2 or 3 carbon atoms, substituted

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - "τ £ τ - 57 466/11

substituted by hydroxy, carbamoyloxy, acyloxy (unsubstituted or substituted by amino), amino, alkylsulfonylamino, acylamino (unsubstituted or substituted by amino), alkyloxycarbonylamino, ureido, or alkylureido,

d) a radical of the general formula II, wherein Alk is alkylene having 1 or 2 carbon atoms, X represents ⁰ * and 'represent oxygen atoms, R ^ alkyl radicals and R represents a hydrogen atom,

e) an alkyl radical having 1-3 carbon atoms, substituted by an alkyloxyimino or hydroxyimino radical.

4 ¹ .l, 3,4-triazol-5-yl or 2-alkoxycarbonyl-l, 3,4-triazol-5-yl substituted in the 1-position by a radical OCE general formula II, as defined above, or by a formylalkyl or 2,3-dihydroxypropyl radical.

5. 1 _f 4-Dial 1 ^ 1-5,6 ^ 10X0-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl; l-alkyl-sialo-dioxo-1-yS-tetrahydro-1-methyl-triazin-3-yl or 2-alkyl-5,6-dioxo-1,2,5,6-tetrahydro-1,2,4 triazine-3-yl,

6., 1-allyl-3-alkyloxycarbonyl-1, 2,4-t-riazol-5-yl,

7 »a) l, 3,4-thiadiazol-5-yl, unsubstituted or substituted by an alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or acylaminoalkyl radical,

b) l, 2,4-thiadiazol-5-yl, substituted by an alkyl radical,

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8. a) 1,3,4-OXa (UaZoI-S-Yl ₁ substituted by alkyl or

phenyl,

b) 4-alkyl-2-oxazolyl

9, 5-tetrazolyl, substituted in the 1-position

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a) an alkyl radical, unsubstituted or substituted by formyl,

b) an alkyl radical having 2 or 3 carbon atoms, substituted by hydroxy, amino, alkylamino, dialkylamino, acylamino or

c) a radical of general formula II as defined above;

wherein the symbol R represents a hydrogen atom, a methyl, vinyl or cyanomethyl radical, and the symbol R 'represents an hydrogen atom, wherein the alkyl or acyl moieties or radicals mentioned above (unless stated otherwise) are 1 or 2 Contain carbon atoms,

Among the particularly effective compounds may be mentioned the compounds of general formula Ia in which

R is methyl, vinyl or cyanomethyl,

R ^{1 is} hydrogen and

R is selected off

1 »2-pyridyl, optionally N-oxidized,

2. 6-methyl-3-pyridazinyl, N-oxidized,

3, 5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl, substituted in the 4-position

an alkyl radical having 1 or 2 carbon atoms, substituted by an alkyloxy, alkylthio, phenyl or formyl radical,

an allyl or 2,3-dihydroxypropyl radical,

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - Ig - 57 466/11

an alkyl radical having 2 or 3 carbon atoms, substituted by hydroxy, carbamoyloxy, acyloxy (unsubstituted or substituted by amino), alkylsulfonylamino, acylamino (unsubstituted or substituted by amino), alkyloxycarbonylamino or alkylureido,

an alkyl radical having 1 to 3 carbon atoms, substituted by an alkyloxyimino or hydroxyimino radical,

4. 2 ~ alkyloxycarbonyl-l, 3,4-triazol-5-yl, substituted in the 1-position by a dimethoxyalkyl radical,

5. 1,4-dialky1-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl,

6. 1-alky1-3-alkyloxycarbony1-1,2,4-triazol-5-yl,

7 _# l, 3,4-thiadiazol-5-yl, substituted by an alkyl, dialkylaminoalkyl or acylaminoalkyl radical, or 1,2,4-thiadiazol-5-yl, substituted by an alkyl radical,

8, phenyl-1,3,4-oxadiazol-5-yl, 4-alkyl-2-oxazolyl,

9. 5-tetrazolyl substituted in 1-position by -an.Alkylrest,

an alkyl radical having 2 or 3 carbon atoms, substituted by hydroxy, dialkylamino or acylamino,

a dimethoxyalkyl radical,

.Where the abovementioned alkyl or acyl radicals and parts, unless otherwise indicated, contain 1 or 2 carbon atoms.

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And among these compounds, the preferred compounds are those having the general formula Ia wherein

R is methyl,

R ^{1 is} hydrogen, and

R is selected under the following meanings

1. 2-pyridyl, N-oxidized,

2. »6-methyl-1-oxide-3-pyridazinyl,

3. 5,6-Dioxo ~ l, 4,5,6-tetrahydro-l, 2,4 ~ triazin-3-yl, substituted in the 4-position

a) an alkyl radical having 1 or 2 carbon atoms, substituted by alkyloxy, alkylthio, formyl,

b) an allyl or 2,3-dihydroxypropyl radical,

c) an alkyl radical having 2 or 3 carbon atoms, substituted by hydroxy, carbamoyloxy, acyloxy or acylamino (whose acyl parts are unsubstituted or substituted by amino), alkylsulfonylamino or alkylureido,

4. 1-alkyl-3-alkyloxycarbonyl-1, 2,4-triazole-5-yl,

5. l, 3,4-thiadiazol-5-yl, substituted by dialkylaminoalkyl or acylaminoalkyl or

6. 5-tetrazolyl substituted in the 1-position by a) an alkyl radical,

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2 2 1 2 7 1 "® °" ^{57 466/11}

b) an alkyl radical having 2 or 3 carbon atoms, substituted by hydroxy or acylamino,

wherein the abovementioned alkyl or acyl radicals, unless stated otherwise, contain 1 or 2 carbon atoms.

Of particular interest are the following compounds:

7 ~2 2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamidoj-2-carboxy-3-f [α- ( 2,3-dihydroxypropyl) -5,6-dioxo-l, 4,5,6 ₇ tetrahydro-1,2,4-triazin-3-yl-2-thio-vinyl} -8-oxo-5-thia-1-azabicyclo Γ4.2.03 -oct-2-ene, syn-isomer, E-form

7 ~ 2- (2-Amino-4-thiazolyl) -2-methoxy-imino-cetarnidol-2-ca rboxy ~ 3 ~ / £ 5,6-dioxo-4- (2-formyloxyethyl) -l, 4 , 5,6-tetrahydrol, 2,4-triazin-3-yl] -2-thiovinyl | -8-oxo-5-thia-1-aza-bicyclo ^ 4.2.Ol -oct-2-ene, syn-isomer, E-form

7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamidoJ-2-carboxy-3- ££ 5,6-dioxo-4- (formylmothyl) -l, 4,5,6-tetrahydro-1 , 2,4-triazine-3-yl-J-2-thiovinyl _i J -S-oxo-S-thia-1-aza-bi.cyclo [4.2.0] octo-2-ene, "syn isomer, E -Shape'

3 - // U4- (2-acetamidoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl3-2-thiovinyl) -7- £ 2- (2-amino-4-thiazolyl) -2-methoxyiminoazetamido] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, E-form

7- £ 2 ~ (2-Amino-4-thiazolyl) -2-methoxyimino-acetarnido] -2-carboxy-3- | ^ 4- (2-methoxyethyl) -5,6-dioxo-l, 4,5, 6-tetrahydrol, 2,4-triazin-3-ylJ-2-thiovinyl J -S-oxo-B-thia-1-aza-bicyclo-i4.2.o3-oct-2-ene, syn isomer, E-form _e

The following examples serve to illustrate the invention without limiting it.

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In the examples, the compounds are designated according to the nomenclature of the Chemical Abstracts. It will be understood that all cephalospororin derivatives mentioned have the stereochemistry represented by the following general sub-formula

example 1

A mixture of 8.03 g of 2-benzhydryloxycaibonyl-7- (2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido3-S-oxo-O-oxide-S is heated in an autoclave for 5 hours - (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo / T4.2.0J Oct-2-ene (syn isomer, mixture of E and Z forms), 80 cm dimethylformamide, 1.59 g methylmercaptan and 1.53 cm of N-ethyl-N, N-diisopropylamine at 40 ° C. The mixture is diluted with 500 cm of ethyl acetate, washed three times with 250 ml of water, 100 ml of 0.1 N hydrochloric acid, 100 ml of 1% sodium bicarbonate solution and 200 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate and concentrated at reduced pressure (26.6 mbar or 20 mmHg) at 20 C. The residue is dissolved in 100 ecm of a mixture of cyclohexane-ethyl acetate (50-50 vol.) and The solution is chromatographed on a column of 300 g silica gel Merck (0.04-0.06 mm) (column diameter 6 cm, height 36 cm). It is eluted with 8 l of a mixture of cyclohexane-ethyl acetate (50-50 vol.) Under a pressure of 40 kPa and gains fractions of 125 ecm. The fractions 25 -

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(2.7 kPa 20 mmHg) evaporated at 20 ⁰ C to dryness 57 are collected and concentrated under reduced pressure. 3 _f 7 g of 2-benzhydryloxycarbonyl-7- / T2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidoj-3- (2-methylthiovinyl) -8-oxo-5-oxide-5-thia are obtained -l-aza-bicyclo "4.2.Oj oct-2-ene (syn isomer, mixture of E and Z forms) in the form of a cream meringue.

Infrared spectrum (CHBr.,), Characteristic bands (cm **)

3380, 1800, 1720, 1680, 1515, 1370, 1205, 1045, 835, 750, 740

NMR ProtoneηSpektrum?

(350 MHz ·, CDCl ₃ / ppm in, 0 Hz), 2.17 (s, 3H, -CH _3, E-form); 2.35 (s, 3H, -CH ₃ , Z-form); 3.23 and 3.98 (AB, '0 = 18, 2H, -SCH ₂ -, E-form); 3.44 and 4.3 (AB, O = 18, 2H, -SCH ₂ -, Z-form); 4.09 (s, 3H, -OCH ₃ ); 4.58 (d, 0 = 9, IH, H in 6); 6.12 (dd, Ό = 4 and 9, IH, H in 7); 6.17 (d, 0 = 10, IH, -CH = CH-S-CH _3, Z-form); 6.65 (d, 0 = 15, IH, -ChJ = CH-S-CH ₃ , E-form); 6.88 (d, D = 10, IH, = CH-S-CH, Z-form); 7.15 (d, Ό = 15, IH, = CH-S-CH, E-form); 6.72 (s, IH, H in the 5-position of the thiazole); 6.98 (s, IH, -COOCHC); 7.07 (s, broad, IH, (CH) CNH-).

Is treated at -10 ⁰ C during 30 minutes a solution of 2.30 g of 2-benzhydryloxycarbonyl ~ 7-C2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidoj-3- (2-methylthiovinyl) -e -oxo-S-oxide-S-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene (syn isomer, mixture of the E and Z forms) in 25 ecm of methylene chloride and 1/04 ecm of dimethylacetamide 0.46 ecm phosphorus trichloride. The mixture is diluted with 500 ecm of ethyl acetate,

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washed twice with 100 cc of a solution of 2% sodium bicarbonate and twice with 100 cc of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure (26.6 mbar or 20 mmHg) at 20 ⁰ C to dryness.

The residue is dissolved in 10 ecm of methylene chloride and the solution is applied to a column of 150 g of silica gel, Merck

29.9.1980 AP C 07 D / 221 271 '221271, - 83 "- 57 466/11

(0.04 - 0.06 mm) chromatographed (diameter of the column: 4 cm, height: 20 cm). Elute with 2 1 of one. Mixtures of cyclohexane-ethyl acetate (60-40 vol.) Under a pressure of 40 kPa, collecting fractions of 125 ecm. Fractions 4 to 8 are concentrated under reduced pressure (26.6 mbar and 20 mmHg, respectively) at 20 ° C, yielding 1.32 g of 2-benzhydryloxycarbonyl-7-2-methoxyimino-2- (2-tritylamino-4 -thiazolyl) -acetamidoj-3- (2-methylthiovinyl) -8-oxo-5-thia-1-aza-bicyclo r4.2.03-oct-2-ene, (syn isomer, mixture of E and Z forms ) in the form of a cream meringue.

Infrared spectrum (CHBr,), characteristic bands (cm)

3390, 1780, 1715, 1680, 1515, 1370, 1200, 1050, 1035, 750, 740.. -

NMR proton spectrum :.

(350 MHz, _CDCl3, ppm CFIN, 0 Hz), 2.18 (s, 3H, CH, E-form); 2.31 (s, 3H, -CH ₃ , Z-form); 3.44 (AB, Ό = 18, 2H, -SCH ₂ -, E-form); 3.80 (AB, O = 18, 2H, -SCH ₂ -, Z-form); 4.08 (s, 3H, -OCH ₃ ); 5.06 (d, 0 = 4, IH, H in'6); 5.80 (dd, 0 = 4 and 9, IH, H in 7, E-form); 5.90 (dd, 0 x = 4 and 9, IH, H in 7, Z-form); 6.14 (d, D = 11, IH, -CH = CHS-, Z-form); 6.64 (d, D = 16, IH, -CH = CHS-, E-form); 6.70 (d, 0 = 11, IH, = CHS, Z form); 6.79 (s, IH, H at the 5-position of the thiazole); 6.93 (s, IH, -COOCH-); 6.98 (d, Ό = 16, IH, = CHS, E form).

Dissolve 1.26 g of 2-benzhydryloxycarbonyl-7-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnido] -3- (2-methylthiovinyl) -8-oxo-5-thia-1-one aza-bicyclo £ 4.2.0j oct-2-ene (syn-form, mixture of E and Z forms) in 35 ecm formic acid,

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Add 13 eq of water and heat to 50 ° C for 15 minutes. Cool, filter and concentrate under reduced pressure (26.6 mbar or 20 mmHg at 20 ° C). The residue is triturated in 20 ecm diethyl ether, filtered and washed with 20 ecm of ether and dried. This gives 0.63 g of 7-f2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-U-2-carboxy-3- (2-methylthiovinyl) -8-oxo-5-thia-laza-bicyclo- 4.2 .03 oct-2-ene (syn isomer, mixture of E and Z forms) in the state of solvate with formic acid, in the form of a cream colored powder.

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Rf = 0.34 and 0.48 /! Silica gel chromatography plate, solvent: ethyl acetate-acetone-formic acid-water, 60-20-1-1

-1 Infrared spectrum (KBr), characteristic bands (cm) 3320, 1770, 1675, 1530, 1035

NMR proton spectrum (350 MHz, DMSO d_, S in ppm, D in Hz) E-form: 2.34 (s, 3H ₁ -SCH); 3.61 and 3.77 (AB, D = 18, 2H, -SCH ₂ -); 3.85 (s, 3H ₁ -OCH ₃ ); 5.14 (d, 0 = 4, IH, H in 6); 5.62 (dd, 0 = 4 and 9, IH, H in 7); 6.77 (s, IH, H at the 5-position of the thiazole); 6.85 (d, D = 16, IH, -CjH = CH-S-); 7.04 (d, 0 = 16, IH, = CH-S-); 9.57 (d, 0 = 9, IH, -CONH-)

Z-form: In particular, the following signals are observed: 2.25 (s, 3H, -SCH ₃ ), 6.74 (d, Ό = 13, IH, -CH = CH-S-CH ₃ ) and 6.83 ( d, 3 = 13, IH, = CH-S-).

The 2-Benzhydryloxycarbonyl-7-r2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamidoJ-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo £ 4.2.Oj-oct-2-ene (syn isomer, mixture of E and Z form) can be prepared in the following manner:

To a solution of 2.5 g of 2-benzhydryloxycarbonyl-7-r2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido J-3-methyl-S-oxo-S-thia-1-aza-bicyclo £ 4.2.0j [oct-2-ene, syn isomer in 50 ml of dimethylformamide at 80 ° C is added 0.91 g of bis (dimethylamino) ethoxymethane. The solution turns brownish green. The mixture is left for 20 minutes at 80 ⁰ C and then cooled rapidly and this solution is poured into 200 ecm of ethyl acetate, washed with three times 80 ecm of water and with 50 ecm of a saturated sodium chloride solution. The ethyl acetate phase

29.9.1930 AP C 07 D / 221 271 212 7 1 * - g2fä - 57 466/11

is then stirred at 20 C for 1 h in the presence of 37.5 ecm 1 η-hydrochloric acid. The aqueous phase is removed, the organic phase is washed with 20 eq of a saturated sodium bicarbonate solution and then with 20 ecm of a saturated sodium chloride solution The organic phase is dried over magnesium sulphate, filtered in the presence of a carbon black, and finally filtered.

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reduced pressure (26.6 mbar or 20 mmHg) at 40 C concentrated to dryness. The residue is dissolved in 10 ecm of anhydrous pyridine. To the cooled by an ice bath to 5 C solution is added 0.87 g of tosyl chloride and the reaction mixture is allowed to rise to 20 ⁰ C. After 1.5 h, the mixture is poured onto 200 ecm of ice water. The precipitate formed is filtered, washed twice with 20 ecm of water and then dissolved in 50 ecm of ethyl acetate. This solution is washed with 20 ecm of a saturated sodium bicarbonate solution, 20 ecm of a saturated sodium chloride solution, dried over magnesium sulfate, filtered in the presence of decolorizing carbon and concentrated to dryness under reduced pressure (26.6 mbar or 20 mmHg) at 40 ° C. The residue is dissolved in 13 ecm of methylene chloride and the resulting solution is cooled to -10 C with an ice-methanol bath. Is added to a solution of 0.226 g of m-chloroperbenzoic acid of 85 Vo in 10 cc of methylene chloride for 15 minutes. The Reaktionsgetnisch is kept for 20 minutes at -10 to +5 ⁰ C and then washed twice with 20 ecm of a saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered in the presence of decolorizing carbon and under reduced pressure (26.6 mbar or 20 mmHg) at 40 ⁰ C concentrated to dryness.

The residue is chromatographed on a column (diameter 1.7 cm, height 21 cm) containing 26 g of silica gel. It is eluted with mixtures of ethyl acetate / cyclohexane: 120, 240, 200, 120 ecm (each 20-80, 30-70, 40-60, 60-40 vol.), Collecting fractions of the eluent of 20 ecm. Evaporate fractions 17-34 and isolate 0.88 g of 2-ßenzhydryloxycarbonyl-7-f2-

29.9.1980 AP C 07 D / 221 271 22 1 2 / * J - -85ta - 57 466/11

methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido} -8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo- £ 4.2.0 J oct 2-en (syn isomer, mixture of E and Z forms),

The 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido "] - 5-thia-1-azabicyclof4.2.0J oct-2 s, syn isomer, can be prepared in the following way:

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22127 1.-Θ6- 57 466/11

be placed:

To a solution of 3 _t 15 g of 7-amino-2-benzhydryloxycarbonyl-3-methyl-8-oxo-5-thia-rl-aza-bicyclo C4.2.0J oct-2-ene in 31.5 ecm of methylene chloride are added Once a solution of 7.2 g of the acid anhydride of 2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-acetic acid (syn-form) in 22.5 ecm of methylene chloride, the temperature rises to 8 to 14 C · The mixture is allowed to stir for a further 1 h, 15 minutes, the temperature rising to 20 C, followed by washing with 10 ecm of 0.5N hydrochloric acid, 10 ecm of distilled water and 20 ecm of a saturated solution of sodium bicarbonate. The resulting insoluble precipitate is filtered, the organic phase is again washed twice with 20 eq of distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (26.6 mbar or 20 mmHg) at 40 ° C. The residue is chromatographed on a column (diameter 3 cm, height 33 cm) containing 125 g of silica gel, eluting with mixtures of ethyl acetate-cyclohexane: 1.2 and 1 l each 20-80 and 40-60 vol .], whereat fractions of the eluent of 50 ecm wins. Map vaporizes fractions 31-44 to give 2.8 g of 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-5-thia -l-aza-bicyclo £ 4,2.03 oct-2-ene, syn isomer, in the form of a pale yellow solid.

The 7-amino-2-benzhydryloxycarbonyl-3-methyl-8-oxo-5-thialazza-bicyclo / "4.2. Octo-2-ene can be prepared by the procedure described in NL patent application 73 03 263.

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Example 2

To a solution of 8.0 g of 2-benzhydryloxycarbonyl-7-f2-methoxy-imino-2- (2-1-rylamino-4-thiazolyl) -acetamido-8-oxo-5-oxide-3- (2-tosyloxy-vinyl) - 5-thia-1-aza-bicyclo Z * 4.2.0jl oct-2-ene (syn isomer, mixture of E and Z forms) in 80 ecm dimethylformamide, cooled to +2 C, under nitrogen, add 0 , 90 ecm of thiophenol and then 1.53 ecm of N-ethyl-N, N-diisopropylamine. The mixture is stirred for 2 h at 20 ⁰ C, diluted with 320 ecm of ethyl acetate, washed with three times 200 ecm of water, 100 ecm 0.1 η hydrochloric acid, 150 ecm of a 5% solution of sodium bicarbonate and twice 150 ecm of a saturated sodium chloride solution, dried Sodium sulfate and concentrated to dryness under reduced pressure (26.6 mbar and 20 mmHg, respectively) at 20 ° C. Dissolve the compound in 35 ecm of methylene chloride and chromatograph on a column of 250 g silica gel Merck (0.04-0.06 mm) (diameter 6 cm, height 30 cm). It is eluted with 4 l of a mixture of cyclohexane-ethyl acetate (55-45 vol.) Under a pressure of 40 kPa, to obtain fractions of 100 ecm. Fractions 12 - 32 will evaporated under reduced pressure (26.6 mbar or 20 mmHg) at 20 ⁰ C, and recovering 4.8 g of 2 ~ benzhydryloxycarbonyl-7- £ 2-methoxyimino-2- (2-tritylamino- 4-thiazolyl) acetamidoJ-8-oxo-5-oxide-3- (2-phenylthiovinyl) -5-thia-1-aza-bicyclo [4.2] O] -oct-2-ene (syn-isomer, Gemis. ch of the E and Z forms) in the form of a yellow meringue.

-1 Infrared spectrum (CHBr,), characteristic bands (cm) 3380, 2820, 1795, 1720, 1680, 1580, 1475, 1445, 1440

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NMR proton spectrum

(350 MHz, CDCl ₃ , cTin ppm, D in Hz), 3.93 and 3.13 (AB, Ό = 19, 2H, -SCH ₂ -, E-form); 4.32 and 5.0 (AB, D = 19, 2H, SCH ₂ Z form); 4.05 (s, 3H, -OCH ₃ , E-form); 4.07 (s, 3H, -OCH ₃ , Z-form); 4.51 (d, IH, 0 = 4, H in 6, E-form); 4.56 (d, IH, 0 = 4, H in 6, Z form); 6.10 (dd, 0 = 4 and 9, IH, H in 7, E-form); 6.14 (dd, 0 = 4 and 9, IH, H in 7, Z-form); , 6.41 (d, Ό = 11, IH, -ClH = CH-S-

29.9.1980 AP C 07 D / 221 22 127 1 - g £ ~ 57 466/11

Z-form); 6.6 (d, 3 = 16, IH, CH = CH-S, Ε-form); 6.71 (s, IH, H at the 5-position of the thiazole, E-form); 6.72 (s, IH, H at the 5-position of the thiazole, Z-form); 6.93 (s, CO ₂ CH); 7.09 (s, -NH-thiazole).

To a cooled to -10 C solution of 4.8 g of 2-Benzhydryloxycarbonyl-7-f2-methoxyimino-2 ~ (2-tritylamino-4-thiazolyl) acetamido] -8-oxo-5-oxide-3- (2 -phenylthiovinyl) -5-thia-1-azabicyclo t 4.2.0) -oct-2-ene (syn isomer, mixture of E and Z forms) in 51 ecm of methylene chloride and 2.02 ecm of dimethylacetamide are added 0, 98 ecm phosphorus trichloride. The mixture is stirred for 1 h at '-10 ⁰ C, taken up in 300 cc of ethyl acetate, washed twice with 150 cc of a 5% sodium bicarbonate solution and 150 · cc of a saturated sodium chloride solution, dried over sodium sulfate and concentrated under reduced pressure (26.6 mbar or 20 mmHg at 20 ^° C.) to dryness. Dissolve the product in 30 ecm of methylene chloride and chromatograph the solution on a column containing 250 g of silica gel Merck (0.02-0.06 mm) (column diameter 5 cm, height 30 cm). It is eluted with 2 l 'of a mixture of cyclohexane-ethyl acetate (65-35 vol.) Under a pressure of 0.4 bar, to obtain fractions of 100 ecm. Fractions 10-16 are evaporated, and recovering 2.6 g of 2-benzhydryloxycarbonyl-7/2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido ~} -8-oxo-3- (2- phenylthiovinyl) -5-thia-l-aza-bicyclo £ 4.2.0jJ oct-2-ene (syn isomer, mixture aer E- and Z-forms) in the form of a cream-colored meringue.

NMR proton spectrum:

(350 MHz, CDCl ₃ , / in ppm ·, 3 in Hz), 3.42 and 3.52 (AB, 3 a 19, 2H, -SCH ₂ -, E-form); 3.50 and 3.88 (AB, 3 = 19, 2H,

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-SCH ₂ - Z-form); 4.07 (s, 3H, -OCH ₃ , E-form); 4.09 (s, 3H ₁ -OCH ₃ , Z-form); 5.07 (d, 0 = 4, IH, H in 6, E-form); 5.10 (d, 0 = 4, IH, H in 6, Z-form); 5.87 (dd, 0 = 4 and 9, IH, H in 7, E-form); 5.93 (dd, 0 = 4 and 9, IH, H in 7, Z-form); 6.41 (d, O = 11, IH, -CH = CH-S-Z form); 6.70 (d, O = 16, IH, -CJHsCH-S-E-form); 6.76 (s, H at the 5-position of the thiazole); 6.95 (s, -CO ₂ CH-); 6.95 (d, O = 11, IH, -CH = CH-S-, Z-form); 7.22 (d, O = 16, IH ₁ -CH = CH-S, E-form);

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Fig

127 1st - ^m - ^'57

7.01 (s, broad, -NH-, thiazole).

Dissolve 2.6 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-8-cxo-3- (2-phenylthiovinyl) -5-thia-1-aza bicyclo C4.2.0J oct-2-ene (syn isomer, mixture of E and Z forms) in 40 cc of formic acid, diluted with 12.5 cc of water and the solution heated for 20 minutes at 50 ⁰ C. Man Cools, removes insoluble fractions by filtration and evaporated to dryness at 20 C under reduced pressure (0.0665 mbar and 0.05 ipmHg, respectively). The residue is triturated in 50 ecm of ethyl ether, filtered, washed with 50 ecm of ether and dried. This gives 1.3 g of 7-f2- (2-AmInO ^ -thiazolyl) -2-methoxy in ino-ace tarn idoj-2-carboxy-3- (2-phenylthiovinyl) -8-oxo-5-thia-l aza-bicyclo £ 4 "0j 2-oct-2-en _t (syn isomer, mixture of E and Z forms) in the state of the solvate with formic acid in the form of a yellow powder,

Infrared spectrum (KBr), characteristic bands (cm ") 3320, 1775, 1680, 1530, 1380, 1045, 945, 745, 690

• NMR ^ proton spectrum:

(DMSO _d6 / 350 MHz, ppm CTin, D in Hz), 3.65 and 3.94 (AB, 0 = 18, 2H, -SCH ₂ -, E-form); 3.84 (s, 3H, -OCH ₃ ); 5.17 (d, 3 = 4, IH, H in 6, E-form); 5.22 (d, 0 = 4, IH, H in 6, Z-form); 5.73 (dd, 0 = 4 and 9, IH, H in 7, E-form), 6.61 (d, u = 11, IH, -CH = CH-S, Z-form); 6.80 (d, D = 11, IH, -CH = C] HS, Z-form); 6.98 (d, D = 15, IH, -C] H = CH-S-, E-form); 7.06 (d, Ό = 15, IH, -CH = CIH-S-, E-form); 6.74 (s, H at the 5-position of the thiazole); 7.18 (broad signal, -NH ⁺ and -CO ₀ H); 8.11 (s, HCOZ); 9.58 (d, 0 = 9, IH, -CONH,).

29.9.1980 AP C 07 D / 221 22 127 1 '- "£ & - 57.466 / 11

Example 3

A solution of 0.1 g of the solvate of 7-f2- (2-amino-4-thiazolyl) -2-methoxyimino-acetarnido7-2-carboxy-8-oxo-3- (2-tosyloxy-vinyl) -5-thia- l-aza-bicyclo 4.2 4.2, Oj oct-2-ene (ssyn isomer, Ε form) with formic acid and 0.02% thiophenol in 1 ecm of anhydrous N, N-dimethylformamide is cooled to 0 ° C. A solution of 0.069 g of Ν, Ν-diisopropyl-N-ethylamine in 3 ecm of N, N-dimethylformamide is added dropwise. The reaction mixture is reheated and stirred at 25 C for 1 h. Evaporation of the solvent under reduced pressure (13.3 mbar or 10 mmHg) at 30 ° C. gives 0.19 g of a residue whose chromatographic analysis shows silica gel chromatography plate, eluent: mixture of ethyl acetate-acetone-water-acetic acid 50- 20-10-10 Vol.3 shows the formation of 7- / 2- (2-amino- A- thiazolyl) -2-methoxyimino-acetamidoJ-2-carboxy-8-oxo-3- (2-phenylthiovinyl) -5 -thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene (syn isomer, Ε-form): Rf = 0.62,

The solvate of 7 ~ / 2- (2-amino-4 ~ thiazolyl) -2-methoxyiminoacetamidoj -2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-thia-bicyclo laza £ 4.2, Oj oct-2-ene (syn isomer, Ε form) with formic acid can be obtained in the following manner:

1.5 g of 2-benzhydryloxycarbonyl-7- C 2 -methoxyimino ~ 2 ~ (2-tritylamino-4-thiazolyl) -acetamidoJ-8-oxo-3- (2-tosyloxyvinyl) ~ 5-thia-1-aza-bicyclo 4.2 4.2.0j oct-2-ene (syn isomer, E-form) are dissolved in a mixture of 30 ecm of formic acid and 10 eq of distilled water. The solution is heated to 50 ^° C. for 30 minutes. After cooling, the precipitate is filtered off and the filtrate is concentrated in dryness

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reduced pressure (13.3 mbar or 10 mmHg) at 30 C. The residue is triturie.rt with 50 ecm diethyl ether. The solid product is filtered off, washed twice with 25 cc of diethyl ether and then dried under reduced pressure (6.65 mbar and 5 mmHg) at 25 ⁰ C. 0.75 g of 7,7-C2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-J is obtained.

29.9.1980 AP C 07 D / 221 221271 - 9Sr - 57 466/11

2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo f4.2.0] -oct-2-ene (syn isomer, Ε-form) in the form of the solvate with formic acid .

Rf = 0.57; Silica chromatography plate; Eluent: Mixture of ethyl acetate-acetone-water-acetic acid (50-20-10-10 vol.).

- 1

IR spectrum (KBr) ₁ characteristic bands (cm): 3400, 3340, 3000, 2820, 2200, 1775, 1720, 1670, 1630, 1370, 1190, 1165, 1070

NMR ProtoneηSpektrum:

(350 MHz, DMSO dg, cf in ppm, O in Hz), 2.42 (s, 3H, -CH ₃ tosyl); 3.55 and 3.78 (AB, O = 19, 2H, -SCH ₂ -); 3.83 (s, 3H, -OCH ₃ ); 5.14 (d, 0 = 4, IH, H in 6); 5.75 (dd, 0 = 4 and 9, IH, H in 7); 6.65 (d, O = 12, IH, -CH = CH-OSO ₂ -); 6.73 (s, IH, H at the 5-position of the thiazole); 7.18 (s, broad, -NH ⁺ ), 9.58 (d, O = 9, IH, -CONH-).

The 2-Benzhydryloxycarbonyl-7-C2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-3- (2-tosyloxy-vinyl) -8-oxo-5-thia-1-aza-bicyclo 4.2 4.2.OJ oct-2-ene (syn isomer, .E-form) can be prepared in the following manner:

3 g of 2-Benzhydryloxycarbonyl-7-O-2-methoxyimino-2 - (2-tritylamino-4-thiazolyl) -acetamido-3- (2-tosyloxy-vinyl) -8-oxo-5-oxide-5-thia-1-azabicyclo - 4.2.03 oct-2-ene (syn isomer, Ε-form) are dissolved in 30 ecm of methylene chloride. It adds 1.2 ecm Ν, Ν-dimethylacetamide. The solution is brought under an atmosphere of dry nitrogen, cooled to -10 ⁰ C and treated with 0.9 g of phosphorus trichloride. The

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221271 "^ ** ⁵ " ^{57 466} Z ¹¹

Reaction mixture is stirred for 90 minutes at a temperature of -10 to -5 C and then diluted with 250 ecm of ethyl acetate and washed with 150 ecm of an aqueous saturated sodium bicarbonate solution and twice with 100 ecm of a saturated sodium chloride solution. After drying over magnesium sulphate and filtration, the organic

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See solution under reduced pressure (26.6 mbar or

20 mmHg) at 30 C to dryness. The residue is redissolved in 20 ecm of methylene chloride and the solution is chromatographed on a column (height 25 cm, diameter 5 cm) containing 240 g of silica (0.04-0.063 mm). It is eluted with 2 l of a mixture of cyclohexane-ethyl acetate (60-40 vol.) And recovering fractions of 100 ecm. Fractions 8-13 are concentrated under reduced pressure (26.6 mbar and 20 mmHg, respectively) at 30 ^° C.

 This gives 1.7 g of 2-benzhydryloxycarbonyl-7-C2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-3- (2-tosyloxyvinyl) -8-oxo-5-thia-1-aza. bicyclo f4.2.0! J oct-2-ene (syn isomer, E ~ form).

Rf = 0.52; Silica gel chromatography plate; Eluent: cyclohexane-ethyl acetate (50-50 vol.).

- 1 infrared spectrum (CHBr ₃ ), characteristic bands (cm):

3400, 1790, 1725, 1685, 1520, 1375, 1190, 1180, 1075, 1050, 755, 740

NMR proton spectrum

(350 MHz, CDCl, S in ppm, 3 in Hz)

2.42 (s, 3H, -CH ₃ tosyl); 3.33 and 3.42 (AB, 0 = 19, 2H,

-SCH ₂ -), 4.07 (s, 3H, -OCH ₃ ); 5.03 (d, 0 = 4, IH, H in 6); 5.87 (dd, 0 = 4 and 9, IH, H in 7); 6.71 (s, IH, H in

5-position of the thiazole); 6.87 (s, IH, -CO ₂ CH-); 6.87

(d, 0 = 10, IH, -CiH = CH-OSO ₂ ); 7.0 (s, broad, IH, -NH-thiazole); 7.78 (d, 0 = 9, IH, -CONH-).

The 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido]] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza -bicyclo £ 4.2.Oj oct-2-ene (syn-isomeres

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Ε-shape and Z-shape) can be prepared in the following manner:

1.85 g of dicyclohexylcarbodiimide are added with stirring to a solution of 7.97 g of syn-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetic acid in 100 ecm of methylene chloride which has been cooled to + 4 ° C.

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The mixture is stirred for 40 minutes at +4 ⁰ C and then for 30 minutes at 20 ⁰ C and filtered the solution.

To the filtered solution, cooled to -30 C, is quickly added a solution of 3.47 g of 7-amino-2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1 -aza ~ bicyclo / "4-2.Oj oct-2-ene in crude form (mixture of E and Z isomers) in 30 ecm of methylene chloride, admixed with 0.84 ecm of TriePfeylamine Stirred for 1 h 50 min. At 20 ⁰ G, The reaction mixture is concentrated to dryness at 20 C under reduced pressure (26.6 mbar or 20 mmHg) and taken up again in 250 ecm of ethyl acetate.The organic phase is washed three times 100 ecm Water, 100 ecm of 0.05 N hydrochloric acid, 100 ecm of a 1% sodium bicarbonate solution and twice 100 ecm of water, half saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure (26.6 mbar and 20 mmHg, respectively). at 20 C) to dryness, The residue is taken up in 20 ecm of ethyl acetate, 20 ecm of cyclohexane are added, filtered and chro The solution is chromatographed on a column of 300 g silica gel Merck (0.04-0.06 mm) (diameter of the column 6 cm, height 30 cm). It is eluted with 4 l of a mixture of cyclohexane-ethyl acetate (40-60 vol.) Under a pressure of 40 kPa, collecting fractions of 125 ecm. Fractions 6-25 were concentrated under reduced pressure (26.6 mbar and 20 mmHg, respectively) at 20 C; 4.8 g of 2-benzhydryloxycarbonyl-7- / 2-methoxyimino-2- (2-tritylamino- A- thiazolyl-1-acetamido-1-S-oxo-S-oxide-S- (2-tosyloxy-vinyl) -5-thia) are obtained. l-aza-bicyclo £ 4.2.0} oct-2-ene (syn isomer, mixture of E and Z forms) in the form of a cream meringue.

29.9.1980 AP C 07 D / 221 2 2 1271- - §aa -. 57 466/11

If a second chromatography is carried out identically to the preceding one, 1.21 g of the Z-isomer are separated off in fractions 12-16 and 1.49 g of the C-isomer in the fractions 22-40, the fractions. 17-21 contain 0.8 g of the E and Z mixture.

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Z isone res

- 1 infrared spectrum (CHBr ₃ ), characteristic bands (cm) 338O ₁ 1800, 1720, 1680, 1510, 1375, 1190, 1175, 1045, 1000, 735

NMR ProtoneηSpektrum

(350 MHz, CDCl ₃ , S in ppm, 0 in Hz) ·· 2.03 (s, 3H, -C ₆ H ₄ -CH ₃ ); 3.36 and 4.07 fcd, ^ = 19, 2H, -SCH ₂ -); 4.09 (s, 3H, -OCH ₃ ); 4.52 (d, 3 = 4, IH, H in 6); 6.16 (dd, 0 = 4 and 9, IH, H in Figure 7); 6.43 (AB, 3 = 8, 2H, -CH = CH-); 6.86 (s, IH, -CH-OCO-); 6.71 (s, IH, H at the 5-position of the thiazole); 7.75 (d, 0 = 9, 2H, H in the ortho position of tosyl).

E-! Some res

Infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3380, 1800, 1725, 1685, 1515, 1380, 1190, 1180, 1070, 1050, 755, 735

NMR proton spectrum

(350 MHz, CDCl ₃ , df in ppm, 0 in Hz)

2.45 (s, 3H, -C ₅ H ₄ CH ₃ ); 3.19 and 3.77 (2d, 3 = 18, 2H, -SCH ₂ -); 4.08 (s, 3H, -OCH ₃ ); 4.6 (d, D = 4, H in Figure 6); 6.18 (dd, 0 = 4 and 9, H in 7); 6.72 (s, IH, H in the 5-position of the thiazole); 6.93 (d, D = 12, IH, -ChI = CH-OSO ^); 7.11 (d, 3 = 12, IH, -CH = CH 0 SO 0 ~); 6.90 (s, IH, -COOCH-); 7.73 (d,

- a · j

0 = 9, 2H, H in the ortho position of tosyl).

The 7-amino-2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo f4.2.0j oct-2-ene (mixture of

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E- and 2-forms) can be produced in the following way:

A solution of 4.06 g of Z-benzhydryloxycarbyphenyl - ^ - t-butoxycarbonyl-amino-S-oxo-B-oxide-3- (2) is stirred at 20 C for 16 h.

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tosyloxyvinyl) ~ 5-thia-1-aza-bicyclo / "4,2" oct-2-ene (mixture of the E and Z forms) in 150 ecm of acetonitrile with 2.28 g of monohydrated p-toluenesulfonic acid.

Concentrate under reduced pressure (26.6 mbar or 20 mmHg) at 20 ° C to a volume of 10 ecm, diluted with 150 ecm of ethyl acetate, washed with 100 ecm of a 2% solution of sodium bicarbonate and then twice with 150 ecm of water. saturated with sodium chloride, dried over sodium sulfate and concentrated under reduced pressure (26.6 mbar or 20 mmHg) at 20 C to dryness, we obtained 3.5 g of 7-amino-2-benzhydryloxycarbonyl-8-oxo-5-oxide ~ 3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (mixture of E and Z forms) in the form of a crude brown solid,

Infrared spectrum (KBr), characteristic bands (cm) 3430, 3360, 1780, 1725, 1370, 1170/1180, 1070, 745, 700.

NMR proton spectrum.

(350 MHz, _CDCl3, <T in ppm, 3 Hz) 2.43 (s, 3H, -CH _3); 3.12 and 3.75 (2d, D = 18, 2H, -SCH ₂ -); 4.36 (d, 0 = 4, IH, H in 6); 4.74 (d, D = 4, IH, H in T); 6.87 (d, 0 = 12, IH, -CH = CH OSO ₂ -); 6.90 (s, IH, -COOCH-);

6.99 (d, Ό = 12, IH, = CH OSO ₂ -); 7.40 and 7.71 (2d, Ό '= 9,

The 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo / 4,4'-octo-2-ene (mixture of E and Z forms) can be prepared according to the procedure described below (Example 47).

29.9.1980 AP C 07 D / 221 271 2 2 12 7 1. - äs - 57 466/11

Example 4

A mixture of 5.02 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5 is stirred at 60 C under nitrogen for 2 h 30 min. Oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo f4.2.0j oct-2-ene (syn isomer, E-form) 75 ecm dimethylformamide, 2.21 g N'-t- Butoxycarbonyl-L-cyctein and 2.61 ecm N, N-diisopropylfilylamine. After cooling, the mixture is diluted with 500 eq of ethyl acetate, and the organic phase is washed with twice 400 eq of water, 250 ecm of 0.1N hydrochloric acid and 250 ecm of water, half saturated with sodium chloride, dried over sodium sulfate, filtered, and added 20 C concentrated under reduced dryness.

20 C under reduced pressure (26.6 mbar or 20 mmHg)

The residue is dissolved in 50 ecm of acetonitrile. Are added at 20 ⁰ C under stirring, a solution of 0.97 g of diphenyldiazomethane in 25 cc of acetonitrile, cooled for 2 h at 20 ⁰ C and diluted with 500 cc of ethyl acetate. Wash in the flask with 100 ml of 0.05N hydrochloric acid, 100 ml of a solution of 1 % sodium bicarbonate and twice 100 ml of a half-saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate under reduced pressure (26.6 mbar or 20 mmHg) at 20 ⁰ C to dryness. The residue is taken up in 50 ecm of a mixture of cyclohexane-ethyl acetate (60-40 vol.) And the solution is chromatographed on a column of 300 g silica gel Merck (0.04-0.06) (diameter of the column 6 cm, height 30 cm). It is eluted with 4 l of the above mixture under a pressure of 40 kPa, obtaining fractions of 115 ecm. The fractions 11 - 23 are combined and at 20 C

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concentrated to dryness under reduced pressure (26.6 mbar or 20 mmHg) to give 3.57 g of 2-benzhydryloxycarbonyl-3-C (2-L-benzhydryloxycarbonyl-2-t-butoxycarbonylaminoethyl) -2-thiovinyl-3-one 7- / T2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoj-8-oxo-5-oxide-5-thia-1-azabicyclo ¢ 4.2.Oj oct-2-ene, syn isomer, e-form.

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- 1 infrared spectrum (CHBr.,), Characteristic bands (cm) 3380, 1795, 1710, 1690, 1510, 1495, 1445, 1365, 1045, 940, 750, 740

NMR proton spectrum

(350 MHz, CDCl ₃ / ppm in, 0 in Hz)

1.48 (s, 9H, -C (CH ₃ J ₃ ); 2.95 and 3.75 (2d, 0 = 18, 2H, "-S CH ₂ -); 3.20 (d, 3 = 7 , 2H, -SCH ₂ -), 4.08 (s, 3H, -OCH ₃ ), 4.48 (d, 0 = 4, IH, H in 6), 4.67 (mt, IH, -CH-) COO-); 6,10- (dd, 0 = 4 and 9, IH ₁ H in 7); 6,39 (d, 0 = 7, IH, -NH COO-); 6,41 (d, 0 = 16, IH, = CHS-); 6.71 (s, IH, H of the thiazole); 6.85 (s, IH, -COOCH-); 6.93 (s, IH, -COOCH-); 7, 10 (s, IH, -NH-C (C ₆ H ₅ J ₃ ).

To a cooled to -10 C solution of 4.14 g of 2-Benzhydryloxycarbonyl-3 - ^ "(2-L-benzhydryloxycarbonyl-2-t-butoxycarbonylaminoethyl) -2-thiovinyl] -7- £ 2-methoxyimino-2- ( 2-tritylamino-4-thiazolyl) -acet't on idoj-8-oxo-5-oxid-5-thia-1-azabicyclo [4.2.0 ] oct-2-ene, syn isomer, Ε-form, in 45 cc of methylene chloride successively 1.35 cc of dimethylacetamide and ecm with stirring 0.59 of phosphorus trichloride is added. the mixture is stirred I h at -10 ⁰ C, ve rdünnt with 600 cc of ethyl acetate, washed twice with 100 cc of a 2% sodium bicarbonate solution and twice 100 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (26.6 mbar and 20 mmHg) at 20 ° C. The residue is dissolved in 60 ecm of a mixture of cyclohexane-ethyl acetate ( 65-35 vol.) And chromatograph the solution on a column of 250 g silica gel Merck (0.04-0.06) (column diameter 5 cm) eluting with 2 liters of a mixture s of cyclohexane-ethyl acetate (65-35 vol.) under a pressure of 40 kPa and

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wins fractions of 130 ecm. Fractions 5-8 are combined and concentrated to dryness at 20 C under reduced pressure (26.6 mbar and 20 mmHg, respectively) to give 2.78 g of 2-benzhydryloxycarbonyl-3- (2-L-benzhydryioxycarbonyl) -2- t-butoxycarbonylaminoethyl) -2-thiovinyl-7-jf2-methoxyimino- 2- (2-tritylamino-4-thiazolyl) -acetarnidoj-8-oxo-5-thia-1-azabicyclo Γ4.2.03 oct-2-ene, syn isomer , Ε shape in shape

15Z

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gets a yellow herring. '

- 1 infrared spectrum (CHBr,), characteristic bands (cm) 340O ₁ 1780, 1690, 1515, 1495, 14'50, 1390, 1370, 1050, 945, 755, 745.

NMR proton spectrum

(350 MHz, CDCl ₃ , (Tin ppm, 3 in Hz), 1.43 (s, 9H, (CH) C-), 3.22 (2 AB boundary, 4H, ^K -S CH ₂ -), 4 , 10 (s, 3H, -OCH ₃ ), 4.70 (m, IH,> CfH NH-), 5.35 (s wide, IH, -NH COO-), 5.04 (d, Ο = 4, IH, H in 6), 5.85 (dd, D = 4 and 9, IH, H in 7), 6.41 (d, D = 16, IH, = CHS-), 6.8 (s , IH, H of the thiazole); 6.88 (s, IH, -CH-COO-CH-); 6.93 (s, IH, -COOCH-); 7.03 (s, IH, -NHC (CH 7,08 (d, D = 16, IH ₁ -CH = CHS-).

Dissolve 2.71 g of 2-benzhydryloxycarbonyl-3- (2-L-benzhydryloxycarbonyl-2-t-butoxycarbonylaminoethyl) -2-thiovinyl-7- (2-methoxyimino-2- (2-tritylamino-1,3-thiazole) -4-yl) -acetamido3-8-OXO-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, in 40 cc of formic acid, diluted with 40 eq of water , and stirred at 50 C for 30 minutes. The mixture is cooled to about 20 C cooled and concentrated at 30 ⁰ C under reduced pressure (0.0665 mbar or 0.05 mmHg) to dryness. The residue is taken up in succession with 75 ml of ethanol three times and evaporated to dryness each time at 20 ° C. under reduced pressure (26.6 mbar or 20 mmHg). The solid residue is refluxed with 200 ecm of ethanol and the cooled suspension is filtered. After washing three times with 25 ecm of diethyl ether and drying, 1.34 g of the formate of 3-ε (2-L-amino-2-carboxyethyl) -2-thiovinyl] -7-ε-2- (2-amino-1, 3-triazol-4-yl) -2-methoxyimino-acetamido-J-2-carboxy-8-oxo-5-thia-1-aza-bicyclo-4,2,0] oct-2-ene, syn-isomer, E -Shape.

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2000, 1750, 1660, 1530, 1035, 940

29.9.1980 AP C 07 D / 221 2 2 1 2 7 1j - '-θ ¥ - 57 466/11

NMR proton spectrum

(350 MHz, DMSO dg, <f in ppm, O in Hz)

3 - 3.70 (massive, 4H, -SCH ₂ - cephalosporin and side chain); 3.87 (s, 3H, -0 CH _3); 5.15 (d, D = 4, IH, H in Figure 6); 5.65 5.72 (solid, 2H, H in 7 and i CH COOH); 6.77 (s, IH, H of the thiazole); 6.92 (AB, 2H, -CH = CH-); 7.20 (s, 3H, -NH ₃ ⁺ ); 9.58 (d, 3 = 9, IH, -CONH-).

Example 5

A solution of 6.0 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidol-8-oxo-5-oxide is stirred at 20.degree. C. for 2 hours under nitrogen. 3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, and 1.33g of 2-mercaptopyridine in 60cm of dimethylformamide and 2 , 1 ecm Ν, Ν-diisopropylethylamine. The mixture is diluted in 400 eq of ethyl acetate and the organic phase is washed twice with 500 ml of distilled water and then with 300 ecm of a half-saturated sodium bicarbonate solution and finally with 300 ecm of a half-saturated sodium chloride solution. It is dried over magnesium sulfate, filtered and concentrated under reduced pressure at 20 ⁰ C (26.6 mbar or 20 mm Hg) to dryness. The residue, dissolved in 25 ecm of methylene chloride, is chromatographed on a column of 300 g of silica Merck (0.04-0.06) (diameter of the column 5 cm) using

4 1 of a mixture of methylene chloride-ethyl acetate

(80-20 vol.) And elute fractions of 100 ecm. Fractions 17-34 are combined and concentrated to dryness under reduced pressure at 35 ° C (26.6 mbar and 20 mmHg, respectively). It is dried for 15 hours under reduced pressure (0.2 mmHg or 0,266mbar) at 20 ⁰ C. This gives 3.9 g of 2-Benzhydryloxycarbony1-7- £ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl ) -acetamido J-8-0x0-5-oxide-3- (2-pyridyl) -2-thiovinyl-7-5-thia-1-aza-bicyclo Γ4.2.03 oct-2-ene, syn isomer, Ε-form , in

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Shape of a yellow meringue,

The mixture is stirred at -15 C for 1 h, a mixture of 3.9 g of 2-Benzhydryloxycarbonyl-7- ^r .2-methoxyimino-2 ~ (2 ~ tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-oxide ~3- (2-pyridyl) -2-thi.ovinyl-5-thia-1-aza-bicyclo / 4-2O oct-2-ene, syn isomer, E form, 1.6 ecm dimethylformamide, 40 ml of methylene chloride and 0.7 ml of phosphorus trichloride The solution obtained is poured into 600 ml of ethyl acetate, and the organic phase is washed twice with 200 ml of a half-saturated sodium bicarbonate solution and then with 200 ml of half-saturated sodium chloride solution, dried over sodium sulphate, filtered, and washed Cake with 100 eq of ethyl acetate, concentrated under reduced pressure (26.6 mbar or 20 mml-1 g) at 35 ° C. The residue is taken up in 30 ecm of methylene chloride and chromatographed on a column of 150 g of silica Merck (0.04 g). 0.06) (diameter of the column 4 cm), eluting with 4.5 l of a mixture of methylene chloride-ethyl acetate (95-5 vol.) Innt fractions of 100 ecm. Fractions 10-40 are combined and_ under reduced pressure (26.6 mbar or "20 mmHg) at 35 ⁰ C and concentrated to dryness. It is then dried under reduced pressure (0.2 mmHg) at 20 ° C for 15 h. This gives 2.4 g of 2-benzhydryloxycarbonyl-7-l-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-8 -oxo-3- (2-pyridyl) -2-thiovinyl-5-thia-1-aza-bicyclo [4.2.0] -oct-2-ene, syn isomer, E-form,

A solution of 2.40 g of 2-benzhydryloxycarbonyl-7-p-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-3- I (2) is stirred for 1 h at 50.degree. pyridyl) -2-thiovinyl} -5-thia-1-azabicyclo [4.2.03 oct-2-ene, syn isomer, Ε-form, in 21 ecm

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Formic acid and 13 ecm of distilled water. After cooling, the suspension is filtered and the cake is washed with 20 eq of distilled water. Concentrate under reduced pressure (0.266 mbar or 0.2 mml-lg) at 35 ⁰ C.

 The residue is taken up in 100 ml of ethanol and concentrated under reduced pressure (26.6 mbar or 20 mmHg). The resulting solid is digested in 20 ecm

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saturated sodium chloride solution. After drying over magnesium sulfate, the solvent is evaporated at 40 ^° C. under reduced pressure (39.9 mbar or 30 mmHg). The residue (3.5 g) is added to 0.5 g of the product, which was obtained in the same way and chromatographed on 80 g of silica gel Merck (0.04-0.06) (diameter of the column 5 cm) eluted with 10 l of a mixture of ethyl acetate and methanol (98-2 vol.) under a pressure of 50 kPa and collected fractions of 120 ecm. In fractions 2-4, 1.1 g of the unchanged starting product are recovered. The fractions 45-75 v / h are concentrated under reduced pressure (39.9 mbar and 30 mmHg, respectively) at 40.degree. C., giving 1.6 g of 2-benzhydryloxycarbonyl-7 - / 2-methoxyimino-2- (2- tritylamino-4-thiazolyl) -acetamido .7-8-oxo-3-ε (1-oxide-2-pyridyl) -2-thiovinyl-S-thia-1-aza-bicyclo- C 4.2.0 J oct-2- en, syn-isomer, Ε-form, in the form of a gray meringue.

Infrared spectrum (CHBr ₃ ), characteristic bands (cm ") 3390, 1780, 1720, 1680, 1585, 1510, 1465, 1420, 1040, 945, 750

NMR proton spectrum

(350 MHz, CDCl ₃ / ppm in, 0 in Hz)

3.60 and 3.69 (AB, O = 18, 2H, -SCH ₂ ); 4.08 (s, 3H, = NOCH); 5.12 (d, D = 4, IH, H in Figure 6); 5.97 (dd, 0 = 4 and 9, IH, H in 7); 6.57 (d, 0 = 16, IH, -CH = CHS-); 6.76 (s, IH, H of the thiazole); 7.0 (s, 2H, -CH (C ₆ H ₅ ) ₂ and (C ₆ H ₅ J ₃ CNH-); 7.1-7.5 (massive, aromatic); 8.25 (d, 0 = 9, IH, -CONH-).

Dissolve 2.3 g of 2-benzhydryloxycarbonyl-7- / T2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) acetamido-8-OXO-S - / 1-oxide-2-pyridyl) - 2-thiovinyl-3,5-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene,

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syn isomer, Ε form, in 54 ecm formic acid. The solution is diluted with 21 eq of distilled water and stirred at 50 ° C for 20 minutes. After filtration in the heat the solvents under reduced pressure (13.3 mbar or 10 mmHg) at 40 ⁰ C comparable

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evaporated. The residue is triturated with 50 ecm of ethanol. It is brought under reduced pressure (39.9 mbar or 30 mmHg) at 40 C to dryness. This operation is repeated once. The residue is taken up in 50 ecm of ethanol. The solid is filtered off with suction, washed with 15 ecm of ethanol and then twice with 25 ecm of ethyl ether and then dried under reduced pressure (13.3 mbar or 10 mmHg) at 25 ° C. 0.98 g of 7-f2- (2-amino-4-thiazolyl) -acetamido-1-carboxy-S-oxo-S- 1- l-oxide-2-pyridyl-2-thiovinyl-1-O is obtained. 5-thia-1-aza-bicyclo £ 4.2.0} oct-2-ene, syn isomer, Ε-form, in the form of a gray powder.

Infrared spectrum (KBr), characteristic bands (cm) 3330, 1770, 1670, 1540, 1470, 1420, 1040, 950, 760

NMR proton spectrum

(350 MHz, DMSO d _& , if in ppm, D in Hz) 3.75 and 4.16 (AB, 0 = 18, 2H, -SCH ₂ -); 3.88 (s, 3H, ^ NOCH ₃ ); 5.24 (d, 0 = 4, IH, H in 6); 5.73 (dd, 0 = 4 and 9, IH, H in 7); 6.78 (s, IH ₁ H of thiazole); 7.05 and 7.32 (AB, O = 16, 2H, -CH = CH-S-); 7.63 (d, 0 = 7, IH, H in the 3-position of the pyridine); 7.1-7.5 (massive, 4H, H at 4- and 5-position of pyridine + -NH ₂ ); 7.63 (d, 0 = 7, IH, H in the 3-position of the pyridine); 8.32 (d, 0 = 6, IH ₁ H in the 6-position of the pyridine); 9.64 (d, 0 = 9, IH, -CONH-).

Example 7

To a solution of 5.0 g of 2-benzhydryloxycarbonyl-7- [Z- methoxyimino-2- (2-t-ritylamino-4-thiazolyl) acetamido] -8-oxo-3- (2-tosyloxyvinyl) -5-thia -l-aza-bicyclo f4.2.oj oct-2-ene, (syn-isomer, EF.orm) in 50 ml of dry N, N-dimethylformamide are added 1.12 g of 2-mercaptopyrimidine and 1.75 ecm Ν , Ν-diisopropylethylamine. The

29.9.1980 ^{AP c 07} D / 221 271 2127 1 - IDS - 57 466/11

The reaction mixture is stirred for 15 minutes at 20 C under nitrogen and then diluted with 250 ecm of ethyl acetate. The organic solution is washed successively with 250 ml of distilled water, 250 ml of an aqueous solution of sodium bicarbonate and finally with 250 ml of saturated sodium chloride solution. After drying over magnesium sulphate and filtering, the solvent is evaporated off under reduced pressure (25 mmHg, 3.3 l <Pa) at 40.degree. C. to give 5 g of crude product, which are chromatographed on a column of silica gel Merck (0.04-0). 06 mm) (diameter of the column 4 cm, height 30 cm), eluting under a pressure of 60.3 kPa with 2.5 l of a mixture of methylene chloride-ethyl acetate (95-5 vol.) And to obtain fractions from 100 ecm. Fractions 15-24 are combined and concentrated under reduced pressure (25 mmHg; 3.3 kPa) at 40 ⁰ C. 3.0 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido} -8-oxo-3-f (2-pyrimidinyl) -2-thiovinyl-J-5 are obtained -thia-1-aza-bicyclo £ 4.2.03 oct-2-ene (syn isomer, E form).

- 1 infrared spectrum (KBr), characteristic bands (cm) 3400, 2820, 1785, 1730, 1685, 1595, 1585, 1575, 1550, 1495, 1450, 1420, 1190, 1045, 945, 770, 750 _e

NMR proton spectrum

(350 MHz, CDCl ₃₁ (T lh ppm, 0 in Hz)

3.63 and 3.77 (2d, 0 = 18, 2H, -SCH ₂ - in 4); 4.06 (s, 3H, = NOCH ₃ ); 5.08 (d, 0 = 4, IH, -H in Figure 6); 5.90 (d, 0 = 4, IH, -H in 7); 6.75 (s, IH, -H of the thiazole ring); 6.94 (s, IH, -CHC of benzhydryl); 6.98 and 7.63 (2d, 0 = 16, 2H, trans-vinyl protons); 7.0 (t, 0 = 5, IH, -H in position 5 of the

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Pyrimidine ring); 7.0-7.4 (Mt ₁ 25H, aromatic); 8.52 (d, 0 = 5, 2H, -H at the 4- and 6-positions of the pyrimidine ring); 9.0 (d, 0 = 9, IH, -CONH-).

2.9 g of 2-benzhydryloxycarbonyl-7-r2-methoxyimino-2- (2-trityl

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amino-4-thiazolyl) acetamido] 1-8-oxo-3-r (2-pyrimidinyl) -2-thiovinyl] -S-thia-1-aza-bicyclo r4.2.0j oct-2-ene (syn- Isomer, Ε-form) are dissolved in 30 ecm of formic acid, 13 ecm of distilled water is added and the mixture is warmed to 50 ° C. for 30 minutes. After cooling, the mixture is filtered and the filtrate is washed with 5 eq of distilled water. The filtrate is concentrated under reduced pressure (1 mm Hg, 0.13 kPa) at 30 ^° C. The residue is taken up successively with 4χ30 ecm of absolute ethanol, and the suspension is evaporated as before each time. The dry residue is taken up in 30 eq of distilled water, filtered, and the cake is washed successively with 15 ecm of water, 30 ecm of ethanol and finally 30 ecm of ether. It is dried under reduced pressure (0.2 mmHg; 0.027 kPa) at 20 ⁰ C. are thus obtained 1.4 g of 7- [2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -2- carboxy-8-oxo-3-ε (2-pyrimidinyl) -2-thiovinyl] -5-thia-1-aza-bicyclo ε 4.2.Oj oct-2-ene (syn isomer, Ε-form) in the form of a beige powder.

Infrared spectrum (KBr), characteristic bands (cm) 3320, 3200, 3100-2100, 1770, 1665, 1560, 1550, 1040, 945, 770, 750.

NMR ProtoneηSpektrum

(350 MHz, DMSO d _β , cfm ppm, 3 in Hz) 3.72 and '3.90 (2d, 0 = 18, 2H, -SCH ₂ - in 4); 3.86 (s, 3H, = NOCH ₃ ) 5.20, (d, 0 = 4, IH, -H in Figure 6); 5.77 (dd, 0 = 4 and 9, IH, -H in Figure 7); 6.74 (s, IH, -H of the thiazole ring); 7, 12 and 7.46 (2d, 0 = 16, 2H, transvinyl protons); 7.14 (s, 2H, -NH ₂ on the thiazole ring); 7.27 (broad, IH, -H at the 5-position of the pyrimidine ring); 8.66 (d, 0 = 5, 2H, -H at the 4- and 6-positions of the pyrimidine ring); 9.60 (d, 0 = 9, IH, -CONH-).

29.9.1980 AP C 07 D / 221 271 22127 1 -JsSS- 57 466/11

To a solution of 4.9 g of 2-benzhydryloxycarbonyl-7-l-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido- 1 -8-oxo-3- (2-tosyloxy-vinyl) -5-thia- l-aza-bicyclo £ 4.2.Oj oct-2-ene, syn isomer, Ε-shape, in 40 cc of dimethylformamide 0.738 g added successively at 22 ⁰ C under a nitrogen atmosphere and with stirring 3-mercapto-6-methyl- l-oxide pyridazine and 0.89 ecm Ν, Ν-diisopropylethylamine. The mixture is stirred for 15 minutes at 25 ⁰ C, diluted with 600 ecm of ethyl acetate, washed successively with two times 200 ecm of water, 120 ecm of 0.1 N hydrochloric acid, twice 120 ecm of a 2 / oigen sodium bicarbonate solution and twice 120 ecm of a half-saturated Nat , dried over sodium sulfate, filtered and concentrated at 20 C under reduced pressure (20 mrnHg, 26.6 mbar) to dryness. The residue is taken up in 10 ecm of ethyl acetate and the solution becomes. of a column of 50 g of silica gel Merck (0.05-0.2) (diameter of column 2.4 cm). It is eluted with 500 ecm of ethyl acetate to give, in succession, a colorless fraction 1 of 100 ecm, a pale yellow fraction 2 of 20 ecm and a fraction 3 of 360 ecm. This latter is concentrated at 20 C under reduced pressure (20 mmHg, 26.6 mbar). This gives 4 g of 2-ßenzhydryloxycarbonyl-7 - / * 2-methoxyimino-2- (2-tr

-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form in the form of a brown-orange meringue.

Infrared spectrum (KBr), characteristic bands (cm) 3400, 1780, 1720, 1680, 1530, 1495, 1450, 1330, 1210, 1050, 1040, 1000, 945, 810, 755, 700

29.9.1980 AP C 07 D / 221 Λ £ I L - £ θ € -β - 57 466/11

NMR proton spectrum

(350 MHz ₁ CDCl ₃ , S in ppm, 0 in Hz)

2.45 (s, 3H, -CH ₃ ); 3.62 and 3.77 (2d, Ό = 18, 2H, 4.09 (s, 3H, -OCH _3), 5.08 (d, 0 = 4, IH, H in 6); 5.93 ( dd, O = 4 and 9, IH, H in 7); 6, .03 (s, IH, (C ₆ H ₅ J

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(s, IH, H of the thiazole); 6.95 (s, IH, -COOCH-).

A solution of 3.9 g of 2-benzhydryloxycarbonyl-7-ε-2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido-7-3-ε (6-methyl-1-oxide) is stirred for 30 minutes. 3-pyridazinyl) -2-thiovinyl] -S-oxo-S-thia-1-aza-bicyclo Γ4.2.0> oct-2-ene, syn isomer, Ε-form, in a mixture of 60 ecm formic acid and 25 cc distilled water at a temperature of 50 ⁰ C. it is filtered, the to about 20 ⁰ C cooled mixture and the filtrate concentrated at 30 C under reduced pressure (0.05 mmHg; 0.0665 mbar) to dryness. The residue is taken up in 50 cc of ethanol, concentrated at 20 ⁰ C under reduced pressure (20 mmHg; 26.6 mbar) to dryness, and repeated this operation twice. The solid residue is refluxed with 40.ecm ethanol for 5 minutes and brought to about 20 ° C. cooled suspension is filtered. After drying, 1.96 g of 7- / T2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido3-2-carboxy-3-r (6-methyl-1-oxide-3-pyridazinyl) are obtained. thiovinyl3-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3420, 3320, 3230, 1765, 1675, 1655, 1620, 1535, 1325, 1210, 1040, 1000, 810

NMR proton spectrum

(350 MHz, DMSO dg, / in ppm, 3 in Hz) 2.33 (s, 3H, -CH ₃ ); 3.70 and 3.97 (2d, 3 = 18, 2H, -SCH -); 3.86 (s, 3H, -OCH ₃ ); 5.23 (d, 0 = 4, IH, H in 6); 5.81 (dd, 0 = 4 and 9, IH, H in 7); 6.76 (s, IH, H of the thiazole); 7.18 to 7.20 (Mass, 5H, -CH = CH- and -NH ⁺ ); 7,31 and

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7.86 (2d, 0 = 7, H of pyridazine); 9.62 (d, 0 = 9, IH, -CONH-).

The S-mercapto-δ-methyl-1-oxide-pyridazine is prepared according to BE-PS 787 635.

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Example 9

A solution of 5 g of 2-benzhydryloxycarbonyl-7-7 * 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-8-OXO-5-oxide-3- (2-tosyloxyvinyl) ~ 5-thia -l-aza-bicyclo Γ4.2.0} oct-2-ene, syn isomer , Ε-form, and 1.05 g of 6-acetamido-3-mercapto-pyridazine in 50 ecm of dry N, N-dimethylformamide is charged with 1 , 1 ecm Ν, Ν-diisopropylethylamine and heated for 1 h 40 min. To 60 β . The reaction mixture is diluted with 300 eq of ethyl acetate, washed three times with 200 eq of distilled water and with 250 ecm of a saturated sodium chloride solution. After drying over magnesium sulfate, the organic phase is concentrated under reduced pressure (30 ipmHg, 39.9 mbar) at 40 ° C and the residue is chromatographed on a column of silica gel (0.06-0.04) (diameter of the column 5 cm ), eluting under a pressure of 50 kPa with a mixture of cyclohexane and ethyl acetate (25-75 vol.), We obtain fractions of about 100 ecm. Fractions 10-22 containing the pure product are concentrated under reduced pressure (30 mmHg, 39.9 mbar) at 40 ° C. 2.2 g of 3- (6-acetamido-3-pyridazinyl) -2-thiovinyl J-2-benzhydryloxycarbonyl-7-P * 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) are obtained. acetamidoJ-8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.2]] octo-2-yne syn isomer, Ε-form, in the form of a brown meringue.

RF = 0.48, chromatography on silica gel plate; Eluent: cyclohexane / ethyl acetate (20-80 vol.).

Infrared spectrum (CHBr,), characteristic bands (cm ") 3380, 3220, 1785, 1715, 1700, 1680, 1450, 1370, 1040, 935, 750

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NMR proton spectrum

(350 MHz, CDCl ₃ , iTin ppm, 0 in Hz) '

2.05 (s, 3H, CH ₃ CONH-); 3.26 and 4.8 (2d, Ö = 18, 2H, -S (O) CH ₂ -) 4.08 (s, 3H, = NOCH ₃ ); 4.62 (d, 0 = 4, IH, H in 6); 6.12 (dd,

• 29.9.1980 AP C 07 D / 221 ^; 2 2 -1 2 7 1- - ί © 8 ~. ⁵⁷ 466/11

D = 4 and 9, IH, H in 7); 6.75 (s, IH ₁ H of the thiazole); 7.0 (s, IH ₁ -CH (C ₅ H ₅ I ₂ ; 7.09 (s, IH, (C ^ H ^ CNH-); 7.18 (d, α = 4, IH, H in 5 Position of pyridazine); 7,12 (d,

0 = 16, IH, -CH _- = CH-S-); 7.25 - 7.5 (mt, aromatic + -CH = CHS- + H in the 4-position of the pyridazine); 8.30 (d, 0 = 9, IH, -CONhI-); 9.50 (s, IH, CH CONH-).

A solution of 2.2 g of 3-β (6-acetamido-3-pyridazinyl) -2-thio vinyl) -2-benzhydyloxycarbonyl-7- / T2-metoxy in ino-2- (2-t ritylarnino -4-thiazolyl) -acetamido-J-8-oxo-5-oxide-5-thia-1-aza-bicyclo ¢ 4.2 _e 0j oct-2-ene, syn isomer, Ε-form, in 12 ecm of methylene chloride containing 0 , 47 cc of N, N-dimethylacetamide, v; ith cooled to -10 ⁰ C and treated with 0.23 cc of phosphorus trichloride. The reaction mixture is stirred for 2 h at about -10 ⁰ C. One adds still 0.47 ecm N, N-dimethylacetamide and 0.23 ecm phosphorus trichloride and stirred for 1 h at about -10 ⁰ C, followed by dilution with 150 ecm of saturated sodium bicarbonate solution and 150 ecm of ethyl acetate.

The aqueous phase is extracted with 100 ecm of ethyl acetate. The combined organic extracts are washed twice with 50 ecm of saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated to dryness under reduced pressure (30 mmHg, 39.9 mbar) at 40 ° C, and the residue is chromatographed on a column of silica gel (0.04-0.06) (diameter of the column 4 cm), under Elute with 1.5 L of a mixture of cyclohexane and ethyl acetate (40-60 vol.) Under a pressure of 40 kPa. One gains fractions of about 100 ecm. Fractions 3-10 containing the pure product are concentrated to dryness under reduced pressure (30 mm Hg, 39.9 mbar) at 40 ° C. You get

1 g of 3- (6-acetamido-3-pyridazinyl) -2-thiovinyl-2-benzo

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hydryloxycarbonyl-7- (2-methoxyimino) -2- (2-t-ritylamino-4-thiazolyl) -acetamido-1-oxo-S-thia-1-aza-bicyclo ζ A. 2.0J oct-2-ene, syn Isomer, Ε-form, in the form of a yellow meringue.

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RF = 0.58; Silica gel chromatography plate; Eluent cyclohexane / ethyl acetate (30-70 vol.).

Infrared spectrum (CHBr,), characteristic bands (cm) 3400, 3360, 2820, 1780, 1715, 1705, 1680, 1580, 1510, 1490, 1445, 1400, 1040, 940, 840, 755

Dissolve 1 g of 3- (6-acetamido-3-pyridazinyl) -2-thiovinyl-3-2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-t-ritylamino-1,3-thiazol-4-yl) - acetamidoj-8-oxo-5-thia-1-aza-bicyclo Z "4.2.oJ oct-2-ene, syn isomer, Ε-form, in 23.5 ecm formic acid and 9 ecm distilled water and finally heated for 25 minutes to 50 ^° C. The precipitate is filtered and the filtrate is concentrated under reduced pressure (10 mm Hg, 13.3 mbar) at 40 ° C. The residue is triturated in 50 ecm of ethanol, which is concentrated under reduced pressure (30 mmHg; , 9 mbar) at 40 ° C. This operation is repeated and the residue is taken up in 50 ml of ethanol, and the insoluble portion is filtered off and washed with 30 ml of ethyl ether, giving 0.51 g of 3- (6-acetamido 3-pyridazinyl) -2-thiovinyl] -7- [2 - (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -carboxy-S-oxo-5-thia-1-azabicyclo [4.2.2 oct-2-ene, syn isomer, Ε-form in the form of a cream-colored solid.

- 1 infrared spectrum (KBr) characteristic bands (cm) 3300, 1760, 1660, 1550, 1510, 1035, 940

NMR proton spectrum

(350 MHz, DMSO d _& J "in ppm, Ό in Hz)

2.10 (s, 3H, CH ₃ CONH-); 3.72 and 3.98 (AB, D = 17, 2H, -SChI ₂ -); 3.86 (s, 3H, = NOCH ₃ ); 5.2 (d, 0 = 4, IH, H in 6);

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• 5.78 (dd, 0 = 4 and 9, IH, H in 7); 6.76 (s, IH, H of the thiazole); 7.20 (s, 2H, -NH ₂ ); 7.19 (d, O = 10, IH, -CH ₁ = CH-S-); 7.33 (d, O = 10, - 1H ₁ -CH = CH-S-); 7.78 (d, 0 = 9, IH, H at the 5-position on the pyridazine), 8, 12 (s, IH, CH, CONIH-); 9.65 (d, 0 = 9, IH, -CONH-); 8.27 (d, 0 = 9, IH, H in the 4-position on the pyridazine); 11.1 (s wide, IH, -CO _? H),

 29.9.1980 AP C 07 D / 221 221 27 Ii-EEO-- 57 466/11

The 3-acetamido-6-mercapto-pyridazine can be prepared according to the method of

M. Kumagai and M. Bando, Nippon Kagaku Zasshi 84, 995 (1963),

Example 10

To a solution of 4 g of 2-benzhydryloxycarbonyl-7- (2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-0X0-5-oxide-3- (2-tosyloxyvinyl) -5- thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene, syn isomer, Ε form, in 40 cm dry Ν, Ν-dimethylformamide is added 0.7 g of 5,6 ~ dioxo-4-methyl- 3-thioxo-l, 2,4-perhydrotriazine and 0.77 ecm Ν, Ν-diisopropylethylamine. The reaction mixture is heated to 60 C for 90 minutes and then diluted with 200 ecm of ethyl acetate and washed four times with 100 eq of distilled water. After drying over magnesium sulphate, filtration and evaporation under reduced pressure (30 mmHg, 39.9 mbar) to dryness at 40 ° C., the residue is chromatographed on silica gel Merck (0.04-0.06) (diameter of the column 4 cm), eluting with 3 L of ethyl acetate under 50 kPa and collecting fractions of 100 ecm. Fractions 11-29 are concentrated under reduced pressure (30 mmHg, 39.9 mbar) at 40 ° C. 2.8 g of 2-benzhydryloxycarbonyl-3- (5,6-dioxo-4-methyl-1, 4,5,6-tetrahydro-1, 2,4-t-riazin-3-yl) -2 are obtained -thiovinyl-3-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-S-oxo-S-oxide-S-thia-1-aza-bicyclo / 44.2.Oj oct-2-ene , syn-isomer, E-Fornu

- 1 infrared spectrum (CHßr _v), characteristic bands (cm) 3360, 3200, 2820, 1795, 1710, 1680, 1590, 1515, 1490, 1450, 1040, 760th

29.9.1980, AP C 07 D / 221 271

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NMR proton spectrum

(350 MHz, CDCl _3, if in ppm, D in Hz)

3.30 (s, 3H, -CH triazine); 3.30 and 4.0 (AB, O = 18, -S (O) CH ₂ -); 3.88 (s, 3H, = NOCH ₃ ); 4.65 (d, 0 = 4, IH, H in Figure 6); 6.02 (dd, 0 = 4 and 9, IH ₁ H in 7); 6.32 (d, 0 = 16, IH, -CIH = CH-S-); 6.68 (s, IH, H of the thiazole); 6.92 (s, IH, -CH (CH) ₂ ) 7.15 - 7.55 (massive, aromatic +

-CONH- + (C ^ hL) ₇ CMH- + -CH = CHS-)

^v 6 5 3 -

To a cooled to -30 ⁰ C solution of 2.8 g of 2-Benzhydryloxycarbonyl-3- £ (5,6-dioxo-4-methyl-l, 4,5,6-tet rahydro-1,2,4-triazine 3-yl) ~ 2-thiovinyl] -7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidoj-8-oxo-5-oxide-5-thia-1-aza-bicyclo C 4.2 .0] oct-2-ene, syn isomer, Ε-form, in 30 ecm of methylene chloride and 1.1 ecm of N, N-dimethylacetamide add 0.53 ecm of phosphorus trichloride and the reaction mixture is stirred for 2 h at -15 to -10 ⁰ C and then diluted with 250 ecm of ethyl acetate. It is washed twice with 100 eq of saturated sodium bicarbonate solution and then with 250 ecm of a saturated sodium chloride solution, dried over magnesium sulphate, filtered and the solvent is evaporated off under reduced pressure (30 mmHg, 39.9 mbar) at 40 ° C. The residue is dissolved in 120 g of silica gel ( 0.04-0.06) (diameter of the column 4 cm, height 20 cm), eluting with 2 l of a mixture of cyclohexane and ethyl acetate (20-80 vol.) Under a pressure of 50 kPa and fractions of 100 ecm collects. Fractions 4-16 are under reduced pressure (30 mml-lg; 39.9 mbar) concentrated at 40 ⁰ C. This gives 1.75 g of 2-Benzhydryloxycarbonyl-3- [{ 5,6-dioxo-4-methyl-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl ] -7- £ 2-methoxyimino-2 ~ (2 "tritylamino-4-thiazolyl) acetamido] -8-oxo-5-thia-

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1-aza-bicyclo £ 4.2.0j oct-2-ene, syn isomer, Ε-form, in the form of a cream colored solid.

Infrared spectrum (CHBr,), characteristic bands (cm) 3380, 1785, 1710, 1680, 1515, 1490, 1445, 1040, 940, 755, 740

29.9.1980 AP C 07 D / 221 2 2 1 27 Vi - " ⁴ ^ ² - 57 466/11

NMR proton spectrum

(350 MHz, CDCl, cTin ppm, D. and Hz) 3.41 (s, 3H, -CH triazine); 3.58 and 3.68 (AB, Cl = 18, 2H, -SCH ₂ -); 4.04 (s, 3H, = NOCH ₃ ); 5.10 (d, D = 4, IH, H in Figure 6); 5.95 (dd, G = 4 and 9, IH, H in Figure 7); 6.74 (s, IH, H of the thiazole); 6.84 (d, D = 17, IH, -CH = CH-S-); 6.96 (s, IH, -CH (C ₅ H ₅ ) ₂ ); 7.03 (d, 0 = 9, IH, -COMH-); 7.15 - 7.55 (solid, aromatic + (CH ₅ J ₃ CNH- + -CH = ChIS-); 10.8 (s, IH, -NH-triazine).

1.7 g of 2-benzhydryloxycarbonyl-3- / (5,6-dioxo-4-methyll, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl] - 7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoj-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, E-form , Are dissolved in 24 ecm of formic acid, after addition of 16 ecm of distilled water, the reaction mixture is heated for 25 minutes at 50 ⁰ C and then filtered while warm and evaporated under reduced pressure (10 mmHg, 13.3 mbar) at 40 C to dryness . the solid is triturated with 40 cc of ethanol, and is brought under reduced pressure (30 mmHg; 39.9 mbar). at 40 ⁰ C to dryness This operation is repeated once and then takes care of the obtained residue in 30 cc of ethanol the. insoluble product is separated by filtration, washed with 10 cc of ethanol and twice 50 cc of ether and concentrated under reduced pressure (10 mmHg; 13.3 mbar) at 25 ⁰ C to give 0.85 g of 7- / 2- (2. amino-4-thiazolyl) -2-methoxyiminoacetamidoJ ~ 2 -carboxy-3- (5,6-dioxo-4-methyl-1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl) -2-thiovinyl-J-8-oxo-5 -thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene, syn isomer, Ε-form, in the form of a cream-colored solid.

29.9.1980 AP C 07 D / 221 12 7 1 - JSSa - 57 466/11

Rf = 0.37; Silica gel chromatography plate; Eluent ethyl acetate-water-acetic acid (3-2-2 vol.).

Infrared spectrum (KBr), characteristic bands (cm) 3300, 3260, 2600, 1770, 1705, 1680, 1630, 1585, 1530, 1375, 1040, 950

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NMR Protoneηspektrum

(350 MHz, DMSO _dβ , cf in ppm, δ in Hz) 3.35 (s, 3H, -CH triazine); 3.65 and 3.88 (AB, J = 18, 2H, -SCH ₂ -); 3.87 (s, 3H, = NOCH ₃ ); 5.22 (d, D-4, IH, H in Figure 6); 5.80 (dd, 3 = 4 and 9, IH, H in 7)); 6.75 (s, IH, H of the thiazole); 6.83 (d, u = 16, -CH = CH-S-); 7.11 (d, O = 16, IH, -ChI = CH-S-); 7.20 (s wide, 3H, -NH ₃ ⁺ ); 9.58 (d, 0 = 9, IH, -CONH-),

The 5,6 ~ dioxo ~ 4-methyl-3-thioxo-l, 2,4-perhydrotriazine can be prepared according to M. Pesson and M. Antoine: Bull. Soc. Chim. Fr. 1590 (1970).

Example 11

The mixture is stirred for 2 h at 60 ⁰ C and under nitrogen a mixture of 7.02 g of 2-Benzhydryloxycarbonyl-7 ~ / 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5-oxide -3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn-isomer, E-form, 50cmole dimethylformamide, 1.34cmole diisopropylethylamine and 1.33g 5,6-dioxo-4-ethyl-3-thioxo-l, 2,4-perhydrotriazine. The cooled mixture is diluted with 600 eq of ethyl acetate, and the organic phase is washed with twice 125 eq. Of water, 150 ecm of 0.5 N hydrochloric acid, twice 125 eq of a half-saturated sodium bicarbonate solution and twice 125 eq. Of water, saturated with sodium chloride. dried over magnesium sulfate and concentrated to dryness at 30 C under reduced pressure (20 mmHg, 25.6 mbar). The residue is dissolved in 150 ml of ethyl acetate and the solution is chromatographed on a column of silica gel Merck (0.04-0.06) (column diameter 7 cm). It is eluted with 3 l of ethyl acetate under a pressure of 40 kPa and gains fractions of 100 ecm. Fractions 10-23 are concentrated at 20 ^° C. under reduced pressure (20 mm Hg, 26.6 mbar). You will gain 5.3 g

29.9.1980 AP C 07 D / 221 271 2212 7 1 -304-. 57 466/11

2-Benzhydryloxycarbonyl-3-ol ( 5,6-dioxo-4-ethyl-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl-JF-7-f2-methoxyimino -2- (2-tritylamino-4-thiazolyl) -acetarnido J-8-oxo-5-oxide-5-thia-1-aza-bicyclo f4.2.0j 'oct-2-ene, syn-isome "~ it, Ε shape, in the form of a light brown solid.

- 1 infrared spectrum (KBr), characteristic bands (cm) 3500, 2000, 1785, 1710, 1685, 1520, 1495, 1450, 1040, 945, 755, 700 '. ". '

NMR proton spectrum

(350 MHz, CDCl ₃ , (f in ppm, 0 in Hz)

1.27 (t, 0 = 7, 3H, -CH ₃ ); 3.40 and 4.12 (2d, 0 = 18, 2H, -SCH ₂ -); 3.86 (q, 0 = 7, 2H, ^ NCH ₂ -); 4.0 (s, 3H, -OCH ₃ ); 4.68, (d, 0 = 4, IH, H in 6); 6.04 (dd, 0 = 4 and 9, IH, H in 7); 6.70 (s, IH, H of the thiazole); 6.85 (d, 0 = 16, -CH = CHS-); 6.97 (s, IH, -COOCH-).

2u of a cooled to -14 ⁰ C solution of 5.2 g of 2-Benzhydryloxycarbonyl-3- £ (5,6-dioxo-4-ethyl-l, 4,5,6-tetrahydro-l, 2,4-triazine 3-yl) -2-thiovinyl3-7-C2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-oxo-5-thia-1-azabicyclo £ 4.2. 0j-oct-2-ene, syn isomer, Ε-form, in 100 ecm of methylene chloride is added successively 1.95 ecm of dimethylacetamide and 1 ecm of phosphorus trichloride. The mixture is stirred for 1 h 20 min. At a temperature of about -12 C and then added again 0.5 ecm phosphorus trichloride and stirred again at -12 C for 15 minutes, the mixture is diluted with 600 ecm of ethyl acetate and twice with 250 ecm of a 2 % sodium bicarbonate solution and twice 250 ecm of a half-saturated sodium chloride solution. The organic phase is dried over sodium sulphate, filtered and reduced in vacuo.

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gertem pressure (20 mmHg, 26.6 mbar) at 20 C concentrated to dryness. The residual oil is purified by chromatography on a column of 100 g of silica gel Merck (0.05-0.2) (column diameter 4.5 cm), the product being previously fixed to 25 g of silica gel, eluting with 500 ecm

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Ethyl acetate, yielding fractions of 50 ecm. The fractions 5-9 are concentrated at 20 ° C. under reduced pressure (20 mmHg, 26.6 mbar), and 5.3 g of 2-benzhydryloxycarbonyl-3- (5,6-dioxo-4-ethyl-1-yl) are obtained , 4,5,6-tetrahydro, 2,4-triazin-3-yl) -2-thiovinyl) -7- £ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido} -8-oxo -5-thia-1-azabicyclo t4.2.0J oct-2-ene, syn isomer, Ε-form, in the form of an orange meringue.

- 1 infrared spectrum (CHBr,), characteristic bands (cm) 3385, 1785, 1710, 1680, 1515, 1490, 1445, 1040, 940, 755, 740

NMR proton spectrum

(350 MHz, CDCl ₃ / ppm in, O in Hz) 1.34 (t, 0 = 7, 3H, -CH _3); 3.60 and 3.70 (2d, O = 18, 2H, -SCH ₂ -) 3.95 (q, O = 7, 2H, ^ NCH ₂ -); 4.05 (s, 3H, -OCH ₃ ); ,,, 5.12, (d, 0 = 4, IH, H in 6); 5.94 (dd, 0 = 4 and 9, IH, H in 7); 6.7 "7 (s, IH, H of the thiazole); 6.87 (d, O = 16, IH, -C] H = CHS-); 6.97 (d, 0 = 9, IH, -CONH 6.96 (s, IH, -COOCH-); 8.20 (s, IH, = NNH CO- or = NN = C-).

OH.

Dissolve 3 g of 2-benzhydryloxycarbonyl-3-one (5,6-dioxo-4-ethylthyl, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl] -7- £ 2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido} -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn-isomer, E Form, in 30 ecm of formic acid, diluted with 14 ecm of water and heated with stirring for 30 minutes at 50 ° C. The mixture, cooled to 20 ° C., is filtered and the filtrate is removed under reduced pressure (0.05 mmHg, 0.0665 mbar ) concentrated at 30 ⁰ C to dryness. Take the solid in 100 ecm

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Ethanol, concentrated to dryness at 20 C under reduced pressure (20 mmHg, 26.6 mbar); this operation is repeated three times and the solid is treated at 60 C with 500 eq of ethanol. After removal of a slight proportion of insoluble product, concentrating the solution to 40 cc (at 30 ⁰ C and 20 mmHg; 26.6 mbar) and cooled to +4 C. After filtering and drying

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of the insoluble product, one obtains 1.49 g of 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-carboxy-3-r (5,6-dioxo-4-ethyl-1,4, 5,6-tetrahydro-1,2,4-triazin-3-yl) -2-thiovinyl-S-oxo-5-thia-1-aza-bicyclo [4.2.2O] oct-2-ene, syn isomer, e-form.

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2200, 1770, 1700, 1680, 1530, 1040, 940

NMR proton spectrum

(350 MHz, DMSO d, <f in ppm, 0 in Hz) 1.22 (t, 0 = 7, 3H, -CH ₃ ); 3.65 and 3.80 (2d, D = 18, 2H, -SCH ₂ -); 3.80 (q, 0 = 7, 2H,> NCH ₂ -); 3.86 (s, 3H, -OCH ₃ ); 5.20, (d, 0 = 4, IH, H in 6); 5.78 (dd, 0 = 4 and 9, IH, H in 7); 6.75 (s, IH, H of the thiazole); 6.95 (d, 0 = 16, IH, -ChI = CHS-); 7.13 (d, D = 16, IH, = CHS-); 7.18 (s, 3H, -NH ₃ ⁺ ); 9.63 (d, 0 = 9, IH, -CONH-).

The 5,6-dioxo-4-ethyl-3-thioxo-l, 2,4-perhydrotriazine can be prepared by the method described in Belgian Pat. No. 830,455.

Example 12

The mixture is stirred at 60 C under nitrogen for 1 h 40 min. A mixture of 9.79 g of 2-Benzhydryloxycarbonyl ~ 7- £ 2-methoxyimino-2- (2-t ritylamino-4-thiazolyl) -acetamido] -8 -oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo ZT4.2 "-Octr-2-ene, syn-isomer, E-form, 50» cm dimethylformamide, 2.28 g 5,6-dioxo-4-isopropyl-3-thioxo-l, 2,4-perhydrotriazine and 2,12 ecm Ν, Ν-diisopropylethylamine. The mixture is diluted with 600 eq of ethyl acetate, washed with twice 150 eq of water, 100 ecm of 1 η-hydrochloric acid, twice 150 ecm of a solution of 2% sodium bicarbonate and twice 150 ecm of a saturated semi-saturated sodium carbonate.

29.9.1980 AP C 07 D / 221 271 2 12 7 1 - Ü? - 57 46.6 / 11

chloride solution, dried over sodium sulfate, filtered and concentrated at 20 C under 20 mmHg, f26.6 mbar) to dryness. The purification is carried out by chromatography on a column of 300 g of silica gel Merck (0.05-0.2) (column diameter 5 cm). It is eluted with 15 1 of a mixture of cyclohexane-ethyl acetate (40-60 vol.), In which one obtains fractions of 1 1. Fractions 9-14 are concentrated at 20 C under 20 mml-Ig (26.6 mbar). You win

7.4 g of 2-benzhydryloxycarbonyl-3- C { 5,5-dioxo-4-isopropyl, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl] -7- / 2 -methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido ^ / - 8-oxo-5-oxide-5-thia-1-aza-bicyclo-4,2,0J oct-2-ene, syn- Isomer, Ε-form, in the form of a yellow-orange meringue.

NMR proton spectrum

(350 MHz, DMSO dg, <f in ppm, 0 in Hz) 1.45 (d, 0 = 7, 6H, -CH (ChI ₃ J ₂ ); 3.68 and 4.29 (2d, 0 = 19, 2H, -SCH ₂ r); 3.84 (.S ₁ 3H, -OCH ₃ ); 4.35 (mt, IH, -CH (CH ₃ J ₂ ;

5.05 (d, 0 = 4, IH, H in 6); 5.86 (dd, 0 = 4 and 9, IH,

H in 7); 6.78 (s, IH, H of the thiazole); 6.97 (s, IH, -COOCH-); 6.96 (d, 0 = 16, IH, -CH _- = CHS-); 7.11 (d, 0 = 16, IH, = CHS ~); 8.74 (s, IH, -NH-C (C ₆ H ₅ ) ₃ ); 9.05 (d, 0 = 9, IH, -CONH-); 12.53 (s, IH, = NNH-CO- or = NN = C ~) _#

OH

A solution of 7.3 g of 2α-benzhydryloxycarbonyl-3-one (5,6-dioxo-4-isopropyl-1,4,5,5-tetrahydroxy) is stirred at -10 ° C with stirring and for 1 h 30 min. 1,2,4-triazin-3-yl) -2-thiovinyl-7-j2-methoxyimino-2- (2-1-ritylamino-4-thiazolyl) -acetamido-S-oxo-S-oxide-S-thia- l-aza-bicyclo ^ 4.2.Oj oct-2-0n, syn isomer, Ε form, and 2.73 ecm dimethylacetamide in 100 ecm methylene chloride with 1.25 ecm phosphorus trichloride. Dilute the mixture with 600 ecm of ethyl acetate, wash

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with twice 150 eq of a solution of 2% sodium bicarbonate and twice 150 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness at 20 g under reduced pressure (20 mmol / l, 26.6 mmol). The residue is fixed to 50 g of silica gel Merck (0.05-0.2), and the powder

09/29/1980

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is applied to a column of 200 g of silica gel (diameter of column 4 cm). It is eluted with a mixture of ethyl acetate-cyclohexane (80-20 vol.) To give fractions of 200 ecm. Fractions 3 and 4 are concentrated to dryness at 20 ^° C. under a pressure of 20 mmHg (26.6 mbar) and 5.3 g of 2-benzhydryloxycarbonyl-3 - / * (5,6-a'ioxo) are obtained. 4-isopropyl-l, 4.5 _{l of} 6-tetra-2-hydoryl, 2,4-t-riazin-3-yl) -2-thiovinyl-1-yl-2-methoxyimi-n-2- (2-tritylamino-4 -thiazolyl) -acetamido-.8-oxo-5-thia-1-azabicyclo L4. 2.Oj oct-2-en, syn-Isorneres, Ε-form, in the form of a yellow-orange meringue.

Infrared spectrum (CHBr ^), characteristic bands (cm) 3400, 1790, 17, 20, 1685, 1520, 1495, 1450, 1045, 945, 760, 740

NMR protonon spectrum.

(350 MHz, DMSO dg, S in ppm, 0 in Hz-) ^ _{λ t} ^? 1.46 (d, 0 = 7, 6H, -CH (CH ₃ ) ₂ ); 3.64 and 3.84 (2d, D = 18 ", 2H, -SCH ₂ -); 3.82 (s, 3H, -OCH ₃ ); 4.36 (mt, IH, -CH (CH ₃ J ₂ ) 5.24 (d, 0 = 4, IH, H in 6); 5.76 (dd, D = 4 and 9, IH, H in 7); 6.72 (s, IH, H of thiazole 6,94 (d, D- 16, IH, -CH = CHS-); 6,94 (s, IH, -COOCH ^); 7,0 (d, 3 = 16, IH, = CHS-) ; 8.78 (s, IH, -NHC (CgH ₅ J ₃ ); 9.58 (d, D = 9, IH, -CONH -); 12.53 (s, IH, = NNHCO- or = NN = C-).

OH

5.25 g of 2-ßenzehydryloxycarbonyl-3-f (5,6-dioxo-4-isopropyl-1, 4, 5, 6-tetrahydro-1,2,4-triazin-3-yl) -2-thiovinyl are dissolved -7-t2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidol-S-oxo-S-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn isomer, E F'orm, in 50 ecm of formic acid, diluted with 20 ecm of water and heated with stirring for 30 minutes

09/29/1980

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at 50 ⁰ C. After cooling to about 20 C, the mixture is filtered and the solution is stirred at 30 C under reduced pressure (0.05 mmHg; 0.0665 mbar) concentrated to dryness. The residue is taken up in 25 ecm of ethanol, the solvent is sold at 20 C under a

09/29/1980

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Pressure of 20 mmHg (26/6 mbar) and repeats this procedure three times. The solid is refluxed with 600 'ecm' of ethanol, filtered and concentrated to 50 ecm at 20 ° C under 20 mmHg (26.6 mbar). After filtering and drying the insoluble product, 2 g of 7-f 2 - (2-amino-4-thiazolyl) -2-methoxyimino-acetamido 3-2-carboxy-3- l { 5,6-dioxo-4-isopropyl -l, ^{4,5,6-tetrahydro-1,2,4-triazin-j} 3-yl) ~ 2 ~ thiovinyl] -8-oxo-5 ~ thia-l-aza-bicyclo (4, 2,0] oct-2-ene, syn isomer, Ε-form, in the form of a yellow powder,

Infrared spectrum, characteristic bands (cm ") (KBr) 3500, 2200, 1775, 1705, 1680, 1530, 1050, 950

NMR proton spectrum

(350 MHz, DMSO d, S in ppm, 0 in Hz) 1.48 (d, 3 = 7, 6H, -CH (CH ₃ ) ₂ ); 3.64 and 3.82 (2d, D = 18,

2H, -SCH ₂ -); 3.85 (s, 3H, -OCH ₃ ); 4.42 (mt, IH, -CH (CH ₃ J ₂ );

5.22 (d, D = 4, IH, H in Figure 6); 5.78 (dd, 0 = 4 and 9, IH, H in 7); 6.74 (s, IH, H of the thiazole); 6.93 (d, J = 16, IH, -CH = CHS-); 7.07 (d, D = 16, IH, = CHS-); 7,18 (s, 3H,

-NH ₃ ⁺ ); 9.62 (d, 0 = 9, IH, -CONH-); 12.55 (s, IH, = NNHCO

or = N-N = C-OH).

The 5,6-dioxo-4-isopropyl-3-thioxo-l, 2,4 ~ perhydrotriazine can be prepared by the method described in BE-PS 830 455.

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2 2 1 ^ '* ^! - ^ ² ® - ⁵⁷

Example 13

The mixture is stirred for 80 minutes at 60 ⁰ C under nitrogen, a solution of 5.8 g of 2 ~ 7 ~ £ benzhydryloxycarbonyl-2-methoxyimino-2 ~ (2 ~ t ritylamino-4-thiazolyl) -acetamidoJ-8-OXO-5- Oxide-3- (2 "tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, E form, 58 ecm dimethylformamide, 1.3 g 4- (2 -Methoxyethyl) -5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine and 0.819 mg diisopropylethylamine The mixture, cooled to about 20 ° C., is diluted with 300 eq of ethyl acetate, the organic phase is extracted four times with a total of 100 eq of water dried, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg, 26.6 mbar) at 20 ° C. The residue dissolved in 250 ecm of ethyl acetate is filtered on a column of 32 g of silica gel and eluted with 500 ecm of ethyl acetate. The eluate is evaporated to dryness under reduced pressure (20 mmHg, 26.6 mbar) at 20 ° C. This gives 5.4 g of benzhydryloxycarbonyl-3, 5,6-dioxo-4- (2-methoxyethyl) -1-one _f 4,5,6-tetrahyd ro-1, 2,4-triazin-3-ylJ-2-thiovinyl} -7 - / * 2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido] -8-oxo-5-oxide -5-thia-1-aza-bicyclo f4.2.03 oct-2-ene, syn isomer, Ε-form, in the form of a beige solid.

Infrared absorption spectrum (KBr), characteristic bands (cm):

3400, 2830, 1800, 1720, 1690, 1590, 1525, 1495, 1450, 1370, 1210, 1110, 1040, 945, 755, 700

NMR proton spectrum

(350 MHz, CDCl ₃ , (f in ppm, 0 in Hz) 3.32 (s, 3H, -CH ₀ OCH-); 3.60 (t, 0 = 5, 2H, -ChLO-); 4, 05

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(t, 0 = 5, 2H, -CH ₂ N -); 3.34 and 4.1 (dd, D = 18, 2H, -S (O) CH-); 4.00 (s, 3H, = NOCH ₃ ); 4.66 (d, 0 = 4, IH ₁ H, in 6); 6.08 (dd, D = 4 and 9, IH, H in 7); 6.71 (s, IH, H of the thiazole); 6.85 (d, O = 16, IH, -ChI = CHS-); 6.97 (s, IH, -COOCH).

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To a cooled to -10 C solution of 5.3 g of 2-Benzhydryloxycarbonyl-3- {j & - (2-methoxyethyl) -5,6-dioxo-l ₁ 4 _J 5,6-tetrahydro-l, 2,4 ~ t, ria2in-3-yl3-2-thiovinyl-7--2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetarnidone J-8-oxo-5-oxide-5-thia-1-aza-bicyclo £ 4.2, Oj-oct ~ 2-ene, syn-isomer, Ε-form, in 53 ecm of methylene chloride, add 2.06 ecm of dimethylacetamide followed by 0.91 ecm of phosphorus trichloride. The mixture is stirred for 2 h at -10 C and then the solution is diluted in 750 ecm of ethyl acetate, washed twice with 100 ecm of a saturated sodium bicarbonate solution, twice with 100 ecm of a saturated sodium chloride solution, dried over magnesium sulfate, concentrated under reduced pressure (20 mmHg; 26.6 mbar) at 50 cc at 20 ⁰ C and added 200 cc to Isopropylethor. The resulting solid is isolated by filtration, washed with 20 ecm of isopropyl ether and dried. This solid, dissolved in a mixture of ethyl acetate-cyclohexane (70-30 vol.) Is added to a column of silica gel Merck (0.04-0.06) (column diameter 6 cm, Height 20 cm). It is eluted with 1500 ecm of a mixture of ethyl acetate-cyclohexane (70-30 vol.) Under a pressure of 40 kPa, to obtain fractions of 75 ecm. Fractions 9-19 are under reduced pressure (20 mmHg; 26.6 mbar) concentrated at 20 ⁰ C to dryness. This gives 2.9 g of 2-ßenzhydryloxycarbonyl-3- £ f5,6-dioxo-4- (2-methoxyethyl) -1,4,5,6-tetrahydro-l _# 2,4-triazine-3-yl3 2-thiovinyl} ~ 7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-thia-1-azabicyclo [4.2.O] oct-2-ene, syn isomer, Ε-form, in the form of a cream-colored solid.

29.9.1980 AP C 07 D / 221 2 12 7 1 - f ^ gr - 57 466/11

Infrared spectrum (KBr), characteristic bands (cm) 3400, 2820, 1785, 1720, 1690, 1590, 1525, 1495, 1450, 1370, 1210, 1110, 104Q, 945, 755, 705

NMR proton spectrum

(350 MHz, CDCl, J ~ in ppm, D in Hz) 3.34 (s, 3H, -CH ₂ OCh) ₃ ); 3.65 (t, D = 5, 2H, -ChI ₂ O-); 4,11 (t

2-9.9.1980

"_92> AP C 07 D / 221 271 ·

2 21271 - ± 22 - 57 466/11

Ο = 5, 2Η, -CH ₂ N-; ); 3.60 and 3.68 (2d, 0 = 18, 2H, -SCH ₂ -); 4.06 (s, 3H, = NOCH ₃ ); 5.11 (d, 0 = 4, IH, H in 6); 5.95 (dd, 0 = 4 and 9, IH, H in 7); 6.76 (s, IH, H of the thiazole); 6.86 (d, O = 16, IH, -CHI = CHS-); 6.93 (d, 0 = 9, IH, -CONH-); 6.97 (s, IH, -COOCHJ.

Dissolve 2.8 g of 2-benzhydryloxycarbonyl-3- {5,6-dioxo-4- (2-methoxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazine-3-yl3- 2-thiovinyl-7-r2-m-thoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-S-oxo-S-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn Isomer, Ε-form, in 50 cc of formic acid, add 25 eq. Of water and heat to 50 ° C with stirring for 15 minutes. The mixture is diluted with 25 ecm of water, cooled, filtered and washed at 40 ° C under 0.05 mmHg (0 , 0665 mbar) to dryness. The residue is taken up three times with 50 ml of ethanol, each time being evaporated to dryness under reduced pressure (0.05 mmHg, 0.0665 mbar). The residue is taken up in 200 eq of ethanol, filtered through a glass frit in the heat, the residue is again taken up with 100 ecm of ethanol under reflux, filtered while heating, the two filtrates are combined and concentrated to 20 ecm, cooled to 0 C, and the resulting solid is filtered and dried. There are thus obtained 1.45 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido3-2-carboxy-3-O-C, 5,6-dioxo-4- (2-methoxyethyl) - l, 4,5,6-tet _ra _ tetrahydro-1,2,4-triazin-3-YLJ-2-thiovinylj-8-oxo-5-thia-1-azabicyclo £ 4.2.o3 oct-2-ene, syn isomer, Ε-form, in the form of a yellow solid.

Infrared spectrum (KBr), characteristic bands (cm) 3480, 2830, 1775, .1710, 1680, 1535, 1590, 1535, 1380, 1110, 1040, 940

29.9.1980 AP C 07 D / 221 "221271-A- 57 466/11

NMR proton spectrum

(350 MHz, DMSO d, <f in ppm, D in Hz) 3.36 (s, 3H, -CH ₂ OCH ₃ ); 3.56 (t, 3 = 5, 2H, -CH ₂ O-); 4.10 t, Ο = 5, 2H, -CH ₂ N Cl); 3.62 and 3.73 (2d, D = 18, 2H, -SCH ₂ -); 3.96 (s, 3H, = NOCH ₃ ); 5.18 (d, 0 = 4, IH, H in Figure 6); 5.81 (dd,

29.9.1980 ·

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Ο = 4 and 9, IH, H in 7); 6.78 (s, IH, H of the thiazole); 6.87 (d, D = 15, IH, -CH = CH-S-); 7.29 (d, D = 15, IH, -CH = CH-S-); 6.70 (s wide, 3H, -NH ₃ ⁺ ); 9.55 (d, O = 9, IH, -CONH-); 12.64 (s, IH, = N NHCO- or = NN = C-).

OH

The 4 ~ (2-methoxyethyl) -5,6-dioxo-3-thioxo-l, 2,4 ~ perhydrotriazine can be prepared according to BE-PS 830 455.

Example 14 '.

The mixture is stirred for 4 h at 60 ⁰ C, a mixture of 8.03 g of 2-Benzhydryloxycarbony1-7-fe-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnide of J-8-oxo-5-oxide - 3- (2-yloxyvinyl) -5-thia-1-azabicyclo- £ 4.2.0.3 oct-2-ene, syn isomer, E form, 150 ecm dimethylformamide, 2.19 g 5,6-dioxo 4- (2-methylthioethyl) -3-thioxo-1, 2,4-perhydrotriazine and 1.7 ecm of diisopropylethylamine. Pour the mixture into 300 cc of ethyl acetate, washed three times with 200 cc water and 200 cc of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. The product, which was previously fixed to 20 g of silica gel Merck (0.05-0.2), was chromatographed on 200 g of silica gel (diameter of column 3.4 cm, height 40 cm). The following cyclohexane / ethyl acetate mixtures were eluted successively: 40-60 vol.), 500 ecm (30-70 vol.), 500 ecm (20-80 vol.), 500 ecm (10-90 vol.), 500 ecm, and it is quenched with 2 liters of pure ethyl acetate one wins fractions of 120 ecm. The fractions 22-32 are concentrated to dryness to give 5.66 g of 2-benzhydryloxycarbonyl-3- {f5,6-dioxo-4- (2-methylthioethyl) -l, 4,5,6-tetrahydrol, 2,4- triazin-3-ylJ-2-thiovinyl ^ -7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido} -8-oxo-5-oxide-5-thia-1-aza-bicyclo / ! "4.2.0J oct-2-en, syn-Isorneres, Ε-form, in the form of a cream-colored meringue.

29.9.1980 g AP C 07 D / 221

221271, - 12a - 57 466/11

1 Infrared Spectrum (KBr) ₁ characteristic bands (cm) 1795, 1715, 1670, 1525, 1495, 1455, 1040, 945, 755, 700

Is treated at -10 ⁰ C for 30 minutes and with stirring a solution of 5.6 g of 2-benzhydryloxycarbonyl ~ 3 ~ # 5,6 · dioxo ~ 4- (2-methylthioethyl) -l, 4,5,6-tetrahydro .dro ~ l, 2,4-triazin-3-yl-2-thiovinyl] -7-r2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-oxide 5-thia-1-aza-bicyclo / 4,2.Oj oct-2-ene, syn isomer, Ε-form, in a mixture of 53.8 ecm of methylene chloride and 1.99 ecm of dimethylacetamide, with 0.941 ecm of phosphorus trichloride. The mixture is diluted with 200 eq of ethyl acetate, washed successively with 100 ecm of a saturated sodium bicarbonate solution, twice 100 ecm of water and 100 ecm of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under 20 mmHg (2.7 kPa) at 20 ⁰ C to dryness.

The product is fixed to 15 g silica gel Merck (0.05-0.2) and the powder is applied to a column of 100 g silica gel (column diameter 3 cm, height 30 cm). It is eluted with 1.5 1 of a cyclohexane-ethyl acetate mixture (20-80 vol.), Were obtaining fractions of 60 ecm. Fractions 3-18 are at 20 mmHg (2.7 kPa) at 20 ⁰ C to dryness. This gives 4.16 g of 2-ßenzhydryloxycarbonyl-3- £ C5,6 ~ dioxo-4- (2-methylthioethyl) -1, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl] - 2-thiovinyl-7-C2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidol-S-oxo-S-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn isomer , Ε-shape, in the form of a yellow meringue.

29.9.1980 AP C 07 D / 221 22127 1. - £ 25 - 57 466/11

- I Infrared spectrum, characteristic bands (cm) (KBr) 1785, 1715, 1680, 1525, 1490, 1445, 1040, 940, 750, 700

NMR proton spectrum (350 MHz, CDCl ₃ , cTin ppm, D in Hz) 2.18 (s, 3H ₁ -SCH ₃ ); 2.78 (t, 3 = 6, 2H, -CH ₂ S-); 3.58 and 3.67 (d, ö = 18, 2H, -SCH ₂ -); 3.95 - 4.05 (m, 5H, -OCH ₃ and> NCH ₂ -); 5.08 (d, 0 = 4, IH, H in 6); 5.93 (dd, 3 = and 9, IH, H in 7); 6.74 (s, IH, H of the thiazole); 6.82 (d, O = 16, IH, -CH = CHS-); 6.95 (s, IH, -COOCH-); 11.55 (s wide, IH, = NNHCO- or = NN = C-).

OH

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The mixture is stirred for 30 minutes at 50 C, a solution of 4.16 g of 2-Benzhydryloxycarbonyl ~ 3- ££ 5,6-dioxo-4- (2 ~ methylthioethyl) -1, 4,5,6-tetrahydro ~ l, 2,4-t riazin-3-yl] - 2-thiovinyl-7-i2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-1-oxo-S-thia-1-aza bicvclo £ 4.2, Oj oct-2-ene, syn isomer, Ε-form, in a mixture of 40 ecm formic acid and 20 ecm water. The cooled mixture is then filtered and concentrated under reduced pressure (40 C ₁ 20 mm Hg; 2.7 kPa) to dryness.

The residue is taken up in 100 cc of ethanol and concentrated at 20 ⁰ C and 20 mmHg (2.7 kPa) to dryness. Repeating this operation twice, followed by dissolving the solid in 250 cc of boiling ethanol, filtered while hot and the solution is concentrated to 20 cc (20 ⁰ g, 20 mmHg; 2.7 kPa). The precipitate is separated on the filter, dried, and 1.95 g of 7 - / "2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido3-2-carboxy-3-5,5,6- dioxo-4- (2-methyllhioethyl) -l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl} -2-thiovinyl} -8-oxo-5-thia-l-aza- bicyclo £ 4.2.oJ oct-2-ene, syn isomer, E ~ form.

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⁵⁷

- 1 infrared spectrum (KBr) characteristic bands (cm) 3600, 2200, 1770, 1710, 1680, 1585, 1535, 1040, 945

NMR proton spectrum

(350 MHz, DMSO dg, ςΓ in ppm, 0 in Hz) 2,12 (S ₁ 3H, -SCH ₃ ); 2.73 (t, 0 = 7, 2H, -CH ₂ S-CH ₃ ); 3.64 and 3.82 (2d, 3 = 18, 2H, -SCH ₂ -); 3.85 (s, 3H, -OCH ₃ ); 4.0 (t, D = 7, 2H, _> NCH ₂ -); 5.20 (d, 3 = 4, IH, H in 6); 5.78 (dd, D = 4 and 9, IH, H in Figure 7); 6.73 (s, IH, H of the thiazole); 6.92 (d, D = 16, IH, -CI ₁ I = CHS-); 7.12 (d, 3 = 16, IH, = CH_S-); 7.15 (s, 3H, -NH ₃ ⁺ ); 9.66 (d, u = 9, IH, -CONH-); 12.61 (s, 1! V = NNHCO- or = NN = C-).

OH

The 5,6-dioxo-4- (2-methylthioethyl) -3-thioxo-l, 2,4-perhydrotriazine can be prepared in the following manner:

To a solution of 1.83 g of sodium in 80 ecm of methanol is added 13.6 g of 4- (2-methylthioethyl) -thiosemicarbazide and then, dropwise over 15 minutes, 10.8 ecm of diethyl oxalate. The mixture is heated for 3 h under reflux, allowed to cool and added with stirring 1 1 diethyl ether. The precipitate is filtered. The resulting yellow solid is dissolved in 100 ecm of water, the pH of the solution by addition of 1 η-hydrochloric acid to 2, wherein it is cooled in an ice bath.

After filtering and drying, 3 g of a white solid are obtained, which is purified by two successive crystallizations in 50 ml of boiling water. This gives 2.4 g of 5,6-dioxo-4- (2-methylthioethyl) -3-thioxo-1,2,4-perhydrotriazine.

09/29/1930

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2 2 12 7 1 " ^{1: Z; c &} " ^{57 466} Z ¹¹

Infrared spectrum (KBr), characteristic bands (cm) 3550, 349O ₁ 3280, 3220, -1690

The ^ -'- ^ - r-ethylthioethylj-thiosemicarbazide. can be prepared by adding 6.8 ecm of hydrazine hydrate to a solution

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of 26.0 g of methyl ~ N ~ (2-methylthioethyl) -dithiocarbamate in 500 ecm of ethanol and refluxing for 3 hours. After concentration to dryness at 20 C under 20 mmHg (2.7 l <Pa), the resulting oil is triturated in 100 ecm of diethyl ether. The crystals formed are filtered and dried. 18.16 g thiosemicarbazide are obtained, mp = 70 C,

-1 Infrared spectrum (KBr), characteristic bands (cm) 3320, 3200, 3150, 1635, 1550, 1260

Example 15

The mixture is stirred at 60 ⁰ C for 3 hours a mixture of 10.04 g of 2-Benzhydryloxyc _a rbonyl-7-f2 ~ methoxyimino ~ 2 ~ (2 ~ tritylamino-4-thiazolyl) -acetamido3-8-oxo-5-oxide 3 ~ (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo £ 4.2.0} oct-2-ene, syn isomer, E ~ form, 200 ecm dimethylformamide, 2.82 g 4-benzyl ~ 5, 6-dioxo-3-thioxo-l, 2,4-perhydrotriazine and 2.1 ecm of diisopropylethylamine. It is poured into 500 cc of ethyl acetate, washed twice with 250 cc water and twice 200 cc of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. The residue is dissolved in 30 ecm of a mixture of cyclohexane-ethyl acetate (20-80 vol.) And this solution is chromatographed on a column of 200 g silica gel Merck (0.04-0.06) (column diameter 8 cm, height 30 cm). It is eluted with 2 l of a mixture of cyclohexane-ethyl acetate (20 ~ 80 vol.), 2 l of a mixture (10 - 90 vol.) And 2 l of ethyl acetate under a pressure of 40 kPa, to obtain fractions of 100 ecm. The fractions 45-60 are evaporated off at 20 ° C under 20 mmHg (2.7 kPa) and 2.68 g of 2-benzhydryloxycarbonyl-3-one (4-benzyl-5,6-dioxo-1,4,5,6 tetrahydro-i; 2,4-triazin-3-yl) -2-thiovinyl] -7- [2- methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoj-8-oxo-S-oxide S-thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene, syn isomer,

29,9.1980

AP C 07 D / 221 271

12 7 1 " ¹ ^ ⁹ " · ⁵⁷

Ε shape, in the form of a cream-colored meringue.

Infrared spectrum (CHBr,), characteristic bands (cm) 3380, 1800, 1720, 1670, 1520, 1495, 1450, 1045, 940, 755 '

NMR proton power (350 MHz, CDCl ₃ , <f in ppm, 0 in Hz) 3.32 and 4 (2d, D = 18, 2H, -SCH ₂ -); 3.97 (s, 3H, -OCH ₃ ); 4.60 (el, 3 = 4, IH, H in 6); 5.0 (s, 2H, ^ NCH ^.) * * 6.02. (dd, D = 4 and 9, IH, H in 7); 5.70 (s, .lH, .H of the thiazole); 6.80 (d, D = 16, IH, -CH = CHS-); 6.94 (s, IH, -COOCH-); 11.87 (s wide, IH, = N-NHCO- or = NN = C-).

OH

A solution of 2.68 g of 2-benzhydryloxycarbonyl-3 - / (4-benzyl-5,6-dioxo-1, 4,5,6-t-tetrahydro-1,2-dicarboxylic acid) is treated with stirring at -10 ° C. for 30 minutes , 4-triazin-3-yl) -2-thiovinylj-7-f2-methoxyimino-2 ~ (2-tritylamino-4-thiazolyl) -acetamidoJ-S-oxo-S-oxide-S-thia-l-aza- bicyclo £ 4.2.0j oct-2-ene, syn isomer, Ε-form, in a mixture of 25 ecm of methylene chloride and 0.95 ecm of dimethylacetamide, with 0.44 ecm of phosphorus trichloride, diluted with 200 ecm of ethyl acetate, washed with 50 A solution of 5% sodium bicarbonate, 50 ml of water and 50 ml of saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated to dryness at 20 ⁰ C below 20 mmHg (2,7 kPa) g silica gel (0.05-0.2) fixed product is applied to a column of 40 g silica gel (column diameter 1.4 cm, height 15 cm), eluting with one liter of a mixture of cyclohexane-ethyl acetate (20-80 vol .), with fractions of 60 ecm g The fractions 2-13 are at 20 ⁰ C under

29.9.1980 ^{AP c 07} D / 221 271 2 12 7 1 - 12§ = a - 57 466/11

20 mmMg (2.7 kPa) evaporated to dryness. 1.78 g of 2-benzhydryloxycarbonyl> -3-Z ^> (4-benzyl-5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-t riazin-3-yl) are obtained. 2-thiovinyl] -7- £ 2 -methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido] -8-oxo-5-thia * 1-aza-bicyclo [4.2.0] oct-2-ene / syn isomer, Ε-form, in the form of a cream-colored

29.9.1980 £ ₀ £ AP C 07 D / 221

22127 1 - »®- 57 466/11

give a meringue.

1 infrared spectrum (CHBr ₇ ,), characteristic bands (cm) 3390, 1785, 1720, 1680, 1520, 1495, 1450, 1045, 940

NMR proton spectrum

(350 MHz, CDCl ₃ , {fin ppm, 0 in Hz)

3.54 and 3.64 (2d, 0 = 18, 2H ₁ -SCH ₂ -); 4.02 (s, 3H, -OCH ₃ );

5.06 (d, 0 = 4, IH, H in 6); 5.10 (s, 2H,> NCH ₂ -); 5.92 (dd, 0 = 4 and 9, IH, H in 7); 6.74 (s, IH, H of the thiazole); 6.82 (d, 0 = 15, IH, -CfH = CHS-); 6.95 (s, IH ₁ -COOCH-); 7.03 (d, 0 = 9, IH, -CONH-); 11.60 (s, IH, = NNH-CO- or = NN = C-).

OH

The mixture is stirred for 30 minutes at 50.degree. C. a solution of 2-.beta.hydrogen oxycarbony-1-one-year (4-benzyl-5,6-dioxo-1,4,5,6-tetrahydahydrol, 2,4-triazine). 3-yl) -2-thiovinyl-3-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-thia-1-azabicyclo / "4.2.O]) oct. 2-ene, syn isomer, Ε-form ECM in a mixture of formic acid and 8 16 cc of water. filter the cooled solution and concentrated at 50 ⁰ C under 20 mmHg (2.7 kPa) to dryness. It takes the residue in 50 cc of ethanol, evaporated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness, and repeated this operation twice. The yellow solid obtained is treated with 100 cc of ethanol under reflux, removing a small amount of insoluble material by filtration and the solution concentrated to 50 cc (20 ⁰ C, 20 mm -log!;

2.7 kPa). After cooling to 4 ° C. for 3 h, the precipitate is dried, giving 0.79 g of 7- / 2- (2-

09/29/1980

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2 12 7 1 - £ 5öa - 57 466/11

Am in 0-4-thiazolyl) -2-methoxy in ino-ace tarn ± do "] - ZC ( 4-benzyl 1-5,6-0,10X0-1,4,5,6-tetrahydro-1,2,4 -triazin-3-yl) -2-thiovinyl-2-carboxy-8-oxo-5-thia-1-aza-bicyclo / 44.2.Oj oct-2-ene, syn isomer, Ε-form, in the form a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2300, 1770, 1710, 1680, 1585, 1530, 1045, 945

09/29/1980

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2 2 1 2 7 1 - * 53 · -,., .57 466/11

NMR proton spectrum

(350 MHz, DMSO cL, (fin ppm, O in Hz) 3.58 and 3.78 (2d, O = 18, 2H, -SCH ₂ -); 3.88 (s, 3H ₁ -OCH ₃ ); 5.10 (s, 2H, NCH ₂ ), 5.18 (d, 0 = 4, IH ₁ H in 6), 5.78 (dd, 0 = 4 and 9, IH, H in 7); , 75 (s, IH, H of the thiazole); 6.86 (d, O = 16, IH, -CH = CHS-); 7.05 (d, O = 16, IH, = CHS-); 7, 20 (s, 3H, -NH ₃ ⁺ ), 9.60 (d, j = 9, IH, -CONH-), 12.69 (s, IH, = NMHCO- or = NN = C-),

OH

The starting triazine can be prepared in the following manner:

To a solution of 20 C of 1.15 g of sodium in 50 ecm of methanol is added 9.06 g of 4-benzyl-thiosemicarbazide prepared according to 17. Baird et al., 0. Chem. Soc. 2527 (1927), followed by 6.76 ecm of diethyl oxalate. The mixture is refluxed for 2 h, cooled to 4 C over 3 h, and the precipitate is separated from the filter. The sodium salt thus obtained is dissolved in 50 ecm of water, and the solution is acidified to pH 2 by the addition of 1N-hydrochloric acid and cooled to 4 ° C. After 1 h, filtered, dried and recovered 9.2 g of 4-benzyl-5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine.

Infrared spectrum (KBr), characteristic bands (cm) 3440, 3320, 1680, 1625, 1495, 1450, 1350, 730, 695

Example 16

The mixture is stirred at 60 ⁰ C under nitrogen for 2 h 30 min. A mixture of 10 g of 2-Benzhydryloxycarbonyl-7- ^ 2-methoxyimino-2 "- (2-t ritylamino-4-thiazolyl) -acetarnido} ~ 8-oxo -5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4.2-octo-2-ene, syn-isomer, E-form, 50 »cm of dimethylformamide, 2.56 g of 4- (2,2-dimethoxyethyl) -

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2 2 12 7 1 - ¹ ^ " ⁵⁷ 466/11

5.6 ^ 10x0-3- ^ 10x0-1,2,4-perhydrotriazine and 1.9 ecm N, N-diisopropylethylamine * The mixture is diluted with 600 ecm of ethyl acetate, washed twice with 125 ecm of water, 150 ecm 1 n- Hydrochloric acid, twice 150 ecm of a half-saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to dryness (20 C, 20 mmHg, 2.7 kPa). The residue is dissolved in 30 ecm of methylene chloride and chromatographed on a column of silica gel Merck (0.02-0.06) (column diameter 7 cm, height 35 cm). It is eluted with 7 l of a mixture of cyclohexane-ethyl acetate (40 vol.) Under a pressure of 40 kPa, to obtain fractions of 100 ecm. Fractions 27-46 are concentrated to dryness at 20 C under reduced pressure (20 mmHg, 2.7 kPa). 8.5 g of 2-benzhydryloxycarbonyl-3- {f4- (2,2-dimethoxyethyl) -5,6 ^ 10x0-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl-1 are obtained -2-thiovinyl} -7- £ 2-methoxyimino-2- (2-trityl on the ino-4-thiazolyl) -acetamido]] -8-oxo-5-oxide-5-thia-1-azabicyclo T4.2.0J oct-2-ene, syn isomer, Ε-form, in the form of a beige meringue.

Infrared spectrum (KBr), characteristic bands (cm) 3380, 3250, 1795, 1720, 1685, 1520, 1490, 1445, 1040, 940, 760, 700

NMR proton spectrum

(350 MHz, CDC1_, <T in ppm, 3 in Hz) 3.34 and 4.12 (2d, 3 = 18, 2H, -SCH ₂ -); 3.40 (s, 6H,

-CH (OCH ₃ J ₂ ); 3.94-4.06 (cn, 5H, -OCH ₃ and J ^ rNCH-); 4,60 -

4.68 (m, 2H, H in 6 and -CH (OCH ₃ J ₂ ); 6.07 (dd, 0 = 4 and 9,

IH, H in 7); 6.70 (s, IH, H of the thiazole); 6.82 (d, 0 = 16, IH, -CH = CHS-); 6.96 (s, IH, -COOCH-).

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2 2 12 7 1 - i32a - 57 466/11

A solution of 8.5 g of 2-β-benzyloxycarbonyl-3 (ZT4- (2,2-dimethoxyethyl) -5,6-dioxo-l, 4,5- _f- 6-tetrahydro-1,2-diol is treated with stirring at -10.degree , 4-triazin-3-yl] -2-thiovinylj-7- £ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidο] -8-oxo-5-oxide

29.9.1980 AP C 07 D / 221 271 22 1271 - fS3 -. 57 466/11

5-thia-1-aza-bicyclo £ 4.2.0j oct-2-ene, syη-1some res, E-form and 3 ecm dimethylacetamide in 100 ecm methylene chloride with 1.4 ecm phosphorus trichloride. After 1 h 30 min. And then 2 h are added (each time) 0.7 ecm phosphorus trichloride. The mixture is diluted with ethyl acetate 600 ecm, washed with twice 150 ecm of a 2% solution of sodium bicarbonate, twice 150 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 C at a pressure of 20 mmHg (2.7 kPa ) to dryness. The residue is taken up in 50 ecm ethyl acetate and the solution is chromatographed on a column of 100 g silica gel Merck (0.05-0.2) (column diameter 3 cm, height 25 cm). It is eluted with 1 1 ethyl acetate, with fractions of 200 ecm wins. Fractions 3, 4 and 5 are concentrated to dryness at 20 ° C (20 mmHg, 2.7 kPa). 7.5 g of 2-benzhydryloxycarbonyl-3- {/ 4- (2,2-dimethoxyethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazine ~ 3 are obtained -yl3-2-thiovinyl-7-2 / 2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido J-S-oxo-S-thia-1-aza-bicyclo f4.2 "03 oct-2 -en, syn-isomer, Ε-form, in the form of an orange meringue.

1 infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3380, 1780, 1720, 1680, 1515, 1490, 1445, 755, 740

NMR proton spectrum

(350 MHz, CDCl ₃ , (fin ppm, 0 in Hz)

3.40, (s, 6H, -CH (OCH) ₂ ); 3.54 and 3.66 (2d, 0 = 18, 2H, -SCH ₂ -); 3.98 (d, 3 = 5, 2H ₁ ^ NCH ₂ -); 4.02 (s, 3H, = NOCH ₃ ); 4.65 (t, 0 = 5, IH, -CH (OCH ₃ J ₂ ); 5.08 (d, 0 = 4, IH, H in 6); 5.92 (dd, 0 = 4 and 9 , IH, H in 7), 6.73 (s, IH, H of the thiazole), 6.83 (d, 0 = 16, IH, -CH = CHS-), 6.95 (s, IH, -COOCH -).

09/29/1980

^ ₀₅ AP C 07 E / 221

2 2 12 7 1 - tSSh - 57 466/11

a) A solution of 1.05 g of 2-benzhydryloxycarbonyl-3-methoxyethyl) -5,6- ^ 10x0-1,4,5,6-tet rahydro-1,2,4- is treated at 50 ° C. for 30 minutes. triazin-3-YLJ-2-thiovinylJ-7 - / '2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -

29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 -ΊΑ- 57 466/11

acetamido 3 ~ 8-oxo-5-thia-1α-aza-bicyclo £ 4.2.0j oct-2-ene, syn isomer, Ε-form, in 20cm of 98% formic acid. Concentrate the mixture at 50 ° C under one Pressure of 0.05 mmHg (0.007 kPa) to dryness, taken up in 50 ecm of acetone, concentrated to dryness at 30 C under reduced pressure (20 mml-1g, 2.7 kPa) and repeating this operation a second time.

The solid obtained is treated with 50 ecm of acetone at 60 ° C. for 10 minutes with stirring, the cooled suspension is filtered, the residue is dried and 0.51 g of 7--2 -2- (2-amino-4-thiazolyl) -2 are obtained -methoxy-imino-acetamido] -2-carboxy-3-l / * 5,6-dioxo-4-fluoromethyl-1-yl-yl-tetrahydro-1,2,4-t-riazin-3-yl] - 2-thiovinyl-8-oxo-5-thia-1-aza-bicyclo [4.2.o] oct-2-ene, eyn isomer, E ~ form.

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2300, 1770, 1715, 1680, 1540, 1050, 950

NMR proton spectrum

(350 MHz, CF ₃ COOD, <Γ in ppm, 3 in Hz) 3.87 (AB limit, 2H, -SCH ₂ -); 4.30 (s, 3H, -OCH ₃ ); 5.20 (s wide, 2H, ^ NCH ₂ -); 5.38 (d, 0 = 4, IH, H in Figure 6); 6.03 (d, 3 SJ 4, IH, H in 7); 7.22 (d, 3 = 16, IH, -ChI = CHS-); 7.50 (s, IH, H of the thiazole); 7.72 (d, 3 = 16, IH, = CHS-); 9.74 (s wide, IH, -CHO).

NMR proton spectrum

(35.0 MHz, CF ₃ COOD + D ₂ O, cT in ppm, 3 in Hz) 3.82 (AB limit, 2H, -SCH ₂ -); 4.26 (s, 3H, -OCH); 5.10 (s wide 2H,> NCH ₂ -); 5.31 (d, 3 = 4, IH, H in Figure 6); 5.96 (d, 3 = 4, IH, H in 7); 7.06 (d, 3 = 16, IH, -CH = CHS-); 7.43 (s, IH, H of the thiazole); 7.56 (d, 3 = 16, IH, - = CHS-); 9.67 (s wide, IH, -CHO).

29.9.1980 ^{AP C 07}

2 2 12 7 1 ^"1 →" ^{57 466/13} ·

b) You can work in the following way:

The mixture is heated with stirring for 30 minutes at 50 C, a mixture of 1 g of 2-Benzhydryloxycarbonyl-3- ^ ^ 4- (2,2 ~ dimethoxyethyl) -5,6 ~ dioxo-l, 4,5,6-tetrahydro-1 , 2,4-triazin-3-yl] -2-thiovinyl-y-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamide 0} -8-oxo-5-thia-1-aza bicyclo / 4.2.Oj-oct-2-ene, syn-isomer, E ~ form, 40 ecm of pure formic acid, 1.27 ecm of water and 6 g of silica gel Merck (0.05-0.2). It is concentrated to dryness at 30 ^° C. under 20 mmHg (2.7 kPa) and the resulting powder is applied to a column of 20 g of silica gel Merck (0.05-0.2) (column diameter 2 cm, height 17 cm). It is eluted with a mixture of ethyl acetate-formic acid-water (3-1-1 vol.) Wins 10 ecm fractions. Concentrate fractions 3-26 at 27 ^° C. under 0.05 mmHg (0.007 kPa) to dryness. The resulting yellow solid is triturated in 60 ecm of ether, filtered, the residue is dried, and 0.4 g of 7 ~~ 2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-J-2-carboxy- 3 ~ / "(5,6-dioxo-4-fluoromethyl-1, 4,5,6-tetrahydro-1, 2,4-triazin-3-yl) -2-thiovinyl-J-8-oxo-5 thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene, syn-isomer, E-form, whose NMR and infrared characteristics are equal to those of the product previously described under a).

2. The mixture is stirred under nitrogen until dissolved, a mixture of 0.297 g of 7- / 2- (2-amino-4-thiazolyl) -2-methoxyimino ~ _i acetamidoJ-2-carboxy-3-r (5,6-dioxo-4 -formylmethyl-1 * 4,5,6-tetrahydro-1,2,4,1-triazin-3-yl) -2-thiovinyi -8-oxo-5-thia-1-aza-bicyclo "4.2.Oj. oct -2-en, syn-isomer,

29.9.1980 AP C 07 D / 221 2 2 1 2 7 1, - X3 && - 57 466/11

Ε-form, 10 ecm of water and 0.042 g of sodium bicarbonate, filtered and lyophilized the solution. 0.28 g of the sodium salt of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -2-carboxy-3 - (5,6-dioxo-4-formylmethyl-1) is obtained , 4,5,6-tetrahydro-1,2,4-triazin-3-yl) -2-thiovinyl J-8-oxo-5-thia-1-aza-bicyclo ¢ 4.2.Oj oct-2-ene, syn Isomer, Ε-form, aldehyde hydrate.

09/29/1980

^ 3 AP C 07 D / 221

'221271 - ± 36 - 57 466/11

Infrared spectrum (KBr), characteristic bands »(cm) 342O ₁ 320O ₁ 1760, 1710, 167O ₁ 1600, 1530, 1040, 945

NMR PrqtoneηSpektrum

(350 MHz, DMSO d + D ₃ O, (f in ppm, O in Hz) 3.54 (AB limit, 2H ₁ -SCH ₂ -); 5.06 (d, Ό = 4, IH, H in 6 5.08 (s, IH, -CH (OH) ₂ ), 5.63 (d, D = 4, IH, H in 7), 6.44 (d, D = 16, IH, -CHl = CHS-); 6.76 (s, IH, H of the 'thi'azpls); 7.24 (d, D = 15, IH, = CHS-); 9.60 (s, 0.05 H, -CHO ).

The NMR spectrum of this sodium salt, aldehyde hydrate, taken in CF COOD shows that in solution in this solvent the compound is in the form of the aldehyde f spectrum identical to that described

3, a solution of 0.233 g of L-lysine distilled in 2.8 ecm ^ water is saturated with carbon dioxide by bubbling. The resulting solution is added to a suspension of 1 g of 7-f 2 - (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-carboxy-3-r (5,6-dioxo-4-formylmethyl, 4.5 , 6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl J-8-oxo-5-thia-1-aza-bicyclo ¢ 4.2.Oj oct-2-ene, syn isomer, Ε -Form, in 2.8 ecm of distilled water added. After stirring for 25 minutes at 20 ⁰ C, the solution is filtered, and the filtrate is lyophilized. There are thus obtained 1.23 g of the lysine salt of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-2-carboxy-3-ol (5,6-dioxo-4-formylmethyl-1) , 4,5,6-tetrahydro-1 _f 2,4-triazin-3-yl) -2-thiovinyl J-S-oxo-5-thia-1-aza-bicyclo / 4,2.Oj oct-2-ene, syn isomer, Ε-form, aldehyde hydrate, in the form of a cream-colored lyophilisate.

09/29/1980

^ ^{AP C} ° ^{7 D} / ^{221 271}

2 2 127 V -. * 36a - · 57 466/11

Infrared spectrum (KBr), characteristic bands (cm) 3420, 3200, 1765, 1710, 1660, 1600, 1530, 1040, 945

The 4- (2,2-dimethoxyethyl) -5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine can be prepared in the following manner:

09/29/1980

AP C 07 D / 221 271

9 2 12 7 1 "^ ⁵⁵⁷ " ^{57 466} S ¹¹

Prepare a solution of sodium methylate by dissolving 4.15 g of sodium in 140 ecm of methanol, add 32.3 g of 4 - (2,2-dimethoxyethyl) thiosemicarbazide and 26.3 g of ethyl oxalate. After stirring for 4 hours, it is allowed to cool. After one night, the suspension obtained is filtered and the precipitate is washed with three times 25 eq of ether. The solid is dissolved in 40 cc of water, and _f after cooling to about 4, the solution C by η 4-hydrochloric acid is acidified to pH 3 and left for 30 minutes at 4 C

 After filtering and drying, 12 g of 4 ~ (2,2-dimethoxyethyl) -5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine in the form of (decomposition),

in the form of a white solid, F (Kofier) = 172 ⁰ C.

-1 infrared spectrum (KDr), characteristic bands (cm)

3280, 3250, 1695, 1380, 1130, 1050

NMR proton spectrum

(80 MHz, DMSO d, cTin ppm, D in Hz)

3.30 (s, 6H, -CH (OCJH) ₂ ); 4.38 (d, D = 5.5, 2H, ^ NCH ₂ -); 4.94 (t, D = 5.5, IH, -CJH (OCH ₃ J ₂ ).

The 4- (2,2-dimethoxyethyl) -thiosemicarbazide can be prepared in the following manner:

To a solution of 14.35 g of hydrazine hydrate in 40 ecm of ethanol is added during 1 h with stirring at a temperature of 5 to 9 ⁰ C 37.7 g of 2,2-dimethoxyethyl isothiocyanate. After 12 h at 4 ⁰ C concentrated the mixture at 20 C under reduced pressure (20 mmHg, 2.7 kPa) to dryness, The resulting yellow syrup crystallized after

29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 - ΐ # ^ δ - 57 466/11

In-the-lVegeleiten. The solid is dissolved with heat in 50 ecm of methanol, filtered and diluted with 200 ecm diethyl ether, After e-tvva for 10 h at 4 C filtered and 32.3 g of 4- (2,2-dimethoxyethyl) thiosemicarbazid in the form of a white solid. Mp (Kofier) = 69 C,

29.9.1980 ^ q AP C 07 D / 221 271

2 2 1 2 7 1 "^ ⁵ ®" ^{57 465} Ai

Example 17

The 2-benzhydryloxycarbonyl-3-O-C4- (2,2-diethoxy-ethyl) -5,6-dioxo-1, 4,5,6-tetrahydro-1,2,4-triazin-3-ylj is prepared -2-thiovinyl-7-p-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-1-oxo-S-oxide-S-thia-1-aza-bicyclo £ 4.2.0 3 oct -2-ene, syn isomer, Ε-form, as described in Example 16, starting from 15.06 g of tosylate and 3 g of 4- (2,2-diethoxyethyl) -5'-6-dioxo-3-thioxo -l, 2,4-Jperhydrot riazine ,. in an amount of 2.85 ecm Ν, Ν-diisopropylethylamine in 75 ecm of dimethylformamide, the chromatography is carried out on a column of 250 g of silica gel Merck (0.05-0.2) (column diameter 5 cm, height 40 cm), eluting with 5 1 of a cyclohexane-ethyl acetate mixture (30-70 vol.). 8.35 g of the expected product are obtained in the form of a brown-red meringue,

NMR proton spectrum

(350 MHz, _CDCl3, S in ppm, D in Hz) 1.15 (t, Ο = 7, 6H, -CH _3); 3.38 (d, D = 18, IH, -SCH-); 3.50 and 3.72 (2q AB, D = 9 and 7, 4H, -OCH ₂ -); 3.90-4.20 (solid, 6H ^ s NCH 2 -, -OCH ₃ and -SCH -); - 4.65 (d, 0 = 4, IH, H in Figure 6); 4.72 (t, 0 = 5, IH, -CH (O Et) ₂ ); 6.04 (dd, Ό = 4 and 9, IH, H in 7); 6.70 (s, IH, H of the thiazole); 6.85 (d, 0 = 16, IH, -CH = CHS-); 6.97 (s, IH, -COOCII-); 11.94 (s wide, IH, = NNHCO- or = NN = C-).

Is treated at -10 ⁰ C for 2 h, a solution of 8.30 g of 2-benzhydryloxycarbonyl-3- {F4- (2,2-diethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro- 1,2,4-triazin-3-ylJ-2-thiovinyl } -7- [ 2-methoximino-2- (2-t-rylato-ino-4-thiazolyl) -ac-etamido] -8-oxo

29.9,1980

^ AP. C 07 D / 221

2 2 12 7 1 - I5S8 - 57 466/11

5-oxide-5-thia-1-aza-bicyclo £ 4.2.0} oct-2-ene, syn isomer, Ε-form, in 100 ecm of methylene chloride and 2.88 ecm of dimethylacetamide with 1.33 ecm of phosphorus trichloride. Nan treated as described in Example 16, on a column of 200 g silica gel Merck (0.05-0.2) (column diameter 4 cm, height 44 cm) and chromatographed with 2 a mixture of cyclohexane-ethyl acetate

29.9.1980 AP C 07 D / 221 2 2 1271 - S9 - 57 466/11

(30-70 vol.) Eluted. 5.3 g of 2-benzhydryloxycarbonyl-3-yl 4- (2,2-diethoxy-ethyl) -5,6-O-10 -X0-l4,5 are obtained and kahydro-1,2,4-UrlaZin-S-YIJ is obtained 2-thiovinyl-7-p-2-methoxy-imino-2- (2-tritylamino-4-thiazolyl) -acetarnidoj-8-oxo-5-thia-1-aza-bicyclo [4.2.2O] oct-2-ene syn isomer, Ε-form, in the form of a yellow-orange meringue, the product is purified by dissolving in 20 cc of ethyl acetate and adding 100 cc of diisopropyl ether to give 4.5 g of an off-white solid,

1 infrared spectrum (CHBr,), characteristic bands (cm) 3390, 1785, 1720, 1685, 1585, 1515, 1495, 1445, 1050, 940, 750, 740

NMR proton spectrum (350 MHz, CDCl ₃ , S in ppm, 0 in Hz) 1.18 (t, 0 = 7, 6H, -CH ₃ ); 3.52 and 3.75 (2q AB, 0 = 7 and 10, 4H, -OCH ₂ -); 3.60 (d, 0 = 18, IH, -SCH =); 3.97-4.05 (solid, 6H, -OCH ₃ ,> NCH ₂ -, -SCH =); 4.76 (t, 0 = 5, IH, -CH (O Et) ₂ ); 5.09 (d, 0 = 4, IH, H in Figure 6); 5.92 (dd, 0 = 4 and 9, IH, H in 7); 6.75 (s, IH, H of the thiazole); 6.85 (d, 0 = 16, IH, -CH = CHS-); 6.92 (d, 0 = 9, IH, -CONH-); 6.92) s, IH, -COOCH-); 11,30 (s, broad, IH, = NNHCO ~ or = NN = C-).

A solution of 1 g of 2-benzhydryloxycarbonyl-3- {4- (2,2-diethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2 is heated at 50 ° C. for 30 minutes , 4-triazin-3-ylj-2-thiovinyl-7-yl-thoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-8-0X0-5-thia-1-aza-bicyclo f4.2.0j oct-2-ene, syn-isomer, E-form in 25 ecm of pure formic acid. Concentrate at 40 ° C

29 * 9.1980

AP C 07 D / 221 271

⁵⁷

to dryness below 20 mmHg (2.7 kPa), take up the residue with 20 ecm of acetone, concentrate at 20 C at 20 mmHg (2.7 kPa) to dryness, repeat the operation twice, triturate the residue in 40 ecm of acetone, heated under reflux for 10 minutes while stirring, and the cooled suspension is filtered. 0.6 g of yellow powder is obtained in the following manner

29.9.1980 AP C 07 D / 221 271 12 7 1 - ± * θ - 57 466/11

cleans:

Dissolve 50 mg of the above product in 5 ecm of pure formic acid, add 2.5 g of silica gel Merck (0.5-0.2) and concentrate at 30 ⁰ C below 0.05 mmHg, 0.007 kPa to dryness Powder on a column of 5 g silica gel (column diameter 2.5 cm, height 3 cm) and eluted. with * 100 ecm of a mixture of ethyl acetate-acetic acid-water (3-2-2 vol.), obtaining fractions of 10 ecm. Concentrating the fractions 2-7 and dried (30 ⁰ C under 0.05 mmHg; 0.007 kPa) to give 30 mg of 7 ~ f2- (2-Amino ~ 4-thiazolyl) -2-methoxyimino-acetamidoJ-2-carboxy ~ 3- £ (5,6-dioxo-4-formylmethyl-1, 4,5,6-tetra-hy ατοί, 2,4-1-riazin-3-yl) ~ 2-thiovinyl-3-oxo-5-thia- l-aza-bicyclo C4.2.03 oct-2-ene, syn isomer, Ε-form, in the form of a cream-colored powder whose infrared characteristics and NMR are identical to those of the compound of Example 16, variant la).

The 4- (2,2-diethoxyethyl) -5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine can be prepared in the following manner:

18.6 g of 4- (2,2-diethoxyethyl) -thiosemicarbazide and 13.15 g of diethyl oxalate are added in succession to a solution of 2.07 g of sodium in 70 ecm of dry methanol and heated under nitrogen for 4 h under reflux. The cooled mixture is diluted with 300 eq of water and 150 ecm of ethyl acetate and then acidified to pH 2 with cooling to 4 C with concentrated hydrochloric acid. After decanting, the aqueous phase is extracted three times with 100 cc of ethyl acetate, the organic phase is washed three times with 100 cc of a geaättigten sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. 22.6 g of a thick yellow oil are recovered,

29.9.1980 AP C 07 E / 221 2 2 1 2 7 Ij - £ 2Ρ3θ -. 57 466/11

which consists mainly of 4- (2 ^ -Di thioxo-1,2,4-perhydrotriazine.

The 4- (2,2-diethoxyethyl) thiosemicarbazide may be mentioned below

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Be made way:

To a solution of 94 g of 2,2'-diethoxyethyl isothiocyanate

ο In 150 ecm of ethanol, add for 1 h at 4 C 27.3 ecm of hydrazine hydrate. The mixture is stirred for a further 20 minutes at 4 ° C. and the mixture is filtered, giving 86 g of the desired product as a white solid of mp = 96 ° C.

Example 18 '· ". =:

The mixture is stirred at 50 ^° C. under nitrogen for 2 h 30 min. A mixture of 7.33 g of 2-benzhydryloxycarbonyl-7- [! 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidO3-8-0XO- 5-oxide-3 ~ (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo Z "4.2.0j oct-2-ene, anti-isomer, E-form, 37 ecm dimethylformamide, 2.04 g 4- (2,2-dimethoxyethyl) ~ 5,6-dioxor-3-thioxo-l, 2,4-perhydrotriazine and 1.39 ecm Ν, Ν-diisopropylethylamine. The mixture is poured into 250 ecm of water, extracted with 250 ecm of ethyl acetate Wash twice with 200 ml of water, 100 ml of 0.1 N hydrochloric acid, 100 ml of water and 100 ml of a saturated solution of sodium chloride, dry over sodium sulfate, filter and concentrate at 20 C under 20 mmL (2.7 kPa) The residue is taken up in 100 ml of diethyl ether and the insoluble product is separated off on the filter After drying, 6.7 g of 2-benzhydryloxycarbonyl-3,8-O-4- (2,2-dimethoxyethyl) -5,6 are obtained dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl] -2-thiovinyl-7-p-2-methoxy Mino-2- (2-tritylamino-4-thiazolyl) -acetamido-S-oxo-5-oxide ~ 5-thia-1-aza-bicyclo f4.2.03-oct-2-ene, anti-isomer, Ε-form in the form of a cream-colored powder.

- 1 infrared spectrum (KBr), characteristic bands (cm) 3400 - 3250, 1800, 1725, 1695, 1590, 1555, 1520, 1495, 1450, 1210, 1080, 1060, 1035, 1025, 940, 755, 745, 700.

"Τ,

29.9.1980 AP C 07 D / 221 22127 ti - £ 4 £ _ 57 466/11

NMR proton spectrum

(350 MHz ₁ DMSO, cTin ppm _f D in Hz) 3.35 (S ₁ 6H, -OCH ₃ ); 3.98 (solid / 5H, '= NOCH and -

3.76 and 4.23 (2d, 3 = 18, 2H, -S-CH ₂ -); 4.58 (0 = 6, IH, -CHCH ₂ -); 5.14 (d, 0 = 4, IH, H in 6); 6.08 (dd, O = 4 and 9, IH ₁ H in 7); 6.98 (s, IH, -C0 ₂ CH (C ₆ H ₅ ) ₂ ; 7.03 and 7.17 (2d, 3 = 16, 2H ₁ -CH = CH-); 8.52 (s, IH , -NH-thiazole); 9.57 (d, 0 = 9, IH, -CONH- in 7); 1272 (s, IH, -N = C-OH or -NH-C-).

I Il

A solution of 6.7 g of 2-benzhydryloxycarbonyl-3-C4- (2,2-dimethoxyethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1 is treated at -8 C for 35 minutes , 2,4-triazin-3-yl] -2-thiovinyl] -7- [2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidoJ-S-oxo-S-oxide-S-thia- l-aza-bicyclo £ 4 * 2.Oj oct-2-ene, anti-isomer, Ε-form, in 70 ecm of methylene chloride and 2.3 ecm of dimethylacetamide with 1.1 ecm of phosphorus trichloride. It is diluted with 200 cc of ethyl acetate, washed with 200 cc of saturated sodium bicarbonate and twice with 100 cc water ,, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. The residue is fixed to 20 g of silica gel (0.06-0.2) and chromatographed on a column of 140 g of silica gel Merck (0.05-0.2) (column diameter 3.5 cm, height 60 cm). It is eluted with 1 1 of a cyclohexane-ethyl acetate mixture (20-80 vol.) And then with 1 1 of ethyl acetate. Concentrate fractions 5-12 (volume of fractions 120 ecm) at 30 ° C under 20 mmHg (2.7 kPa) to dryness. The residue is dissolved in 50 ml of ethyl acetate and 200 g of diisopropyl ether are added with stirring

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to. After filtration and drying, 3.8 g of 2-benzhydryloxycarbonyl-3-bis / 4- (2,2-dimethoxyethyl) -5,5-dioxo-1,4,5,6-tetrahydro-1,2 'are obtained, 4-t riazin-3-yl] -2-thiovinyl} ~ 7- (2-methoxyimino) -2- (2-tritylamino-4-thiazolyl) -acetamido3,8-oxo-5-thia-1-aza bicyclo f4.2.0j oct-2-ene, anti-isomer, Ε-form, in the form of a white solid,

1 infrared spectrum (KBr), characteristic bands (cm J ^ 3400, 1785, 1720, 1695, 1585, 1510, 1490, 1445, 1205, 1075,

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1020, 94O ₁ 75O ₁ 700,

NMR Protoneηspektrum

(350 MHz ₁ CDCl ₃₁ cf in ppm, O in Hz) 3.41 (S ₁ 6H ₁ -OCH ₃ ); 3.50 and 3.57 (2d, D = 18, 2H, -SCH ₂ -); 4.00 (d, 0 = 6, 2H, r NCH ₂ -); 4.10 (s, 3H, = NOCH ₃ ); 4.66

(t, 0 = 6, IH ₁ > CH-CH ₂ -) '/ 5.08 (d, O = 4, IH ₁ H in 6); 5.02 (dd, 3 = 4 and 9, IH, H in Figure 7); 6.77 (d, D = 16, IH, -CH = CH-S-); 6.96 (s, IH, -COOCH C ^); 9.55 (d, 0 = 9, IHi -CONH-); 10.90 (s, IH, -N = C-OH or -NH-C-).

1 Jl

The mixture is stirred at 50 C for 30 minutes, a solution of 3.5 g of 2 ~ Benzhydryloxycarbonyl-3- ££ 4- (2,2 ~ dimethoxyethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l , 2,4-triazin-3-yl]] -2-thiovinyl-7-f2-methoxyimino-2- (2-tritylamiho-4-thiazolyl) -acetamido] -b-oxo-S-thia-1-aza bicyclo £ 4.2.Oj oct-2-ene, anti-isomer, Ε-form, in 300 ecm of formic acid. Dry to dryness at 30 ° C under 0.05 mmHg (0.0067 kPa), take up in 250 ecm of acetone, concentrate to dryness at 20 ° C under 20 mmHg (2.7 kPa) and repeat this operation a second time. The resulting solid is refluxed in 100 eq of acetone, allowed to cool, filtered and washed with 50 ecm of diethyl ether, giving 2.1 g of the expected product, which can be purified in the following way: 2 g of the above product are suspended in 62 ecm of water, add under nitrogen with vigorous stirring, 0.3 g of sodium bicarbonate dissolved in 16.5 ecm of water, allowed to cool lukewarm, treated with animal charcoal and filtered. The filtrate has a pH of 5.4, acidified to pH 3.2 by adding acetic acid, heated to 80 ^° C., treated with carbon, filtered and allowed to stand for 1 h

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1. - && β - 57 466/11

Cool to 4 ° C. After filtration and drying, 1.2 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-2-carboxy-3-f (5,6-dioxo-4-formylmethyl) -2- 1,4,5,6-tetrahydrol- _f 2,4-triazin-3-yl) -2-thiovinyl] J-8-oxo-5-thia-1-a2a-bicyclo-4,2'-O-oct-2-ene , anti-isomer, Ε-form, in the form of a cream-colored powder.

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Infrared spectrum (KBr) ₁ characteristic bands (cm) 3700-2300, 177O ₁ 1715, 1685, 1630, 1590, 1525, 1060, 1030, 940 "',

NMR proton spectrum

(350 MHz, CF ₃ COOD, (Tin ppm, D in Hz) 3.86 (s wide, 2H, -SCH ₂ -); 4.43 (s, 3H, ^ NOCH ₃ ); 5.18 (s wide , 2H, J ^ N-CH ₂ -), 5.35 (d, 3 = 4, IH, H in 6), 5.88 (d, D = 4, IH, H in 7), 7,24 and 7.74 (2d, 3 = 16, 2H, -CH = CHS-); 8.14 (s, IH, H of the thiazole); 9.77 (s, IH, -CHO).

The 2-benzhydryloxycarbonyl-7-2-methoxyimino-2- (2-t-rityl-amino-4-thiazolyl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia- 1-aza-bicyclo-4,2-octo-2-ene, anti-isomeric, E-form can be prepared as follows:

Dissolve 8.5 g of 7-amino-2-benzhydryloxycarbonyl-3- (2-tosyloxyvinyl) -8-oxo-5-oxide-5-thia-1-aza-bicyclo f4-r2.o! L oct-2-one. en, Ε-isomer, in 100 ecm of methylene chloride, adds 7.1 g of 2-Mo-thoxyimino-2- (2-tritylamino-4-thiazolyl) -acetic acid, anti-isomer prepared according to R, Bucourt, Tetrahedron 34, 2233 - 2243 (1978), and 0.1 g of 4-dimethylaminopyridine to cool-t to 5 C and dropwise added over 25 minutes a solution of N, N-dicyclohexylcarbodiimide in 50 ecm of methylene chloride. The mixture is stirred for 2 h at 20 ⁰ C, concentrated at 20 C under 20 mmHg (2.7 kPa) to dryness, the residue is taken up in 300 ecm of ethyl acetate, filtered, washed with 100 ecm of water and 100 ecm of saturated water with sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness at 20 ^° C. under 20 mmHg (2.7 kPa). The product is fixed on 50 g of silica gel Merck (0.06-0.2) and chromatographed on a column of 200 g

29.9.1980 AP C 07 E / 221 2 2 1 2 7 1j - Μ = ίΏ - 57 466/11

Silica gel Merck (0.06-0.2) (column diameter 4 cm, height 60 cm). It is eluted successively with mixtures γ, οη cyclohexane-ethyl acetate: 0.5 1 mixture 70-30 (vol.), 0.5 1 mixture 60-40 (vol.) And 41 mixture 50-50 (vol.), Where. one wins fractions of 120 ecm. Concentrate the fractions 17 - 32 at 20 ⁰ C under

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20 mmHg (2.7 kPa) to dryness and recovering 7.33 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido]] - 8-oxo-5-oxide 3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo C4.2.0Ü oct-2-ene, anti-isomer, E-form.

Infrared spectrum (CHBr,), characteristic bands (cm) 3400, 3280, 1805, 1730, 1680, 1555, 1520, 1495, 1450, 1375, 1190, 1180, 1070, 1035, 1025, 935

NMR proton spectrum

(350 MHz, CDCl ₃ , S in ppm, 3 in Hz) 2.44 (s, 3H _t -C ₆ Jj ₄ CH ₃ ); 3.16 and 3.48 (2d, 0 = 18, 2H,

-SCH ₂ -); 4.14 (s, 3H, -NOCH ₃ ); 4.59 (d, Ό = 4, IH, H in Figure 6); 6.34 (dd, 0 = 4 and 9, IH, H in.7); 6.90 (s, IH, -COOCHc); 6.92 and 7.15 (2d, D = 12, 2H, -CH = CH-); 7.47 (s, IH, H at the 5-position of the thiazole ^; 7,43 and J, 77 (2d, 0 = 8, 4H, -OSO ₂ C ₆ H ₄ CH ₃ );

Example 19

A mixture of 22.59 g of 2-benzhydryloxycarbonyl-7-C 2 -methoxyimino-2- (2-ethyl-4-thiazolyl) acetamido-3-8-oxo-5-oxide is stirred at 50 ° C. under nitrogen for 5 hours. 3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn-isomer, Z-form, 112 ecm dimethylformamide, 6.29 g 4- (2.2- Dimethoxyethyl) -5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine and 4.27 ecm Ν, Ν-diisopropylethylamine. It is poured into 500 cc of water in the presence of 500 cc of ethyl acetate, decanted, "washed twice with 250 cc of water, 100 cc of 0.1 N hydrochloric acid and 200 cc of water, saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C below 20 mmol (2.7 kPa) to dryness. The product is fixed to 75 g of silica gel Merck (0.06-0.2) and chromatographed on a column of 500 g

29 ..9.19SO AP C 07 D / 221 "221271. -Sß- 57 466/11

Silica gel Merck (0.06-0.2) (column diameter 4 cm, height 80 cm). It is eluted with 4 l of ethyl acetate, whereupon one obtains fractions of 300 ecm. Concentrating the fractions 5-12 at 20 ⁰ C under 30 mml-lg (4 kPa) to dryness to obtain 18.5 g of 2 ~ benzhydryloxycarbonyl-3- (2,2-dimethoxyethyl) -576-dioxo-1,4, 5,5-tetrahydro-1,2,4-triazin-3-yl] -2-thiovinyl-7- (2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-8-oxo-5- Oxide-5-thia-1-oza- bicyclo 4.2 4.2.Oj oct-2-ene, syn isomer, Z-form, in the form of a cream-colored powder.

-1 Infrared Spectrum (KBr), characteristic bands (cm) 3380, 3200, 1800, 1725, 1685, 1585, 1515, 1495, 1445, 1080, 1040, 750, 740

A solution of 18.5 g of 2-ßenzhydryloxycarbonyl-3 ~ jf4- (2,2-dimethoxyethyl) -5,6-dioxo ~ l, 4,5,6-tetrahydro- is treated at -8.degree. C. for 45 minutes with stirring. l, 2,4-triazine-3-yl-2-t-thiovinyl-7-l-2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido-S-oxo-S-oxide-S-thia- l-aza-bicyclo £ 4.2.Oj oct-2-ene, syn-isomer, Z-form, in 137 ecm of methylene chloride and 6.43 ecm of dimethylacetamide with 3.03 ecm of phosphorus trichlorido. Pour the mixture into 400 ecm of ethyl acetate, wash with 150 ecm of a saturated sodium bicarbonate solution and twice 100 ecm of water, dried over sodium sulfate, filtered and concentrated under 20 ⁰ C under 20 mml-Ig (2.7 kPa) to dryness, The product is fixed to 40 g of silica gel Merck (0.06 g). 0.2) and chromatographed on a column of 400 g of silica gel Merck (0.06-0.2) (column diameter 4.5 cm, height 80 cm), eluting with 2% ethyl acetate to give fractions of 360 ecm the fractions 2-5 are evaporated at 30 ^° C. under 20 mmHg

29.9.1980 AP C 07 E / 221 271 2 2 127 1 - & t & ® - . 57 466/11

(2.7 kPa) to dryness. The residue is taken up in 100 ml of ethyl acetate and 1 1 of diisopropyl ether is added with stirring. After filtration and drying, 6.8 g of 2-benzhydryloxycarbonyl-3- {CA- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-l _/ 2,4- are obtained triazine - 3-yl3-2-thiovinylj-7 ~ 2-methoxyimino ~ 2 ~ (2-tritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5-thia-1-aza-bicyclo C4.2.03 oct 2-s, syn-isomeric _f 2 -form form,

09/29/1980

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in the form of a cream-colored powder.

1 infrared spectrum (CHBr ₇ ), characteristic bands (cm) 3400, 1790, 1720, 1685, 1585, 1515, 1495, 1450, 1220, 1080, 1050, 1040, 750, 740

NMR proton spectrum

(350 MHz, DMSO d, <f in ppm, 0 in Hz) 2.30 (s, 6H ₁ ,> C (OCH) ₃ ) ₂ ) '; 3.22 and 3.78 (2d, 0 = 18, 2H,

-SCH ₂ -); 3.85 (s, 3H, = N.OCH ₃ ); 3.88 (d, J = 5, 2H,> NCH ₂ -) 4.50, (t, 0 = 5, IH, -CH (OCH ₃ J ₂ ), 5.23 (d, 0 = 4, IH , H in 6), 5.78 (dd, 0 = 4 and 9, IH, H in 7), 6.58 and 6.70 (2d, 0 = 10, 2H, -CH = CHS-), 6, 72 (d, IH, H of thiazole); 6.88 (s, IH, -COOCH ^); 8.75 (s broad, IH, -NHC (C H _{beta) 3);} 9.58 (d, 0 = 9, IH, -CONH-), 12.63 (s wide, IH,> i \! - NHC0-)

A solution of 5 g of 2-benzhydryloxycarbonyl-3-C4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2-H is heated at 50.degree. C. for 30 minutes , 4-triazin-3-yl] -2-thiovinyl-3-t-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acotamido-J-8-oxo-5-thia-1-aza-bicyclo. "4.2. Oj oct-2-ene, syn isomer, Z-form, in 200 cc of formic acid. It is concentrated at 30 ⁰ C under 0.05 mmHg, 0.007 kPa to dryness, the residue is taken up with 200 cc of acetone, concentrated at 20 ⁰ C., and repeating this procedure a second time, refluxing the remaining solid in 200 cc of acetone, allowing to cool, filtering and washing with 100 cc of diethyl ether to yield 2.8 g The final purification of the product may be carried out in the following manner: 1 g of the above product is suspended in 31 ecm of water, added with vigorous cooling and stirring vigorously 0.15 g

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Sodium bicarbonate, dissolved in 9 ecm of water, the pH is adjusted to 6.2 by addition of further sodium bicarbonate, treated with decolorizing carbon, filtered and acidified to pH 3.2 by the addition of acetic acid. The resulting suspension is heated to 80 C, treated with carbon, filtered and left at 4 ° C for 3 h.

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After filtration and drying, 0.4 g of 7-f2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-2-carboxy-3-one (5,6-dioxo-4-formylmethyl-1) is obtained , 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl J-8-oxo-5-thia-1-azabicyclo C4.2.0 J oct-2-ene, syn Isomer, Z-form, in the form of a white powder,

- 1 infrared spectrum (KBr), characteristic bands (cm) 3700 - 220O ₁ 1770, 1715, 1680, 1590, 1530, 1045

NMR proton spectrum

(350 MHz, CF ₃ COOD ₁ S in ppm, D. in Hz) 3.77 and 3.84 (2d, 0 = 18, 2H, -SCH ₂ -); 5.18 (s, 2H, ^ N-CH ₂ -); 5.38 (d, 0 = 4, IH, H in Figure 6); 6.02 (el, D = 4, IH, H in 7); 6.84 and 7.05 (2d, D = 10, 2H, -CH = CHS-); ,

7.48 (s, IH, H of the thiazole); 9.72 (s, IH, -CIIO).

Example 20

The mixture is stirred at 60 ^° C. for 5 hours and a mixture of 1 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetarnido, 1-J-2-carboxy-8-oxo-3- (2-tosyloxyvinyl) 5-thia-1-aza-bicyclo f4.2.0j oct-2-ene, syn-isomer, E-form, 20 cm.sup.-dimethylformamide and 0.44 g of the sodium salt of 5,6-dioxo.sup.4- (2,2 -dimethoxyethyl) -3-thioxo-l, 2,4-perhydrotriazine The mixture is concentrated to dryness at 30 ° C. under 0.05 mmi-1 g (0.007 kPa), the residue is taken up in 30 eq of water, filtered and dried 0.9 g of crude product.

The purification can be carried out as follows: 0.5 g of the above crude product is treated with 2 × 10 ml of boiling isopropanol, filtered and the mixture is allowed to cool. After the fii

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2 2 1 2 7 Ij " ^{: fs} ^ ^Sa " ^{57 465/1 : L}

After drying and drying, 0.215 g of 7-C2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamidoj-2-CaTbOXy-B-C4- (2,2-dimethoxyethyl-5,6-d10X0-1 , 4 ^ 5,6-tetrahydro-1,2,4-triazin-3-yl] -2-thiovinyl-5-8-oxo-5-thia-1-aza-bicyclo f4.2.0 ^ 1 oct-2-ene, syn isomer,

09/29/1980

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Ε shape, in the form of a yellow powder.

- 1 infrared spectrum (KBr), characteristic bands (cm) 3500, 3300, 1780, 1715, 1680, 1590, 1535, 1050, 950

NMR proton spectrum

(350 MHz, DMSO d, cTin ppm, 0 in Hz) 3.62 and 3.81 (2d, 0 = 18, -SCH ₂ -); 3.84 (s, 3H, -OCH ₃ ); 3.97 (d, 0 = 3, 2H,> NCH ₂ -); 4.58 (t, 0 = 3, IH, ~Ch [(OCH ₃ ) ₂ ); 5.20 (d, 0 = 4, IH, H in 6); 5.77 (dd, 0 = 4 and 9, IH, H in Figure 7); 6.74, s, IH, H of the thiazole); 6.91 (d, 0 = 16, IH, -CH = CHS-); 7.09 (d, 0 = 16, IH, = CHS-); 7.17 (s, 3H, -NH ₃ ⁺ ); 9.60 (d, 0 = 9, IH, -CONH-); 12.64 (s, IH, = NNHCO- or "NN = C-).

OH

The 7-C2- (2-amino-4-thiazofy-2-methoxyimino-acetamido) J-2-carboxy-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo f4. 2.0] | -oct-2-en, syn-isomer, Ε-form, can be prepared in the following manner:

The mixture is stirred at 50 C for 30 minutes, a mixture of 0.35 g of 7 ~ / "2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamidoJ-2 ~ benzhydryloxycarbonyl-8 ~ oxo-3- (2- tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2, O] oct-2-ene, syn isomer, E form, 10 ecm formic acid and 3 ecm water. Then added 8 cc of water, filtered and concentrated at 30 ⁰ C under 0.05 mml-lg (0.007 kPa) to dryness. It is taken up twice with 20 ecm of ethanol, each time concentrated at 20 ⁰ C below 20 mml-Ig (2.7 kPa) to dryness. The resulting solid is triturated in 20 ecm diethyl ether. After filtering and drying, 0.12 g of 7-2- (2-amino-

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4-thiazolyl) -2-methoxyiminoacetamido] -2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo4.2.Ο3 oct-2-ene, syn- Isomer, Ε-form, in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3360, 3200, 3100, 2000, 1770, 1670, 1630, 1530, 1370, 1190, 1175, 1070, 1045, 925, 810

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NMR proton spectrum

(350 MHz, DMSO d _B, CTin ppm, 0 Hz) 2.45 (s, 3H, CH); 3.58 and '3.80 (2d, 0 = 18, 2H, -SCH ₂ -3.88 (s, 3H, -OCH ₃ ); 5.18 (d, 0 = 4, IH, H in Figure 6) 5.78 (dd, 0 = 4 and 9, IH, H in 7); 6.68 and 7.20 (2d, 0 = 12, 2H, -CH = CH-); 6.74 (s, IH , H of the thiazole), 7.20 (s, 2H, -NH ₂ ), 7.51 and 7.88 (2d, 0 = 8, 4H, tosyl group), 9.58 (d, 0 = 9, IH, -CONH-).

The 7-f 2 - (2-Amino-thiazolyl) -2-methoxy in the ino-amido] -2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -5-thia-laza-bicyclo / Γ4 .2.0] oct-2-ene, syn isomer, Ε-form, can be prepared as follows:

To a cooled to -10 C solution of 4.7 g of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo- £ 4.2.0] octane 2-en, Ε-form, in 50 ecm of acetone, 5 ecm of water and 2.8 g of sodium bicarbonate is added over 7 min. A solution of 2 g of 4-bromo-2-mothoxyimino-3-oxo-butyryl chloride, syn-form , in 10 cm of acetone. The mixture is stirred for 1 h at -10 ⁰ C and concentrated at 20 ⁰ C below 20 mmHg (2.7 kPa) to dryness. This gives 11 g of a chestnut-colored solid A, 6 g of this solid A are chromatographed on a column of silica gel Merck (0.04-0.06) (column diameter 5 cm, height 25 cm). It is eluted with 2.5 l of a mixture of cyclohexane-ethyl acetate (65-35 vol.) Under a pressure of 40 kPa, to obtain fractions of 125 ecm. The fractions 10-14 are concentrated to dryness at 20.degree. C. under 20 ml.sup.-1 g (2.7 kPa) and 1 g of 2-.beta.-hydroxycarbonyl-7- (4-bromo-2-methoxyimino) -3-oxo-butyryl is obtained amino) -8-oxo-3- (2-tosyloxy

29.9.1980 AP C 07 D / 221 271 22127 1, - »fife- 57 466/11

vinyl) ~ 5-thia-1-aza-bicyclo "4.2.Oj oct-2-ene, syn isomer, E-form _f in the form of a yellow meringue,

 I Infrared Spectrum (CHBr,), characteristic bands (cm) 3390, 1785, 1720, 1685, 1515, 1495, 1455, 1375, 1190, 1180, 1075, 1045, 950, 810, 760, 740

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NMR proton spectrum

(CDCl ₃ , 350 MHz, cTin ppm, 0 in Hz) 2.43 (s, 3H, -C ₆ H ₄ CH ₃ ); 3.35 (AB, 0 = 17, 2H, -SCH ₂ -); 4.14 (s, 3H, = NOCH ₃ ); 4.35 (s, 2H, BrCHgCO -); 5.02 (d, 0 = 4, IH, H in Figure 6); 5.34 (dd, 0 = 4 and 9, IH, H in 7); 6.89 (s, IH, -CH (C ₅ H ₅ J ₂ ); 6.85 and 6.92 (2d, 0 = 12, 2H, -CH = CH-); 7,17 (d, 0 = 9, IH, -CONH-); 7.2-7.4 (massive, 12H, -CH (C HJ ₂ and 2H meta of tosyl); 7.74 (d, 0 = 8, 2H, 2H ortho of tosyl ).

A solution of 5 g of the crude product A obtained above in 25 ecm of tetrahydrofuran is poured into a solution of 20 C, 0.5 g of thiourea, 50 eq of water and 25 ecm of ethanol for 5 minutes. The mixture is stirred for 30 minutes at 20 C and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness, the residue is taken up in 150 ecm of ethyl acetate and 50 ecm of a saturated sodium chloride solution, decanted, the organic phase washed with twice with 100 cc water and 100 cc of a saturated rJatriumchloridlösung, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. The product obtained is (on a column of 120 g silica gel Merck 0.04 - 0.05) (column diameter 4 cm, height 20 cm), eluting with 2 1 of a cyclohexane-ethyl acetate mixture (30 - 70 vol.) Under a pressure of 40 kPa, with fractions of 50 ecm wins Concentrates fractions 16-38 to dryness at 20 ° C below 20 mmHg (2.7 kPa) and recovers 0.75 g of 7- £ 2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido J-2. benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo / 14.2.Oj oct-2-ene, syn isomer, Ε-form, in Form of a cream-colored solid.

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The 7-amino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo C4.2.03 oct-2-ene, Ε-form, can be prepared in the following manner:

To a solution of 35 C of 6.1 g of 2-benzhydryloxycarbonyl-7

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t ~ butoxycarbonylamino-8-oxo-3- (2-tosyl-oxyvinyl) -5-thiazolaza-bicyclo C4.2.0J oct-2-ene, Ε-form, in 75 ecm of acetonitrile is added dropwise over 25 minutes to a solution of 3 ·, 49 g of p-toluenesulfonic acid hydrate in 25 ecm of acetonitrile, stirred for 45 minutes at 35 ⁰ C, the mixture is poured into 500 ecm of a saturated sodium bicarbonate solution. After 30 minutes of contact with stirring is extracted with 500 cc of ethyl acetate, the organic phase is washed with 100 cc of l '/ ater, .trocknet over sodium sulfate, filtered and concentrated under 20 mmHg (2.7 kPa) at 20 ⁰ C to dryness. 4.7 g of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4.2.2Ojoct-2-ene, E-Fortn, in the form of a brown meringue.

Rf = 0.18 ^ silica gel chromatography plate, cyclohexane-ethyl acetate (50-50 vol.) 3.

The 2α-benzhydryloxycarbonyl-7-E-butoxycarbonylamino-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo-ε-4,2,7,7-oct-2-ene, Ε-form, can be prepared as follows getting produced:

7.1 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo4 is reduced as described in Example 19 4.2.0J oct-2-ene, Ε-form, dissolved in 75 ecm of methylene chloride and 4.62 ecm of dimethylacetamide, with 2.03 ecm of phosphorus trichloride. Chromatography on silica gel eluent: cyclohexane-ethyl acetate (50-50 vol.) J yields 6.1 g of 2-.beta.-hydroxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3- (2-tosyloxyvinyl) -5-thia- l-aza-bicyclo £ 4.2.Oj oct-2-ene, E-form.

29.9.1980 AP C 07 D / 221 2 2 12 7 1 - f53a - 57 466/11

Infrared spectrum (CHBr,), characteristic bands (cm ") 3425, 1730, 1720, 1505, 1370, 1190, 1180, 1075,

NMR ~ proton spectrum

(350 MHz, CDCl ₃ , cTin ppm, 3 in Hz) 1.50 (s, 9H, -C (CH ₃ ) ₃ ); 2.42 (s, 3H, -CH ₃ ); 3.35 and 3.42

29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 - $ 52 - 57 466/11

0 = 18, 211, -SCH ₂ -); 4.92 (d, 3 = 4, IH, H in 6); 5.59 (dd, 0 = 5 and 9, IH, H in 7); 6.84 (d, 3 = 12, IH, -CH = CHS-); 6.88 (s, 1H,., COOCHc :); 6.90 (d, D = 12, IH, = CHS-).

The 4-bromo-2-methoxyimino-3-oxobutylchloride, syη-1some res, can be prepared in the following manner:

To a solution of 20 C of 4.08 g of 2-methoxyimino-3-oxo-butyric acid, syn-isomer, in 50 ecm of diethyl ether, is added 2 drops of dimethylformamide and then, over 15 minutes, 2 ecm of oxalyl chloride dissolved in 5 ecm of diethyl ether , Stirred at 20 C for 1 h, one more drop of dimethylformamide added and the reaction is carried out for 15 minutes. Concentrate at 20 C under 20 mml-Ig (2.7 l <Pa) to dryness, take up with twice 30 ecm of petroleum ether, each time the solvent is evaporated at 20 ⁰ C below 20 mmHg (2.7 kPa). The 2-f, ethoxyimino-3-oxobutanoyl chloride, syn isomer, thus obtained, is dissolved in 50 ecm of methylene chloride, to this solution is added at 20 ° C 0.2 ecm of 5.4 N hydrochloric ether and 1.14 ecm bromine, stirred for 20 h at 20 ⁰ C, concentrated at 20 ⁰ C under 20 mml-Ig (2.7 kPa) to dryness and receives 5.42 g of a brown oil, which consists mainly of 4-bromo-2-methoxyimino ~ 3-oxobutyryl chloride, syn-isomeres.

NMR proton spectrum

(60 MHz, CDCl ₃ , cti'n ppm, 3 in Hz)

4.25 (s, 3H, -OCH ₃ ); 4.34 (s, 2H, -CH ₂ -)

The 2-methoxyimino-3-oxo-butyric acid, syn-isomer, can be prepared in the following manner:

29.9.1980 AP C 07 D / 221 2 12 7 1 _ £ 55a "57 466/11

The mixture is heated for 15 h, a mixture of 52 g of ethyl 2-methoxyimino-3-oxo-butyrate, syn isomer, 300 ecm of ethanol and 330 ecm of 1 η-sodium hydroxide under reflux. Concentrate the ethanol at 20 C under a pressure of 20 mmHg (2.7 kPa) and extract with 150 ecm of methylene chloride. The aqueous phase is washed with 1 g

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5 12 7

Charcoal treated, filtered, saturated with sodium chloride, cooled to 4 C and acidified to pH 2 with 2 N hydrochloric acid in the presence of 200 ecm of methylene chloride. The aqueous phase is extracted again with twice 100 ecm of the same solvent and then with six times 200 ecm of ethyl acetate. The organic phases are dried over sodium sulfate and concentrated to dryness separately at 20 ° C. under 20 mmHg (2.7 kPa). The residues are combined and treated with vigorous stirring with 80 ecm of diisopropyl ether for 4 h. The resulting crystals are filtered off with suction and dried to give 8.9 g of 2-methoxyimino-3-oxobutyric acid, syn-isomer »

Infrared spectrum (CHCl-), characteristic bands (cm) 3400, 2830, 2300, 1730, 1695, 1370, 1035

NMR proton spectrum

(60 MHz, CDCl ₃ , / in ppm, D in Hz)

2.48 (s, 3H, CH ₃ CO-); 4.18 (s, 3H, -OCH ₃ ); 11.2 (s, IH,

COOH).

The ethyl 2-methoxyimino-3-oxobutyrate, syn isomer, is prepared according to R, Bucourt et al., Tetrahedron 34, 2233 (1978). ·

Example 21

The mixture is stirred at 50 C for 30 minutes, a solution of 0/1 9 7- £ 2 ~ (2-amino-4-thiazolyl) -2-methoxyimino-acetamidoJn

2-carboxy-3-f £ 4- (2,2-dimethoxyethyl) -5,6 ~ dioxo-4,5,6-

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tetrahydro-1,2,4-triazin-3-yl] -2-thiovinyl-8-oxo-5-thia-1-octa-bicyclo C4.2.03 oct-2-ene, syn-isomeric, Ε-form, in 10 ecm of pure formic acid, concentrated to dryness at 50 C under 30 mmHg (4 kPa), the residue taken up in 10 ecm of acetone, concentrated

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at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness, the residue is treated with 20 ecm of acetone under reflux, allowed to cool and filtered. 0.088 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-J-2-carboxy-3 -) (5,6-dioxo-4-morphylmethyl-1,4,5,6 -tetrahydro-1,2,4-triazin-3-yl) -2-thiovinyl] ~ 8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene, syn isomer, Ε- Mold, in the form of a yellow powder, whose characteristics are identical to those of the products obtained in Example 16 (la).

Example 22

To a solution of 3.7 g of 2-benzhydryloxycarbonyl-7- / 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1 -azabicyclo 44,2,0 ^ oct-2-ene, syn isomer, Ε-form, in 70 ecm of dry Ν, Ν-dimethylformamide, are added 1.5 g of 4-carbamoylmethyl-5,6-dioxo 3-thioxo-i, 2,4-perhydrotriazine and 0.65 ecm Ν, Ν-diisopropylethylamine. The reaction mixture is heated for 3 h at 60 to 65 C under nitrogen and then diluted with 300 ecm of ethyl acetate and washed with three times 100 ecm of distilled water. After drying over magnesium sulfate and filtering, the solvent is evaporated under reduced pressure (35 mmHg, 4.4 kPa) at 40 ° C to give 3.1 g of the expected crude product.

3.7 g of a crude product obtained by the procedure described above are chromatographed on a column of silica gel Merck (0.04-0.06) (column diameter 4 cm, height 30 cm), under a pressure of 40 kPa with ethyl acetate elutes and fractions of 200 ecm wins. Fractions 11 - 32 are added under

2 1271 -

3J5Ö

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ringertem pressure (35 mmHg; 4.4 kPa) at 40 ⁰ C and concentrated to dryness. 2.7 g of 2-benzhydryloxycarbonyl-3- (4-carbamoylmethyl) -5,6-dioxo-1, 4,5,6-tetrahydro-1,2,4-triazin-3-yl) -2-thiovinyl are obtained ] ~ 7-f2-methoxyimino

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2- (2-tritylamino-4-thiazolyl) -acetamido3,8-oxo-S-thia-1-aza-bicyclo / 4,2,0J oct-2-ene, syn isomer, E-form.

Infrared spectrum (CHBr,), characteristic bands (cn ") 3450, 3390, 3190, 2820, 1780, 1720, 1685, 1590, 1475, 1450, 1050, 945, 755, 700

NMR proton spectrum

(350 MHz, CDCl ₃ , <f in ppm, 3 in Hz) 3.62 and 388 (AB, O = 16, 2H, -SCH ₂ -); 3.83 (s, 3H, = NOCH ₃ ); 4.41 (s wide, 2H, -CH ₂ CONH ₂ ); 5.22 (d, D = 5, IH, H in Figure 6); 5.75 (dd, 3 = 5 and 9, IH, H in 7); 6.71 (s, IH, H of the thiazole); 6.85 and 6.95 (AB, J = 16, -CH = CH-S-); 6.94 (s, IH, -CH (C ₆ H ₅ ) ₂ ); 7.15 - 7.50 (Mt, 25H, aromatic); 7.71 and 8.80 (2s, 2 χ IH, -CONH ₂ ); 9.58 (d, 0 = 9, IH, -CONH-C ₇ ); 12.65 (s, IH, = NN = C-OH or = N-NH-C-).

I Il

2.7 g of 2-ßenzehydryloxycarbonyl-3- (4-carbamoylmethyl-5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl J-7 - / "2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnido3-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn-isomer, After addition of 30 eq of distilled IVasser, the reaction mixture is warmed to 50 ° C. for 30 minutes, then diluted with 17 eq of distilled water, filtered, and the filtrate is removed under reduced pressure (5 mmHg, 0 , 67 kPa) at 40 C. the residue is triturated with 50 cc of anhydrous ethanol, which is under reduced pressure (30 mmHg;. 4 kPa) at 40 ⁰ C. This procedure is repeated twice, the residue is dissolved in 50 cc.. anhydrous ethanol, the insoluble

09/29/1980

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Residue is filtered off with suction and gewaschen.und with 25 cc of anhydrous ethanol and 50 cc of ether twice under reduced pressure (5 mmHg; 0.67 kPa) at 20 ⁰ C. This gives 1.3 g of 7-ε-2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido3-3-C (4-carbamoylmethyl-5,6-dioxo-l _# 4j5,6-tetrahydro-1, 2,4-triazin-3 ~ yl) -2-thiovinylj-2-C

29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 · .- ISZ. - 57 466/11

5-thia-1-aza-bicyclo [A, 2.0 ] oct-2-ene, syn isomer, E-form, in the form of a beige powder,

Infrared spectrum (KBr), characteristic bands (cm ") 3410, 3320, 3200, 3100, 2000, 1770, 1710, 1680, 1630, 1590, 1380, 1040, 945

NMR proton spectrum

(350 MHz, DMSO d, tf in ppm, D in Hz) 3.63 and 3.83 (AB, D = 18, 2H, -SCH ₂ -); 3.87 (s, 3H, = NOCH ₃ );

4.45 (s wide, 2H, -C ₁ H ₂ -CONH ₂ ); 5.20 (d, 0 = 4, IH, H in 6); 5.78 (dd, D = 4 and 9, IH, H in Figure 7); 6.75 (s, IH, H of the thiazole); 6.90 and 7.08 (2d, D = 16, 2 χ IH, -CH = CH-S-);

7.32 (s broad, 2H, -NH ₂ thiazole); 7.70 (s wide, 2H, -CONH ₂ ); 9.60 (d, O = 9, IH, -CONH-C ₇ ); = NN = C-OH or = NNH-C-, ff-7 12 ppm

The 4-carbamoylmethyl-5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine can be prepared in the following manner:

8.33 g of 4-ethoxycarbonylmethyl thiosemicarbazide (Gante and Lantsch Chem. Ber., 97, 989 (1964) are suspended in 250 ecm of a saturated ammonia solution in ethanol, and the reaction mixture is stirred at 25 ° C. The insoluble product is filtered off with suction twice 25 ecm of alcohol and washed twice with 50 ecm of ether, after drying gives 6.2 g of 4-carbamoylmethyl-thiosemicarbazid, mp = 188 ⁰ C.

3.8 g of 4-carbamoylmethyl-5,6-dioxo-3-thioxo-1,2,4-perhydrotriazine are obtained by condensation of 6.8 g of 4-carbamoylmethylthiosemicarbazide and 6.7 g of ethyl oxalate by the method of M. Pesson and M, Antoine, Bull. Soc. Chim. France 1590 (1970).

- 1 infrared spectrum (KBr), characteristic bands (cm) 3550, 3480, 3430, - 3270, 3100, 2000, 1710, 1690, 1670, 1365, 1200

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Example 23

A solution of 4 g of the sodium salt of 4-N, N-dimethylcarbamoylmethyl-5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine in 240 ecm of N, N-dimethylformamide is treated with 0.60 ecm of formic acid and then heated to 60 C under nitrogen. 8 g of 2-benzhydryloxycarbonyl-7- (2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia are then added thereto -l-aza-bicyclo £ 4.2.01 oct-2-ene, syn isomer, Ε-form, added dropwise and a solution of 2.8 ecm N _t N-diisopropylethylamine in 20 ecm Ν, Ν- for 10 min. Dimethylformamide too. The mixture is stirred for 2 h 20 min. At 60 ⁰ C and then diluted with 600 ecm distilled water and extracted with twice 250 ecm of ethyl acetate. The organic extracts are washed successively with 200 ecm of 0.1 N hydrochloric acid solution, 200 ecm of half-saturated sodium bicarbonate solution and 200 ecm of half-saturated sodium chloride solution and then dried over magnesium sulfate. The residue obtained by concentration under reduced pressure (30 mmHg; 4 kPa) at 30 C of the solvent to dryness is chromatographed on a column (height 30 cm, diameter 5 cm) of silica gel (0.04-0.06 mm) eluted under a pressure of 50 kPa with 2.5 l of ethyl acetate and then with 1.5 l of a mixture of ethyl acetate and methanol (95-5 VoI). Fractions 32-37 (of 100 ecm) are mixed and concentrated to dryness. 2.5 g of 2-benzhydryloxycarbonyl-3-O4-N- (N, N-dimethylcarbamoylmethyl) -5,6-dioxo-1, 4,5,6-tetrahydro-1,2,4-t-riazine are obtained 3-yl] -2-thiovinyl-7-f2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido J-8-oxo-5-oxide-5-thia-1-aza-bicyclo f4. 2.0j oct-2-ene, syn isomer, Ε form) in the form of a salmon-colored solid.

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Infrared spectrum (CI-IBr ₃ ), characteristic bands (cm) 3380, 3200, 1800, 1725, 1685, 1670, 1590, 1520, 1495, 1450, 1040, 945, 755, 740

A cooled to -10 C solution of 2.4 g of 2-ßenzhydryloxycarbonyl-

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3 ££ 4-N, N ~ DirnGthylcarbamoylmethyl-5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3 ~ YLJ-2-thiovinylj-7- £ 2 ~ methoxyimino 2- (2-tritylamino-4-thiazolyl) -acetamide O3-8-OXO-5-oxide-5-thiai-aza-bicyclo / 14.2.0] oct-2-ene, (syn-isomer, E-form) in 48 ecm of methylene chloride is treated with 1.47 ecm of N, N-dimethylacetamide and then with 0.44 ecm of phosphorus trichloride and then stirred at about -10 ⁰ C for 3 h. The reaction mixture is diluted with 100 ecm of methylene chloride and poured into 100 ecm of a half-saturated sodium bicarbonate solution. The organic phase is washed with 100 ecm semisaturated sodium chloride, dried over magnesium sulfate and then concentrated under reduced pressure (30 mmHg, 4 kPa) at 30 ^° C. The residue is chromatographed on a column of silica gel (0.04-0.06 mm) (column diameter 2.2 cm, height 30 cm) eluting with 600 ecm of ethyl acetate and collecting fractions of 25 ecm. Fractions 10-21 are combined and concentrated to dryness. This gives 1.3 g of 2-Benzhydryloxycarbony1-3- ^ r4- (N, N-dimethylcarbamoylmethy3) -5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin ~ 3- yl] -2-thiovinyl-7-filte hxy in 0-2- (2-1-ritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5-thia-1-aza-bicyclo f4.2.0j oct. 2-ene, syn isomer, E form.

Infrared spectrum (CHBr ₃ ); characteristic bands (cm) 3400, 1790, 1730, 1690, 1670, 1590, 1520, 1500, 1460, 1050, 760, 740

NMR proton spectrum

(350 MHz, CDCl ₃ , ' (fin ppm, 0 in Hz) 2.97 and 3.40 (2s, 2 χ 3H, --CON (CH ₃ J ₂ ), 3.60 and 3.75 (2d, 0 = 18, 2H, -

29.9.1980 AP C 07 D / 221 22 127 1, - cZ5J- - 57 465/11

4.08 (s, 311, SNOCH ₃ ); 4.73 (s wide, 2H, -CHgCON <); 5.08 (d, 0 = 4, IH, H in 6); 5.93 (dd, 0 = 4 and 9, 1H, H in 7);

6.77 (s, IH, H at the 5-position of the thiazole); 6.88 (d,

O = 16, IH, -CH = CH-S-); 6.92 (s, IH, -CO ₂ CH (C ₅ H ₅ J ₂ ); 7.0 7.6 (solid, 27H, aromatic, -CONH-, and -CH = CHS-); 7.81

(s wide, IH, trityl -NH-); 11.25 (s wide, IH, -N = C-OH or

-N-C-triazine). '

ι ο HO

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Add 9 eq of distilled water to a solution of 1.3 g of 2-benzhydryloxycarbonyl-3-pi-pl- (N, N-dimethylcarbamoylmethyl) ~ 5,6 ^ 10x0-1,4,5,6-tefrahydro-l, 2,4-triazin-3-yl] -2-thiovinyl J-7-2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido] -8-oxo-5-thia-1α-aza bicyclo £ 4.2.Oj oct-2-ene (syn isomer, Ε-form) in 15 ecm of 98% formic acid and the reaction mixture is warmed to 50 C for 45 minutes. After filtration to remove insoluble matter, the mixture is concentrated under reduced pressure ( 10 mmHg; 1.33 kPa) at 40 ⁰ C to dryness. The residue is taken up in 20 ecm of ethanol and triturated and concentrated thereon under reduced pressure (30 mmHg; 4 kPa) at 30 ° C. The residue is taken up in 25 eq of ethanol, filtered off with suction and then washed successively with 3 × 5 cm of ethanol and finally with washed 3 times 10 ecm of ethyl ether and dried. 0.62 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamidoj-2-carboxy-3-one is obtained (N, N-dimethylcarbamylmethyl) -j-dioxo-1-one tetrahydro-ly2y4-t-riazin-3-ylJ-2-thiovinyl-5-thia-1-aza-bicyclo f4.2.0! oct-2-ene (syn isomer, E form),

- 1 infrared spectrum (KBr), characteristic bands (cm J 3420, 3320, 3210, 1780, 1720, 1690, 1660, .1530, 1040, 945

NMR proton spectrum

(350 MHz, DMSO _d, "Tin ppm, D in Hz) 2.88 and 3.08 (2s, 3H χ 2 ₁ -CON (CH ₃ J _2), 3.61 and 3.82 (2d, D = 18, 2H ₁ -SCH ₂ -); 3.85 (s, 3H, = NOCH ₃ ); 4.80 (s broad, 2H, -CH ₂ CON <c), 5.21 (d, 0 = 4 , IH, H in 6), 5.79 (dd, 0 = 4 and 9, IH, H in 7), 6.75 (s, IH, H thiazole), 6.88 and 7.10 (2d, 0 = 16, 2H, -CH = CH-S-); 7.19 (s wide, 2H, -NH ₂ ); 9.60 (d, .O = 9, IH, -CONH-O ₇ ); 12, 73 (s IH ₁ -N = C-OH or -NH-C-

ιriazin). '0

29.9.1980 AP C 07 D / 221 '22 127 t. - b $ ° i - 57 466/11

The sodium salt of 4- (N _/ N-dimethylcarbamoylmethyl) -5,5-dioxo-3-thioxo-l, 2,4-perhydrotriazine can be prepared by the method of M. Pesson and M. Antoine, Bull. Soc. Chim. Fr. (1970) 1590 by the action of ethyl oxalate on 4- (N _# N-dimethyl ~

09/29/1980

^{AP C 07 D} / 221 271 57 466/11

carbamoylmethyl-thiosemicarbazide in methanol in the presence of sodium methylate.

Infrared spectrum (KBr), characteristic bands (cm) 3200, 1696, 1640, 1580, 1530.

Example 24

Heat for 1 h 20 min, a solution of 18.2 g of 2-benzhydryloxycarbonyl-7-l-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido3,8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn-isomer, E-form, 8 "4 9 5,6-dioxo-4-ethoxycarbonyl-mothyl 3-thiox-o-1,2,4-perhydrotriazine and 3.11 ecm of diisopropylethylamine in 182 ecm of dimethylformamide at 80 ° C. The mixture is cooled, diluted with 2,000 eq of ethyl acetate and washed with three times 100 eq of a saturated sodium bicarbonate solution, twice 100 ecm of a saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) The residue is chromatographed on a column of 313 g of silica gel Merck (0.06-0.2) ( Column diameter 4.9 cm, height 31 cm) and eluted with 2000 ecm of a mixture of cyclohexane-ethyl acetate (20-80 vol.) And then with 2200 ecm of ethyl acetate on 100 ecm, concentrate fractions 10-40 under reduced pressure (20 mmHg; 2.7 kPa) to give 6.15 g of 2-ßenzehydryloxycarbonyl-3-C (5,6-dioxo-4-ethoxy-carbonylmethyl-l, 4 _f 5,6-tetrahydro-l, 2,4- triazin-3-yl) -2-thiovinyl-3-7-r2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-8-oxo-5-oxide-5-thia-1-aza-bicyclo £ 4.2 .01 oct-2-en, syn-isomer, Ε-form, in the form of a yellow meringue.

29.9.1930 AP C 07 D / 221 271 22127t - tea - 57 466/11

Infrared spectrum (KBr), characteristic bands (cm) 3400, 1795, 1720, 1685, 1590, 1515, 1490, 1445, 1210, 1040, 935, 750, 700

NMR proton spectrum

(350 MHz, CDCl ₃ , of in ppm, D in Hz) 1.28 (t, D = 7, 3H, -CH ₂ CH ₃ ); 3.32 and 4.50 (2d, D = 18, 2H,

-SCH ₂ -); 4.02 (s, 3H, -OCH ₃ ); 4.23 (q, D = 7, 2H, -O-CH ₂ CH ₃ ); 4.60 (s, 2H, ^ NCH ₂ COO-); 4.63 (d, Ό = 4, IH, H in Figure 6); 6.05 (dd, D = 4 and 9, IH, H in 7); 6.70 (s, IH, H of the thiazole); .5.75 (d, 0 = 16, IH, -CH = CHS-); 6.95 (S, IH ₄ -COOCH <;); 11.54 (s, IH, = N-NHCO- or = NM = C-).

OH

To a cooled to -10 ⁰ C solution of 6 g of 2-Benzhydryloxycarbony1-3- £ (5,6-dioxo-4-ethoxycarbonylmethyl-l, 4,5,6-tetrahydro-l, 2,4-triazine-3 yl) -2-thiovinyl} -7-C2-methoxy-imino-2- (2-t-ritylamino-4-thiazolyl) -acetamido 3-8-oxo-5-oxide-5-thia-1-aza-bicyclo / 4.1 Octo-2-ene, syn-isomer, E-form, and 2.27 ecm of dimethylacetamide in 60 ecm of methylene chloride, add 1 ecm of phosphorus trichloride and hold at -10 ° C for 1 h for 20 min. The mixture is then poured into 750 ethyl acetate, washed three times with 100 eq of a saturated sodium bicarbonate solution, with twice 100 eq of a saturated sodium chloride solution and evaporated to dryness under reduced pressure (20 mmHg, 2.7 kPa). The residue is chromatographed on a column of silica gel Merck (0.05 0.2) (column diameter 2.1 cm, height 18 cm) and eluted with 0.5 l of ethyl acetate to give fractions of 30 ecm. Concentrate fractions 2-7 below 20 mmHg (2.7 kPa) to dryness to obtain

29.9.1980 ^{ΑΡ C} ° ⁷

2 2 12 7 1 " ^iS ^ ^G ~ ^{57 465/1 : L}

5.2 g 2 ~ Benzhydrylpxycarbonyl-3- £ (5,6 ~ dioxo ~ 4-ethoxycarbonyl · methyl-l _/ 4 _{1 5/6-tetrahydro-l #} 2 ₁ 4-tria2in-3-yl) -2-thiovinyl ] -7- £ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-thia-1-aza-bi-cyclo C4.2.03 oct-2-ene, syn isomer _f in the form of a yellow meringue.

09/29/1980

yfi AP C 07 D / 221 271

2 2 1 2 7 ti - tSS -. 57 466/11

Infrared spectrum (KBr), characteristic bands (cm) 3400, 1780, 1720, 1685, 1590, 1525, 1490, 1445> 1210, 1035, 940, 750, 700.

NMR proton spectrum (350 MHz, CDCl ₃ , / in ppm, 0 in Hz)

1.28 (t, 0 = 7, 3H, -CH ₂ CH ₃ ); 3.55 and 3.54 (2d, 0 = 18, 2H, -SCH ₂ -); 4.06 (s, 3H, -OCH ₃ ); 4.26 (q, 0 = 7, 2H, -OCH ₂ CH ₃ ); 4.63 (s, 2H, J> N-CH ₂ COO-); 5.09 (d, 0 = 4, IH, H in 6)> 5.94 (dd, 0 = 4 and 9, IH, H in 7); 6.72 (s, IH, H of the thiazole); 6.75 (d, 0 = 16, IH, -CH = CHS-); 6.94 (s, IH, -COOCHCT); 11.05 (s, IH, = N-NHCO- or = NN = C-).

OH

A solution of 5 g of 2-benzhydryloxycarbonyl-3-r (5,6-dioxo-4-ethoxycarbonylmethyll, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2 is heated for 15 minutes -thiovinyl] 3-7-r2-methoxyimino ~ 2- (2-tritylamino) -thiazolyl-J-acetamido-1-oxo-S-thia-1-aza-bicyclo [4.2.0.7 oct-2-ene, syn Isomer, E-form, in 100 cc of formic acid and 30 ecm of distilled water at 50 ° C. The mixture is cooled, diluted with 70 cc of water, filtered, and the filtrate is removed under reduced pressure (20 mmHg; The residue is taken up with three times 50 eq of ethanol and concentrated each time under reduced pressure (20 mmHg, 2.7 kPa) to dryness, and the resulting solid is then suspended in 50 ecm of ethanol at reflux, cooled filtered, dried in vacuo (20 mmHg, 2.7 kPa) to give 1.9 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-J-carboxy-S). - £ (5,6-dioxo-4-ethoxycarbonylmethyl-l, 4,5,6-tetrahydro-l, 2 _/ 4-triazin-3-yl) -2-thiovin yl 3 ~ 8-oxo-5-thia-1-aza-bicyclo f4.2.0) oct-2-ene, syn isomer, Ε-form, in the form of a yellow solid.

29.9.19SO AP C 07 E / 221 2 1 2 7 1j - ISSa. -. , 57 466/11

Infrared Spectrum (KBr), characteristic bands (cm) 3340, 3220, 3130, 1780, 1725, 1690, 1590, 1530 ", 1040,

29.9.1980 AP C 07 D / 221 271 2 127 1. - Si - 57 465/11

NMR proton spectrum (350 MHz, DMSO d cfin ppm, O in Hz) 1.22 (t, 0 = 7, 3H, CH ₃ -CH ₂ -); 3.60 and 3.85 (2d, O =, 18, 2H, -SCHg-) '; 3.85 (s, 3H, -OCH ₃ ); 4.15 (q, 0 = 7, 2H, -OCH ₂ -CH ₃ ); 4.66 (s, 2H, ^ N -CH ₂ CO-); 5.18 (d, O = 4, IH, H in Figure 6); 5.77 (dd, O = 4 and 9, IH, H- in 7); 6.72 (s, IH, H of the thiazole); 5.87 (d, O = 16, IH, -CH = CHS-); 7.08 (d, O = 16, IH, -CH = CHS-); 7.15 (s wide, 2H, -NH ₂ ); 9.58 (d, 0 = 9, IH, -CONH-); 12.80 (s, IH, = NNHCO- or = NN = C-).

OH

The S-dioxo-ethoxycarbonylmethyl-S-thioxo-1-hydroxybenzidine can be obtained in the following manner:

To a suspension of 24.4 g Ethylhydrazinooxalat in 185 ecm anhydrous ethanol is added over 5 minutes at 25 C, a solution of ethyl isothiocyanate in 185 ecm of anhydrous ethanol. The mixture goes into solution and a white precipitate forms again. The mixture is left to stir for 20 hours under nitrogen and then for 15 minutes, a solution is added, starting from 8.5 g of sodium in 185 ecm of ethanol and refluxing the mixture for 4 hours. The resulting red-brown suspension is removed under reduced pressure (20 mmHg, 2.7 kPa) and the residue is dissolved by adding 100 ecm of 4N hydrochloric acid and 2000 ecm of ethyl acetate. The insoluble portion is filtered off on the filter and the organic phase is washed four times with 250 ecm of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa). This gives 43 g of a brown-red gum, which is dissolved in 300 ecm of a saturated sodium bicarbonate solution. The obtained brown

29 * 9.1980 AP C 07 D / 221 271 2 2 1271, - * § = * S - 57 466/11

Solution brought v / ill be washed three times with 100 cc of isopropyl ether, and with the necessary amount of 1N-hydrochloric acid to pH rt-V7 _e 1 and extracted with 500 cc of ethyl acetate. The organic phase is washed with twice 50 ecm of a saturated sodium chloride solution, over

29.9.1980 AP C 07 D / 221 22127 1. - &> - 57 466/11

Dried magnesium sulfate, filtered in the presence of decolorizing carbon and concentrated under reduced pressure (20 mml-Ig, 2.7 kPa). 9.5 g of 5,6-dioxo-4-ethoxycarbonylmethyl-S-thioxo-1H-perhydrotriazine are thus obtained in the form of a brown solid,

Infrared spectrum (KBr), characteristic bands (cm) 3500-2800, 1740, 1700, 1645, 1380, 1235, 1200

NMR proton spectrum

(80 MHz, DMSO d _Q , <T in ppm, 0 in Hz) 1.38 (t, D = 7, 3H., -CH ₂ CH ₃ ); 4.30 (q, 3 = 7, 2H, -CH ₂ CH ₃ ); 5.03 (s, 2H, ^ N-CH ₂ CO-); 12.50 (s, IH, -NHCO-),

The ethylisothiocyanacetate can be prepared according to D, Hoppe and R, Follmann, Chem. Ber. 109, 3047 (1976).

Example 25

The mixture is stirred at 60 ⁰ C under nitrogen for 3 hours a mixture of 10.04 g of 2-ßenzhydryloxycarbonyl-7 ~ £ 2 ~ methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido ^ -8-oxo-5- oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo f4.2.0j oct-2-ene, syn isomer, E form, 200 ecm dimethylformamide, 2.22 g 4-allyl-5 , 6-dioxo-3-thioxo-l, 2,4-perhydrotriazine and 2.1 ecm N, N-diisopropylethylamine. The mixture is diluted with 600 eq of ethyl acetate, washed with twice 200 eq of water and twice 100 ecm of water, half saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. The residue is taken in 50 cc methylene chloride, add 20 g silica gel Merck (0,05 - 0,2) to and concentrated at 20 ⁰ C under 20 rnmHg (2.7 kPa) to dryness. The powder is applied to a column of 200 g of silica gel Merck (0.05-0.2) (column diameter 6.1 cm). It elutes with mixtures

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 l · - ^ 8 - 57 466/11

of cyclohexane-ethyl acetate, 2 l 20 - 80 (vol.) ', 1 l 10 - 90 (v / v) and then with 2 l of ethyl acetate to yield fractions of 120 ecm. Fractions 8-28 are grown at 20 ⁰ C under 20 mmHg (2.7 l <Pa) concentrated to dryness. 3.7 g of 3-f (4-allyl-5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl J-2-benzhydryloxycarbonyl are obtained -7-j2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-S-oxo-S-oxide-S-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn- Isomeric, Ε-form in the form of an orange meringo.

Infrared spectrum (CHBr,), characteristic dandes (cm) 3380, 1800, 1720, 1670, 1515, 1045, 940;

NMR proton spectrum

(350 NHz, DNSO d ₅ , (Tin ppm, 0 in Hz) 3.60 and 4.29 (2d, D = 18, 2H, -SCH ₂ -); 3.85 (s, 3H, -OCH ₃ ) 4.45 (d, D = 5, 2H ₁ ^ NCH ₂ -), 5.05 C ^d , 3 = 4, IH, H in 6); 5.17 to 5.27 (Nt, 2H, = CH ₂ ); 5.78-5.92 (2Nt, 2H, H in 7 and ~ m = CH ₂ ); 6.78 (s, IH, H of the thiazole); 6.95 (d, 0 = 16, IH, -CIH = CHS-); 6.97 (s, IH, -COOCHC); 7.09 (d, D = 16, IH, = CHS-); 8.78 (s, IH, -NHC (C ₅ H ₅ J ₃ ); 9.04 (d, 0 = 9, IH, -CONH-); 12.62 (s, IH, = N-NH-CO or = NN = C-).

"OH

To a cooled to -10 C mixture of 2.34 g of 3- (£ 4-allyl-5,6-dioxo-l, 4,5,6-tetrahydro-l, 2 _t 4-triazin-3 ~ yl3-2 -thiovinyl-2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-1,3-t-riazol-4-yl) -acetamidoj-8-oxo-5-oxide-5-thia-1-aza bicyclo £ 4.2.o3-oct-2-ene, syn isomer, e-form and 0.85 cc of dimethyl acetamide in 23 cc of methylene chloride is added 0.40 cc of phosphorus trichloride and stirred for 30 min. at -10 ⁰ C, is poured the mixture in 250 ecm of ethyl acetate, washed

29.-9.1980. AP C 07 D / 221 271-

2 2 1 2 7 1.. μ _{m 57 456/11}

with 50 ecm of hater, 50 ecm of saturated sodium bicarbonate solution, and 50 ecm of saturated sodium chloride solution twice, dried over sodium sulfate, filtered, and concentrated to dryness at 30 ° C under 20 mmHg (2.7 kPa). The residue, dissolved in 10 ecm of methylene chloride, is added to 10 g

29.9.1980 AP C 07 D / 221 271 2 2 1271 - ³ ^ ⁰ " 57 466/11

Fused silica gel Merck (0.05-0.2) and applied to a column of 30 g silica gel (column diameter 1.4 cm). It is eluted with 500 ecm of a mixture of cyclohexane-ethyl acetate (20-80 vol.), Fractions of 60 ecm wins. Fractions 2-4 are evaporated to dryness at 20 ^° C. under reduced pressure (20 mmHg, 2.7 kPa). 1.34 g of 3- {f4-allyl- _5f 6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl} -2-thiovinyl-2-benzhydryloxycarbonyl- 7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-S-oxo-S-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε- Shape, in the form of a yellow meringue.

Infrared spectrum (CHBr,), characteristic bands (cm) 3380, 1780, 1720, 1680, 1515, 1490, 1445, 1040, 940, 750, 735.

NMR proton spectrum (350 MHz, CDCl ₃ , </ * in ppm, D in Hz) 3.57 and 3.66 (2d, 0 = 18, 2H / -SCH ₂ -); 4.03 (s, 3H, -OCH ₃ ); 4.52 (d, 0 = 4, 2H, ^ NCH ₂ -); 5.09 (d, 0 = 4, IH, H in Figure 6); 5.26-5.38 (2d, 2H, = CH ₂ ); 5.78-5.88 (mt, IH ₁ -CiH = CH ₂ ); 5.92 (dd, 0 = 4 and 9, IH, H in 7); 6.74 (s, IH, H of the thiazole); 6.86 (d, 0 = 16, -CH = CHS-); 6.96 (s, IH, -COOCHc); 7.05 (d, 0 = 9, IH, -CONH-); 11.68 (s, IH, = NNHCO- or = NN = C-) _# OH

Dissolve 1.34 g of 3- / C4-allyl ~ 5,6-dioxo-l, 4,5,6-tetrahydrol, 2,4-triazin-3-ylJ-2-thiovinyl-J-benzhydryloxycarbonyl ^ - C 2- methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn isomer, Ε-form, in 13 ecm Formic acid, adds 6.5 eq. Of water and

09/29/1980

£} \ AP C 07 D / 221 271

127V - 3r & Äa - 57 466/11

heated with stirring for 30 minutes at 50 ⁰ C, After cooling, the mixture is filtered and the solution is concentrated at 30 C under reduced pressure (0.05 mmmg), The residue is taken up in 50 cc of ethanol, it distributes the solvent under reduced pressure (20 mmHg, 2.7 kPa) at 20 ^° C. and again

09/29/1980

AP C 07 D / 221 271 '2 2 1 27 1i' - SAS - 57 466/11

get this operation three times. The residue is refluxed with 100 eq of ethanol, a small amount of insoluble material is removed by filtration, the filtrate is concentrated to 50 ecm at 30 ° C. under a reduced pressure (20 mm 2 -7.7 kPa) and allowed to cool lh down to +4 C After filtering and drying the precipitate, 0.37 g of 3- [f4-allyl-5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-ylJ-2 are obtained. thiovinyl-7-7- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-J-2-carboxy-S-oxo-5-thia-1-aza-bicolc / "4,2.OJOct-2" en, syn-isomer, E-form, in the form of a yellow powder.

- 1 infrared spectrum (KBr), characteristic bands (cm) 3600, 2300, 1775, 1710, 1680, 1535, 1040, 945

NMR ProtoneηSpektrum

(350 MHz, DMSO d _& , <f in ppm, 0 in Hz) 3.63 and 3.80 (2d, 0 = .18, 2H, -SCH ₂ -); 3.88 (s, 3H, -OCH ₃ ); 4.48 (d, 0 = 4, 2H, -NCH ₂ -); 5.19 to 5.27 (mt, 3H, = CH ₂ and H in 6); 5.74-5.92 (mt, 2H, -CH = CH ₂ and H in Figure 7); 6.74 (s, IH, H of the thiazole); 6.91 (d, 0 = 16, IH, -CH = CHS-Jk 7.09 (d, 0 = 16, IH, = CHS-); 7.18 (s, -NH ₃ ⁺ ); 9.60 (d, 0 = 9, IH, -CONH-); 12.61 * (S, IH, = M-NHCO- or = NM = C-). -

OH

The 4-allyl-5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine can be prepared according to the procedure described in BE-PS 830 455.

Example 26

The mixture is stirred at 60 C under nitrogen for 3 h, a mixture of 5.02 g of 2-ßenzhydryloxycarbonyl-7-f2-methoxyimino-2 "(2-t ri tylamino-4-thiazolyl) acetamido.] - 8-oxo-5 -oxide-3- (2-tosyl-oxyvinyl) -

09/29/1980

2> 3 ^{AP c 07}

2 2 1 2 7 1 " ^isg " ⁵⁷

5-thia-1-aza-bicyclo £ 4.2.0J oct-2-ene, syn-isomeros, E-form, 93 ecm dimethylformamide, 1.5 g 4- (2,2-dimethyl-4-dioxolanylmethyl-4- methyl) -5,6-dioxo ~ 3-thioxo ~ l, 2,4-perhydrotriazine and 1.05 ecm Ν, Ν-diisopropylthiopropylamine. Dilute the mixture with 200 eq of ethyl acetate, wash four times with 200 eq of water, dry over sodium sulfate, filter and concentrate to dryness at 20 C under 20 mmHg (2.7 kPa). The residue is fixed to 10 g of silica gel Merck (0.06-0.2) and the powder is applied to a column of 100 g of silica gel Merck (0.05-0.2) (column diameter 2.5 cm, height 40 cm ),on. It is eluted with 1.3 1 of ethyl acetate to yield fractions of 60 ecm. Concentrate fractions 6-20 at 20 ^° C. under 20 mmHg (2.7 kPa) to dryness and recover 2.48 g of 2-benzhydryloxycarbonyl-3- [4- (2,2-dimethyl-4-dioxolanylmethyl). ~ 5,6-dioxo-1, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl-7-r 2 -methoxyimino-2- (2-t-ritylamino) -4 -thiazolyl) -acetamidoJ-8-oxo-5-oxide-5-thia-1-aza-bicyclo jf4.2.0joct-2-ene, syn isomer, * Ε-form, in the form of a yellow meringue,

NMR proton spectrum

(350 MHz, CDCl _3. , </ * In ppm, 0 in Hz)

1.32 and 1.43 (2s, 6H, -C (CH ₃ J ₂ ), 3.34 and 4.05 (2d, " D = 18,

-SCH ₂ -); 3.74 (t, 0 = 6, 2H, -CH ₂ O-); 3.84 (s, 3H, = NOCH); 3.95 (t, 3 = 6, 2H,. ^: N-CH ₂ -); 4.38 (Quint., 0 = 6, IH, ·>CH-O-); 4.65 (d, 3 = 4, IH, H in Figure 6); 6.06 (ddr 3 = 4 and 9, IH, H in 7); 6.71 (s, IH, H of the thiazole); 6.84 (d, 3 = 16, IH, -CH = CHS-); 6.95 (s, IH, -COOCH ^); 11.60 (s, IH, = N-NI-! CO-). ,

29.9.1980 AP C 07 D / 221 271 12 7 1 - ^ ⁵⁷ 466/11

Treat at -10 C for 40 minutes a solution of 2.48 g of 2-benzhydryloxycarbonyl-3-/''- ( _2H 2-dimethyl-4-dioxolanylmethyl) ~ 5 _# 6-dioxo ~ l, 4,5 , 6-tetrahydro-l, 2,4-triazin-3 ~ ~ 2-YL3 thiovinylJ-7- / 2 ~ methoxiimino-2- (2 ~ ~ tritylamino 4-thiazolyl ^ acetamidoJ-S-oxo-S-oxide S -thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn isomer, Ε-form, in methylene chloride (22.9 ecm) and dimethylacetamide (0.85 ecm), containing 0.4 ecm of phosphorus trichloride the mixture in 250 ecm of ethyl acetate, washed successively with 200 ecm of a

29.9.1980 AP C. 07 D / 221 271 2 2 1271 - Ι ⁷ "· ⁵ " sy 465/11

Sodium bicarbonate solution, twice 100 ecm of hate and 100 ecm of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness at 20 C under 20 mmHg (2.7 kPa) and the residue taken up in 20 ecm of methylene chloride, add 10 g of Merck silica gel (0.06 to 0.2) to and concentrated at 20 ⁰ C under 20 mmHg to dryness and brings dasferhaltene powder to a column of 40 g silica gel Merck (0.06 to 0.2) (column diameter 1.5 cm, height 15 cm). It is eluted with 500 ecm of methylene chloride, with fractions of 60 ecm wins. Combine fractions 2-7, concentrate to dryness at 20 ° C below 20 mmHg (2.7 kPa) and recover 1.4 g of 2-benzhydryloxycarbonyl-3-O-C4- (2,2-dimethyl-4-dioxolanylmethyl ) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl3-2-thiovinylj-7-f2-methoxyimino-2- (2-t-ritylamino-4-) thiazolylJ-acetamidoJ-S-oxo-S-thia-l-aza-bicyclo /"4.2.0J-oct-2-en, syn isomer, e-FRCM, in the form of a yellow pegs. * *

The mixture is heated at 50 C for 30 minutes, a mixture of 1.4 g of 2-Denzhydr loxycarbonyl-3- {f4- (2 ^ -Dim

3-ylJ-2-thiovinyl-3-7- ^ 2-fiethoxyimino-2- (2-tritylamino-4-thiazolyl) -J-acetamido-1-oxo-S-thia-1-aza-bicyclo [4.2.1O] oct-2 -en, syn isomer, e-form, 13 cc of formic acid and 6.5 cc of water. the mixture is cooled to 20 ⁰ C and filtered and concentrated at 30 ⁰ C under 0.05 mm Hg (0.007 kPa *) to dryness. Man the residue is taken up in 100 cc of ethanol, the solvent distributes at 20 ⁰ C under 20 mmHg (2.7 kPa), and repeats this operation twice. take the yellow solid in 100 cc of boiling ethanol, filtered, concentrated

29.9.1980 AP C 07 D / 221 271 2 12 7 11- <& * ° ~ 57 466/11

FIIT the rat at 50 cc at 20 ⁰ C (20 mmHg; 2.7 kPa), filtered, the solid is washed with 20 cc of diethyl ether and dried. 0.49 g of 7 ~~ 2 ~ (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-1-carboxy-S-1,4-2,3-dihydroxypropyl-5,6-dioxo-l is obtained. 4,5,6-tetrahydro-1, 2,4-triazin-3-yl3-2-t.-thiovinyl-3-oxo-5-thia-1-aza-bicyclo [4.2.2. Octo-2-ene, syn Isomer, E-form.

The Nf-IR spectrum shows that this product contains about 25 % formic acid

29.8.1980 AP C 07 D / 221 '2 2 127 1' - ^ -l- - 57 466/11

ester of one or the other alcohol function.

-1 Infrared Spectrum (KBr), Characteristic Bands (cm) 3650 - 2200, 1770, 1710, 1680, 1590, 1530, '1045, 945 ·

NMR proton spectrum

(350 MHz, DMSO d + D ₃ O, <f in ppm, 0 in Hz)

Diol: -

3.87 (s, 3H ₁ = N0CH); 5.20 (d, D = 4, IH, H in Figure 6); 5.75 (d, 3 = 4, H in 7); 6.74 (s, IH, H of the thiazole); 6.95 and 7.10 (2d, ö = 16, 2H, -CH = CH-S-);

Formic acid ester: ". ..,

3.87 (s, 3H ₁ = NOCH ₃ ); 5.18 (d, 0 = 4, IH, H in Figure 6); 5.75 (d, 0 = 4, IH, H in 7); 6.74 (s, IH, H dos thiazoles); 6.93 and 7.08 (2d, D = 16, 2H, -.CH = CIIS-); 8.22 (s, IH, HCOO-).

The 4α (2,2-dimethyl-4-dioxolanylmethyl) -5,6-dioxo-3-thioxo-1,2,4-perhydrotriazine can be prepared as follows:

Prepare a solution of 1.12 g of sodium in 50 eq of anhydrous methanol, add under nitrogen and with stirring at 25 C 10 g of 4- (2,2-dimethyl-4-dioxolanylmethyl) thiosemicarbazide and then dropwise over 10 min 6.6 ecm of diethyl oxalate and heated at reflux for 2 h. The mixture is allowed to cool to 20 ⁰ C, diluted with 1 1 diethyl ether, filtered and recovered after drying 3.7 g of a whiter solid. The product is taken up in 200 ecm of methylene chloride and stirred in the presence of 10 ml of 1N hydrochloric acid. It is decanted, washed with twice 50 ecm of sodium chloride saturated water, dried over sodium

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sulfate and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness, the residual oil is taken up in 50 cc of methylene chloride, the crystallization initiates by scratching and leaving for 3 hours at 4 C, After filtration and drying wins 1.5 g of 4α (2,2-dimethyl)

29.9.1980 AP G 07 D / 221 271 221271,-Zl ⁰ I- 57 466/11

4-dioxolanylmethyl) -5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine in the form of white crystals.

Infrared spectrum (KBr) ₁ characteristic bands (cm ") 3600 - 3100, 1680, 1575, 1535, 1210, 1060

NMR proton spectrum

(80 MHz, DMSO d, <T in ppm, D in Hz) 1.30 and 1.42 (2s, 6H,> C (CH ₃ J ₂ V; 3.95 (m, 2H, -CH 0-) 4.50 (rn, 3H, -CHO- and -N-CH ₀ -).

The 4- (2,2-dimethyl-4-dioxolanylmethyl) -thiosemicarbazide can be prepared in the following manner.

The mixture is heated for 2 h 30 min, under reflux, a mixture of 23.6 g of methyl N- (2,2-dimethyl-4-dioxolanylmethyl) dithiocarbamate according to US Patent 4,064,242, 500 ecm of absolute ethanol and 5, 5 g of hydrazine hydrate. It is concentrated to dryness at 20 C below -20 mmHg (2.7 kPa) and taken up in 100 ecm of diethyl ether. After filtration and drying, 15.2 g of 4- (2,2-dimethyl-4-dioxolanylmethyl) thiosemicarbazide are obtained in the form of a cream-colored solid of mp 145 ⁰ Co

Infrared spectrum (KBr), characteristic bands (cm) 3340, 3200, 1630, 1555, 1510, 1380, 1370, 1240, 1210, 1050

NMR proton _{spectrum A}

(80 MHz, CDCl ₃ , <f in ppm, 0 in Hz)

1.38 and 1.48 (2s, 6H, iC (CH ₃ J ₂ ); 3.72 (dd, 0 = 5 and 6, 2H, -CH ₂ N-); 3.90 (s, 2H, - NH ₂ ); 4.10 (dd, 3 = 6 and 7, 2H, -CH ₂ O-); 4.38 (m, IH, ^ CHO-); 7.78 (t, -0 = 5, IH , -CH ₂ NH-).

7.98 (s, IH, -NH-N).

29.9.1980 AP C 07 D / 221 1 2 7 1 - ώ & - 57 '466/11

Example 27

One solution 0.53 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-3-2-CaTbOXy-S-OXo-S- (2-tosyloxy-vinyl) -5-thia-1-aza £ bicyclo 4.2.0] oct-2-ene _f syn isomer, Ε-form and 0.31 g of the sodium salt of 5,6 ~ dioxo-4- (2 ~ hydroxyethyl) -3 ~ thioxo ~ l, 2, 4-perhydrotriazine in 10 ml of N, N-dimethylformamide is heated for 4 h 30 min. At 60 C, the reaction mixture is cooled and diluted with 150 ecm of ethyl ether. The precipitate is deposited on the filter and washed twice with 25 ecm of ether and dried. 0.6 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxy-acetamido-2-carboxy-3- {[ 5,6-dioxo-4-bis (2-hydroxyethyl) -l] is obtained, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl3-2-thiovinyl-8-oxo-5-thia-1-aza-bicyclo, ε 4.2, θ3 oct-2-ene, syn isomer , Ε-form, in raw form, in the form of a beige, amorphous powder.

Rf = 0.42; Silica gel chromatography plate; Eluent: Mixture of ethyl acetate-acetic acid-water (60-20-20 vol.)).

The product can be purified in the following way: Dissolve again in 50 ecm of a dilute sodium hydroxide solution (pH = 8) and then bring to pH 5 with dilute hydrochloric acid. After filtering a small insoluble portion, the resulting solution is dissolved in a solution Chromatograph the column of XAD-2 resin (diameter 2.4 cm), successively eluting the impurities with 1 1 of distilled water and then the pure product with 1 1 of the mixture of water-ethanol (95 - 5 vol.) «After Concentrate under reduced pressure (5 mmHg, 0.67 kPa) at 30 ° C and dry to obtain

29.9.1980 AP C 07 D / 221 221271t- i ^ Sa -. 57 466/11

0.2 g of 7- (2-amino-4-thiazolyl) -2-methoxyacetamido-2-carboxy-3-f5 _/ 6-dioxo-4- (2-hydroxyethyl) -1,4,5 6-tet rahydro-1,2,4-tia2in-3-yl3-2-thiovinyl-8-oxo-5-thia-3l-α2a-bicyclo f4,2.03 oct-2-ene, syn isomer, E-Fprm in the form of yellow, bright crystals.

NMR proton spectrum

(350 MHz, DMSO d, cf in ppm, Ό in Hz)

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3.60 (t, 0 = 5, 2H, ^ N-CH ₂ -CH ₂ OH); 3.84 (s, 3H, = NOCH ₃ ); 3.92 (t, 0 = 5, 2H,>N-CHgCHgOH); 5.10 (d, 3 = 4, IH, H in Figure 6); 5.65 (dd, 0 = 4 and 9, IH, H in 7); 6.39 (d, O = 16, IH, -ChI = CH-S-); 6.73 (s, IH, H at the 5-position of the thiazole); 7.17 (s wide, 2H ₁ -NH ₂ ); 7.37 (d, O = 16, IH, -CH = ChI-S-); 9.54 (d, 0 = 9, IH, -CONH-C ₇ ).

Dissolve 0.13 g of 7-i2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido1-2-carboxy-3-5 f5,6-dioxo-4- (2-hydroxyethyl) -1,4,5 , 6-tetrahydro-1,2,4-triazin-3-yl3-2-thiovinylj-8-oxo-5-thia-1-aza-bicyclo C4.2.O3 oct-2-ene, syn isomer, Ε Form, in one eighth of a cc of sodium bicarbonate solution. The solution is gelled at -80 C and lyophilized. 0.145 g of the sodium salt of 7-~2 ~ (2-amino-1,3-thiazol-4-yl) -2-methoxyiminq-acetamido] -1-2-carboxy-3-C5,6-dioxo-4- ( 2-hydroxyethyl) -l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl3-2-thiovinyl ^ -S-oxo-S-thia-1-aza-bicyclo f4.2.0j oct -2-ene, syn isomer, Ε-form, in the form of a white lyophilisate.

Rf = 0.28; Silica gel chromatography plate, eluent: Mixture of ethyl acetate-acetic acid-1 water (60-20-20 vol.).

NMR ProtoneηSpektrum

(350 MHz, DMSO d, cf in ppm, 0 in Hz) 3.50 (AB unresolved, 2H, -SCH ₂ -); 3.60 (t, 0 = 6, 2H,> NCH ₂ CH ₂ OH); 3.91 (t, 0 = 6, 2H,> N-CH ₂ CHgOH); 3.87 (s, 3H, SNOCH ₃ ); 5.07 (d, 0 = 4, IH, H in 6); 5.60 (dd, 0 = 4 and 9, IH, H in 7); 6.31 (d, 0 = 16, IH, -CH = CH-S-); 6.71 (s, IH, H at the 5-position of the thiazole); 7.17 (s wide, 2H,

-NH ₂ ); 7.36 (d, 0 = 16, IH, -CH = CHS-); 9.54 (d, 0 = 9, IH, -CONIH-).

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The 5,6-dioxo-4- (2-hydroxyethyl) -3-thioxo-l, 2,4-perhydrotriazine can be prepared by the method / method described by M. Pesson and M. Antoine, Bull. Soc. Chim. France 1590 (197O) _{1 working} in the following way:

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To a solution of sodium methylate prepared from 0.85 g of sodium in 37 ecm of methanol is added 5 g of 4- (hydroxyethyl) thiosemicarbazide and 5.5 ecm of ethyl oxalate and the mixture is refluxed for 3 hours. After cooling, the precipitate is separated by filtration and washed twice with 5 ecm of methanol. The crude sodium salt is obtained, which is then taken up in 25 eq of distilled water; The solution is filtered and acidified to pH 2 with 1 N hydrochloric acid. The precipitate is separated by filtration, washed with water and dried in air. This gives 2.4 g of 5,6-dioxo-4- (2-hydroxyethyl) -3-thioxo-l, 2,4-perhydrotriazine (mp = 230 ⁰ C).

The sodium salt can be prepared by treating 4.73 g of 5,6-dioxo-4- (2-hydroxyethyl) -3-thioxo-l, 2,4-perhydrotriazine in anhydrous methanol with sodium 2-ethylhexanoate to give 4 , 7 g of the sodium salt.

Infrared spectrum (KBr), characteristic bands (cm ") 3420, 3200, 3070, 1655, 1575, 1560, 1395, 1205, 1080, 1045, 835

The 4α- (2-hydroxyethyl) -thiosemicarbazide can be obtained according to the method of Y. Kazakov and I.Y. Potovskii, Doklady,

The 7- i 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetarnidoj-2-carboxy-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo £ 4.2.0} oct-2-ene, syn isomer, Ε-form, can be prepared in the following manner:

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A solution of 5.93 g of 2-benzhydryloxycarbonyl-7-f2-inethoxyimino-2- (2-tri-ethyl with iho-4-thiazolyl) -a-ce-tarn-idoj-8 is heated at 50 ° C. for 30 minutes. oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo-4,2-octo-2-ene, syn isomer, Ε-form, in a mixture of 80 ecm of pure formic acid and 25 ecm Water. The cooled to 20 C mixture is filtered and concentrated to dryness at 30 ⁰ C under 20 mmHg (2.7 kPa). Take the residue _¥

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Recover to 150 mL of acetone, concentrate at 20 C under 20 mmHg (2.7 L <Pa) to dryness, repeat the procedure twice, triturate the residue in 75 ecm of ether and filter. 3.4 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido3-2-carboxy-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-aza are obtained -bicyclo f4,2.03 oct-2-ene, syn isomer, E-form, in the form of a yellow powder.

Example 28 ^:

A mixture of 10.04 g of 2-benzhydryloxycarbonyl-7-r2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamide amido is stirred at 60 ^° C. for 3 h 30 min. oxo-5-o; cid-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo & .2.0] oct-2-ene, syn isomer, Ε-form, 200cc dimethylformamide, 3.46g 4- (2-t-Butoxycarbonylaminoethyl) -J-dioxo-S-thioxo-1-yl-perhydrotriazine and 2.1 ecm Ν, Ν-diisopropylethylamine, diluted with 800 eq of ethyl acetate, washed with 400 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness at 30 ^° C. under 20 mmHg (2.7 kPa). The product, dissolved in 50 ecm of methylene chloride, is chromatographed on a column of 100 g Merck silica gel (0.06-0.2 (Column diameter 3 cm, height 30 cm). »» Elute with 500 ecm of a mixture of cyclohexane-ethyl acetate (50-50 vol.), 500 ecm of a mixture (25-75 vol.) And 1.5 1 ethyl acetate, wherein You can win factions of 125 ecm and concentrate the factions n 9-21 (below 20 mmHg; 2.7 kPa at 20 ° C) to dryness and recovering 7.69 g of 2-benzhydryloxycarbonyl-3-f, 4- (2-t-butoxycarbonylaminoethyl) -5,6-dioxo-l, 4,5,6-tetrahydrol _f 2 , 4-triazin-3-YL3 ~ 2-thiovinyl) -7- £ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-S-oxo-5-oxide-5-thia-laza-bicyclo £ 4.2.03 oct-2-en, syn-isomer, Ε-form, in the form of a brown meringue.

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~~ - 1

Infrared Spectrum (KBr) ₁ characteristic bands (cm) 3380, 1795, 1715, 1690, 1590, 1520, 1495, 1445, 1205, 1160, 1040, 940, 750, 700. ,

NMR proton spectrum

(350 MHz, CDCl ₃ , </ * in ppm, μ in Hz) 1.36 (s, 9H, -C (CH ₃ J ₃ ), 3.30 and 4.65 (2d, 0 = 18, 2H, -SCH ₂ -), 3.38 (m, 2H, -CH ₂ NHCO-), 3.95 (m, 2H, - CH_ ₂ -CH ₂ NH-);

4.0 (s, 3H, CH ₃ ON =); 5.20 (d, 0 = 4, H ₅ ) To, 03 (dd, D = and 9, H ₇ ); 6.70 (s, H of thiazole); 6.86 (d, D = 16, -CfH = CHS-); 6.94 (s, -COOCHcC); 11.7 (s wide, -NH-triazine).

March treated at -10 ° _{C for lh 30 M ± n # with stirring,} a solution of 3.36 g of 2-benzhydryloxycarbonyl-3- ^ 4- (2-t-butoxycarbonylaminoethyl) -5,6-diox0-1,4,5,6 -tetrahydrol, 2,4-triazin-3-yl] -2-thiovinylJ-7-r2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5-oxide-5-thia- laza-bicyclo / 44.2.oJ- oct2-ene, syn isomer, Ε-form, in 30 ecm of methylene chloride and 1.2 ecm of dimethylacetamide with 1.04 ecm of phosphorus trichloride. It is diluted with 250 cc of ethyl acetate, washed with 150 cc of a solution of 2% sodium bicarbonate and twice with 100 cc water, half saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness , The product is fixed on 5 g silica gel Merck (0.06-0.2), chromatographed on a column of 50 g silica gel Merck (0.06-0.2) (column diameter 3 cm, height 15 cm). It is eluted with 6 l of ethyl acetate to give fractions of 600 ecm. Concentrating the fractions 2-7 at 20 ⁰ C under 20 rnmHg (2.7 kPa) to

29.9.1980 AP C 07 D / 221 2 2 1 27 1i " ¹ ^ * ⁸ - 57.466 / 11

Dryness and obtains 1.97 g of 2 ~ benzhydryloxycarbonyl-3- f / 4- (2-t-butoxycarbonylaminoethyl) -5,6-dioxo-l, 4 _i 5,6-tetrahydro-1,2,4-triazin-3 -yl3-2-thiovinyl J-7-f2-methoxyim: i.no-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-thia-1-azabicyclo f4.2.03 oct. 2-s, syn isomer, E-form _f in the form of a yellow meringue.

09/29/1980

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- 1

Infrared Spectrum (KBr) ₁ characteristic bands (cm) 340O ₁ 3280, 1790, 1715, 1695, 1590, 1520, 1495, 1450, 1040, 945, 755, '700'

NMR proton spectrum

(350 MHz, DMSO, cf in ppm, D in Hz) 1.33 (s, 9H, -C (CH ₃ ) ₃ ); 3.20 (m, 2H, -CH ₂ CH ₂ N ^); 3.64 and 3.86 (2d, D = 18, 2H, -SCH ₂ -); 3.83 (t, 3 = 6, 2H, -CH ₂ * CH ₂ N <:); 3.84 (s / 3H, ^ NOCH ₃ ); 5.25 * '(d, 3 = 4 ", IH,' * 'H), 5.77 (dd, 0 = 4 and 9, IH, H ₇ ), 6.72 (s, IH, H of the thiazole 6,92 (s, IH, -COOCH ^), 9,93 and 7,02 (2d, D =: '...

12, 2H, -CH = CH-S-); 8.82 (s, IH, -NH-); 9.58 (d, 0 = 9, IH, -NHCO-); 12.55 (s, IH, -NH-triazine).

The mixture is heated at 50 C for 30 minutes, a mixture of 1.88 g of 2-Benzhydryloxycarbonyl-3- ^ 4- (2-t-butoxycarbonylaminoethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1 , 2,4-triazin-3-yl3 -2-thiovinyl-i7-f2-methoxyimino-2- (2-t-ritylamino-4-l ^: hiazolyl) -acetamido-1-S-oxo-S-thia-1-aza-bicyclo Γ4.2.03 oct-2-ene, syn isomer, e-form, 35 cc of formic acid and 15 cc of water are added 20 cc of water to it, allowed to cool to 20 ⁰ C, filtered and concentrated at 50 ⁰ C and 0 05 mmHg (0.007 kPa) to dryness. the residue is taken up in twice 100 cc of ethanol to obtain jedecmal at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. the residue is treated with 50 cc of ethanol at 45 ⁰ C for 15 minutes, filtered, the solid is washed with twice 20 ecm of ether and dried to give 1.08 g of 7 - / '2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido J-3- ££ * 4- (2-aminoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl) -2-thiovinyl J-2-carboxy-8 -oxo-5-thia-1-aza-bicyclo C4.2.0 J oct-2-ene, syn isomer, Ε-form, in the form of the formate, in

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Shape of a yellow powder.

•• I Infrared spectrum (KBr), characteristic bands (cm) 3500, 2200, 1770, 1710, 1680, 1630, 1530, 1380, 1040, 930

29.9.1980 AP C 07 D / 221 22 127 1. - ^ '57 466/11

NMR proton spectrum ·

(350 MHz, DMSO, <f in ppm, O in Hz) 3.12 (m, 2H, -CH ₂ -C ₁ H ₂ -NH ₂ ); 3.51 and 3.60 (2d, O = 18, 2H, -SCH ₂ -); 3.85 (s, 3H, CH ₃ ON =); 4.12 (t, 0 = 6, 2H, ^ rNCH ₂ -CH ₂ -NH ₂ ); 5.12 (d, 0 = 4, IH, H ₅ ); 5.67 (dd, 0 = 4 and 9, IH, H ₇ ); 6.44 (d, O = 8, IH, -CH = CHS-); 6.73 (s, IH, H of the thiazole); 7.2 (s wide, 2H, -NH ₂ ); 8,18 (s, IH, H of the formate); 9.55 (d, 0 = 9, IH, -NHCO).

The 4- (2-t-butoxycarbonylaminoethyl) -5,6-dioxo-3-thioxo ~ 1,2,4-perhydrotriazine can be prepared in the following manner: * - * * '-'

To a solution of 0.92 g of sodium in 40 cc of methanol are added at 20 ⁰ C. 9.37 g of 4- (2-t-ßutoxycarbonylaminoethyl) ~ thiosemicarbazide and added dropwise during 10 minutes. 5.4 g of diethyl oxalate. The mixture is refluxed for 3 h. Allow to cool, add 100 cc of water are added, dropwise, 3 cc of concentrated hydrochloric acid to, extracted twice with 100 cc of ethyl acetate, washed twice with 50 cc of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2, 7 kPa) to dryness, the residue is taken up in 65 ecm of methylene chloride, initiates the crystallization, left for 2 h at 20 ⁰ C, filtered and recovered 4.59 g of white crystals of mp = 160 C of 4- (2-t -butoxycarbonylaminoethyl) ~ 5,6-dioxo-3-thioxo-1,2,4-perhydrotriazin.

Infrared spectrum (KBr), characteristic bands (cm 3380, 3150, 1685, 1640, 1545, 1370

29.9.1980 AP.C 07 D / 221 22 1 27 ti - # * __ 57 466/11

NMR proton spectrum

(80 MHz, DMSO, (fin ppm, O in Hz)) 1.45 (s, 9H, -C (CH ₃ J ₃ ), 3.32 (q, O = 5, 2H, -CHgCHgNH-J, 4, 38 (t, O = 5, 2H, -CH ₂ -CH ₂ -NH-); 6.72 (d, 0 = 5, IH, CH ₂ CH ₂ NH-); 12.3 (s wide, IH, -NH-triazine),

The 4- (2-t-butoxycarbonylaminoethyl) -thiosemicarbazide can

29.9.1980 ΛΡ C 07 D / 221 271 22 1 27 1 - # tf- 57-466 / 11

be prepared in the following way:

A mixture of 22.53 g of methyl N- (2-t-butoxycarbonylaminoethyl) dithiocarbamate, 90 ecm of ethanol and 4.4 ecm of hydrazine hydrate is heated under reflux for 1 h 30 min. The solution is concentrated to dryness at 30 C under 20 mmHg (2.7 kPa) and the residue is triturated in the presence of 100 ecm of diethyl ether. The crystallization begins in 5 "minutes." It is left for 1 h at 20 ⁰ C, filtered and dried to give 11.3 g of rose-white crystals of mp = 85 C of 4- (2-t-butoxycarbonylaminoethyl) thiosemicarbazide.

Infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3450, 3350, 1700, 1620, 1545, 1510, 1390, 1370, 1250, 1225 and 1160

NMR proton spectrum

(80 MHz, CDCl ₃ , (f in ppm, D in Hz) (s, 9H, -C (CH ₃ J ₃ ), 3.45 and 3.80 (2t, 3 = 5, 4H,

To a solution of 17.62 g of 2-t-Butoxycarbonylaminoethylamin in 110 ecm of 95% ethanol is added 15.5 ecm of triethylamine and added dropwise over 10 min. 6.65 ecm carbon disulfide, the temperature at 20 to 25 ⁰ C holds. It is stirred for 1 h 30 min. At 22 ⁰ C. It it adds 6.85 g of methyl iodide and stirred for 1 h 30 min. At 22 ⁰ C, is concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness , taken up in 200 ml of ethyl acetate, washed with three times 100 ecm of water, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. 23.2 g of methyl N- (2-t-butoxycarbonylaminoethyl) -dithiocarbamate are obtained in the form of a yellow oil.

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Infrared spectrum (CHBr,), characteristic bands (cm) 3440, 3370, 1700, 1505, 1430, 1380, 1370, 945 -

NMR proton spectrum

(60 MHz, <f in ppm, 0 in Hz)

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1.50 (s, 9H ₁ -C (CH ₃ J ₃ ), 2.65 (s, 3H, -CH ₃ ), 3.50 and 3.80 (2t, 0 = 5, 4H, -CH ₂ )

The 2-t-butoxycarbonylaminoethylamine is prepared by hydrazinolysis of N-t-butoxycarbonyl-phthalimidoethylamine:

To a suspension of 53.7 g of 2-Nt-Butoxycarbonylphthalimidoethylamin in 540 ecm of ethanol is added 10.8 ecm hydrazine hydrate ¹ , and the Gemi'sch is heated for 25 minutes under reflux. It is cooled to 0 C and the mixture filtered. The filtrate is concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa). Are thus obtained 19.6 g 2RN-t-butoxycarbonylaminoethylamine in the form of a ^f = yellow oil.

-1 infrared spectrum (CHCl-); characteristic bands (cm) 3460, 3380, 3320, 1700, 1585, 1500, 1390, 1370, 1150, 490

NMR proton spectrum (60 MHz, _CDCl3, </ * in ppm, 3. in "Hz)

1.48 (s, 9H, -C (CH ₃ J ₃ ); 2.20 (s wide, 2H, -NH ₂ ); 2.80 (t, 0 = 5, 2H, H ₂ N-CH ₂ - CH ₂ -); 3.18 (t, 3 = 5, 2H, CIH ₂ -); 5.50 (s wide, IH, -NHCO-).

Example 29

A mixture of 10.04 g of 2-benzhydryloxycarbonyl-7- (2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido) -8-0X0-5- is stirred at 60 ^° C. for 3 hours under nitrogen. Oxy-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo £ 4.2.0} oct-2-ene, syn isomer, E-form, 200 ecm dimethylformamide, 2.76 g 4- (2 Acetamido-ethyl) -5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine and 2.1 ecm of diisopropylethylamine. The cooled mixture is then diluted with 800 ecm of ethyl acetate, the organic phase is washed with 1.2 l of water

29.9.1980 AP C 07 D / 221 22 127 1 - W ~ 57 466/11

washed, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 20 ° C. The residue is triturated in 150 ecm of ether, the insoluble product is isolated on the filter and, after drying, 9.5 g of 3- [C4- (2-acetamidoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro are obtained 1,2,4-triazine-S-yl -., - thiovinyl-1-benzhydryloxycarbonyl-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidol-8-oxo-5-oxide-5- thia-1-aza-bicyclo £ 4.2.0} oct-2-ene, syn isomer, Ε-form, in the form of a light brown solid.

-1

Infrared spectrum CHBr,), characteristic bands (cm) 3370, 1795, 1710, 1680, 1520, 1495, 1445, 750, 735

NMR proton spectrum

(350 MHz, DMSO d, tf in ppm, 3 in Hz) 1.75 (s, 3H, -COCH ₃ ); 3.65 and 3.90 (2d, 3 = 18, 2H, -SCH ₂ -); 3.86 (s, 3H, -OCH ₃ ); 3.88 (t, 2H, J ^ NCH ₂ -); 5.26 (d, 3 = 4, IH ₁ H in 6); 5.78 (dd, 3 = 4 and 9, 1H, H in 7); 6.73 (s, IH, H of the thiazole); 6.92 (d, 3 = 16, IH, -CIH = CHS-); 6.95 (S, IH, -COOCH-); 7.0 (d, 3 = 16, IH, = CHS-); 7.78) t, 3 = 6, -NhICOCH ₃ ); 8.81 (s, IH, -NHC (C ₅ H ₅ ) ₃ ); 9.60 (d, 3 = 9, IH, -CONH-); 12.60 (s, IH, = N-NHCO- or = NN = C-).

OH

To a cooled to -10 C solution of 9.03 g of 3 ^ 4- (2-acetamidoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazine-S- yl ^^ - thiovinylJ ^ -benzhydryloxycarbonyl ^ - ^ -methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnide-8-oxo-5-oxide-5-thia-1-aza-bicyclo / '4.2.Oj oct-2-ene, syn-isomer, E-form, in 85 ecm of methylene chloride, add 3.4 ecm of dimethylacetamide and then 1.49 ecm of phosphorus trichloride, and stir for 2 h

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2 2 1271 "^ ^ - ^{57 4} δ6 / 11

> '* - / S

at -10 C, diluted with 500 ecm of methylene chloride, washed with 250 ecm of a half-saturated sodium bicarbonate solution and 250 ecm of a saturated sodium chloride solution, dried over sodium sulfate and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 20 ^° C dissolves the resulting chestnut-colored solid

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in a mixture of ethyl acetate-methylene chloride-methanol (120-120-80 ecm) and the solution chromatographed on a column of silica gel Merck (0.04-0.06) (column diameter 4 cm). It is eluted with 1.5 l of a mixture of ethyl acetate-methanol (95-5 vol.) Under a pressure of 40 kPa, to obtain fractions of 125 ecm. Fractions 6-10 are under reduced pressure (20 mmHg; 2.7 kPa) at 20 ⁰ C to dryness. 3.33 g of 3- {f4- (2-acetamidoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl] -2-thiovinyl-1-one are obtained. 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-S-oxo-S-thia-1-aza-bicyclo [4.2.03 oct-2-ene, syn-Isorneres , Ε-form, in the form of a beige solid.

- 1 infrared spectrum (CHBr,), characteristic bands (cm) 3380/1785, 1710, 1680, 1520, 1495, 1445, 755, 740

NMR proton spectrum

(350 MHz, DMSO d _& quot; Tin ppm, 3 in Hz) 1.75 (s, 3H, -COCH ₃ ); 3.32 (mt, 2H, -Ch, NHCO-); 3.62 and 4.30 (2d, 0 = 18, 2H, -SCH ₂ -); 3.86 (t, 2H, ^ NCH ₂ -); 3.86 (s, 3H, -OCH ₃ ); 5.05 (d, 0 = 4, IH, H in Figure 6); 5.85 (dd, 3 = 4 and 9, IH, H in 7); 6.80 (s, IH, H of the thiazole); 6.96 (d, 0 = 16, IH, -CIM = CHS-); 6.97 (s, IH, -COOCH-); 7.12 (d, .0 = 16, IH, = CHS-); 7.98 (t, 0 = 6, IH, -NH COCH ₃ ); 8.75 (s, IH, -NHC (C ₆ H ₅ J ₃ ); 9.04 (d, 0 = 9, IH, -CONH-); 12.60 (s, IH, = N-NHCO- or = NN = C-).

OH

Dissolve 3.15 g of 3-O.sub.4 4- (2-acetamidoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-t-riazin-3-yl-1-thiovinyl-yl -benzhydtyloxycarbonyl-7- £ 2-rnethoxyimino-2 ~ (2-tritylamino-4-thiazolyl) -

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22 127 1, - W. _{57 466/11}

acetamido] -8-oxo-5-thia-1-aza-bicyclo / 4,2'-octo-2-ene, syn isomer, Ε-form in 80 cc formic acid, add 30 cc of water and heat while stirring at 60 C for 30 minutes the cooled mixture is filtered and concentrated under reduced pressure (0.05 rnmHg; 0.007 kPa) at 50 ⁰ C to dryness, the residue is taken up in 250 cc of ethanol, concentrated under reduced pressure.

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^{57 4} 66 / ll

(20 mmHg, 2.7 kPa) at 30 ⁰ C to dryness, this procedure repeated and then takes up the solid with 40 ecm of ethanol, stirring at 40 ⁰ C is stirred. After cooling, filtration and drying, 1.56 g of 3- {/ 4- (2-acetamidoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazine-3 are obtained -yl 3 ~ 2-thiovinyl J-7 "- /" 2 "- (2-amino-4" thiazolyl) -2-methoxyiminoacetamido] -2-carboxy-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2500, 1775, 1710, 1685 to 1630, 1540, 1045, 950

NMR proton spectrum

(350 MHz, DMSO dg, egg in ppm, 3 in Hz) 1.90 (s, 3H, -CH ₃ ); 3.48 (m, 2H, -CH ₂ NH-); 3.62 and 3.73 (2d, 0 = 18, 2H, -SCH ₂ -); 4.0 (s, 3H, -OCH ₃ ); 5.15 (d, 0 = 4, IH, H in Figure 6); 5.82 (dd, 3 = 4 and 9, IH, H in Figure 7); 6.78 (S, IH, H of the thiazole); 6.86 (d, 0 = 16, 1H, -CIj = CHS-); 7.31 (d, 3 = 16, IH, = CHS-); 7.73 (s, 3H, -NH ⁺ ); 9.50 (d, 0 = 9, IH, -CONH-); 12.54 (s wide, IH, -CONHN = or

-C = N-N =)

 OH

Dissolve 0.128 g of the above product in 2 ecm of a 0.1 M solution of sodium bicarbonate, filter and lyophilize the solution. 0.127 g of the sodium salt of 3-c ^ 4- (2-acetamidoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-ylJ-2-thiovinyl are obtained -7-f2- (2-arnino-4-thiazolyl) -2-methoxyiminoacetarnido3-2-carboxy-8-oxo-5-thia-1-azabicyclo / 4,2.03 oct-2-ene, syn-isomer, E -Shape,

29.9.1980 AP C 07 D / 221 22127t - 80Λ - 57 466/11

3.61 g of (2-acetamidoethyl) -5,6-dioxo-3-thioxo-1,2,4-perhydrotriazine Fp inst. Kofier> 260 ⁰ C

Infrared spectrum (KBr), characteristic bands (cm) 3365, 3050, 2000, 1710, 1630, 1600-1580, 1545, 1350, 1330, 1200

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2 2 1 2 7 1i "^" ^{57 465/11}

NMR Protoneηspektrum

(30 MHz, DMSO d, / "in ppm, 3 in Hz)

1.7 (s, 3H ₁ -CH ₃ ); 3 - 3.7 (mt, -CH ₂ NHCO 3 and H ₂ O); 4.3

(t, 2H,> N CH ₂ -); 7.85 (t, IH, -NHCO-); 12.5 (m, 2H,

-NH- of the cycle)

starting from 4.41 g of 4 ~ (2-acetamidoethyl) -thiosemicarbazide and 3.4 ecm of ethyl oxalate in the presence of sodium methylate by the method described by M, Pesson and M. Antoine, Bull. Soc. Chim, France 1590 (1970).

The starting thiosemicarbazide can be obtained by working in the following manner:

A solution of 57.7 g of methyl N- (2-acetamidoethyl) dithiocarbamate and 14.6 ecm of hydrazine hydrate in 300 eq of absolute ethanol is refluxed for 2 hours. The mixture is cooled to 4 C, filtered and the insoluble material is dried at 30 ⁰ C below 0.05 mmHg (0.007 kPa). 39.5 g of 4 ~ (2-acetamidoethyl) thiosemicarbazide in the form of white crystals are obtained (mp. Inst. £ l <oflerj = 171 ⁰ C).

- 1 infrared spectrum (KBr), characteristic bands (cm)

3280/380, 1650, 1560-1535, 1360, 1280.

Example 30

The mixture is stirred at 60 ⁰ C for 6 h and at 20 ⁰ C for 8 hours a mixture of 10.04 g of 2-benzhydryloxycarbonyl-7-f2 ~ methoxyimino-2- (2-t ritylamino-4-thiazolyl) -a cetamidoJ- 8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene, syn-isomer, E-form, 50 ecm dimethylformamide, 3.95 g l- (2,2-dimethoxyethyl) -5-mercapto-2-methoxycarbonyl-l, 3 _i 4-tri azole and 1.91 · ecm Ν, Ν-diisopropylethylamine. The mixture is poured into 700 ecm of ethyl acetate,

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Wash twice with 125 cc of water, 150 cc of 0.1 N hydrochloric acid, twice with 150 cc of a half-saturated sodium bicarbonate solution, and twice with 150 cc of water

ti -;

is half saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness at 20 mmHg (2.7 kPa) at 20 ° C. The product is fixed to 50 g of silica gel Merck (0.06-0.2) and chromatographed on a column of 200 g silica gel Merck (0.06-0.2) (column diameter 4 cm, height 46 cm). It is eluted with 3.5% ethyl acetate to yield fractions of 250 ecm. The fractions 5-14 are evaporated to dryness at 30 C under 20 mmHg (2.7 kPa) and 4.35 g of 2-benzhydryloxycarbony1-3- (ri- (2,2-dimethoxyethyl) -2-methoxycarbonyl-1 are obtained. 3,4-triazol-5-yl} -2-thiovinylj-7- ^ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5-oxide-5-thia-1- aza-bicyclo C4.2.0Ü-oct-2-ene, syn isomer, Ε-form, in the form of an orange solid.

Infrared spectrum (KBr), characteristic bands (cm) 3400, 1800, 1730, 1685, 1515, 1495, 1450, 1210, 1050, 945, 755, 700

NMR Protcrcnspektrum

(350 MHz, DMSO d ₆ , <f in ppm, 0 in Hz) 3.30 (s, 6H ₁ > C (OCH ₃ J ₂ ); 3.86 (s, 3H, CH ₃ ON =); 3, 94 (s, 3H, CH ₃ OCO-); 3.64 and 4.35 (2d, 0 = 18, 2H, -SCH -); 4.35 (d, 0 = 6, 2H,:> CH-CH ₂ NCC); 4.58 (t, 0 = 6, IH, 2 CH-CH ₂ ~ N <), 5.05 (d, 0 = 4, IH, H in 6); (dd, 5.86; 0 = 4 and 9, H ₇ ), 6.80 (s, IH, H of the thiazole), 6.98 (s, IH, -COOCH <), 7.06 (d, 0 = 16, -ChI = CH -S-); 7.17 (d, 0 = 16, IH, -CH = CJH-S-); 8.72 (s, IH, -NH _- - thiazolyl); 9.0 (d, 0 = 9 , IH, -CONH-).

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A solution of 4.15 g of 2-benzhydryloxycarbonyl-3-yl-l- (2,2-dimethoxyethyl) -2-methoxycarbonyl-ljS-1-riazole-5 is treated at -6.degree. C. for 1 h 20 min. ylJ-2-thiovinyl-7-8-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-8-oxo-5-oxide ~ 5-thia-1-aza-bicyclo £ 4.2.03 oct 2-ene, syn isomer, Ε form, in 60 ecm

29.9.1980 AP C 07 D / 221 22 127 1 _ .305. * Sy 466/11

Methylene chloride and 1.46 ecm of dimethylacetamide, with 0.67 cc of phosphorus trichloride. It is diluted with 700 cc of ethyl acetate, washed with 150 cc of water, 150 cc of a saturated sodium bicarbonate solution and 150 cc of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. The residue is chromatographed on a column of 150 g of silica gel Merck (0.06-0.2) (column diameter 4.5 cm, height 28 cm). It is eluted with 1.7 l of ethyl acetate, collecting fractions of 250 ecm. Fractions 2-6 are evaporated to dryness at 20 ^° C. under 20 mmHg (2.7 kPa). You gain 4 g of an orange meringue. This product is dissolved in 70 ecm of ethyl acetate, 450 g of diisopropyl ether are added with stirring, filtered and dried. This gives 3.4 g of 2-benzhydryloxycarbonyl-3-lb / 'l- (2,2-dimethoxyethyl) -2-methoxycarbonyl-l, 3,4-triazol-5-yl3-2-thiovinyl-7-r2-methoxyimino -2- (2-tris-ylamino-4-thiazolyl) -acetamido-S-oxo-S-thia-1-aza-bicyclo ¢ 4.2.Oj oct-2-ene, syn isomer, Ε-form, in Form of a beige solid.

I Infrared Spectrum (KBr), characteristic bands (cm) 3400, 1790, 1730, 1690, 1520, 1495, 1450, 1210, 1090, 1050, 945, 755 and 705

NMR proton spectrum

(350 MHz, DMSO d, cf in ppm, 0 in Hz) 3.29 (-S-, 6H, -C (OCH ₃ ) ₂ ); 3.65 and 3.87 (2d, 0 = 18, 2H, -SCH ₂ -); 3.86 (s, 3H, = N-OCH [ ₃ ]; 3.94 (s, 3H, C] H OCO-); 4.35 (d, 0 = 6, 2H,> NCH ₂ CHcC); 4.57 (t, 0 = 6, IH, ^ NCI-I ₂ ChI-); 5.23 (d, 0 = 4, IH, H ₅ ); 5.77 (dd, 0 = 4 and 9, IH, H ₇ ); 6.73 (s, IH, H of the thiazole); 6.94 (s, IH, -COOCJH <T); 7.0 (d, 0 = 12, IH, -CH = CH-S-); 7.10 (d, 0 = 12, IH, -CH = C] HS);

29.9.1980 AP C 07 D / 221 2 2 1 2 7 1 - 2E -> 57 466/11

8.77 (s, IH, r NH); 9.57 (d, 0 = 9, IH, -CONH-).

A solution of 3.3 g of 2-benzhydryloxycarbonyl-3-ω-1-L- (2,2-dimethoxyethyl) -2-methoxy is stirred at 50 ° C. for 40 minutes.

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carbonyl-l, 3,4-triazol-5-yl] -2-thiovinylJ-7-fe-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoj-8-oxo-5-thia-1-aza -bJLcyclo f4.2.03 oct-2-ene, syn isomer, Ε form, in 100 ecm formic acid. It is concentrated to dryness at 30 ° C under 0.05 mmHg (0.007 kPa), taken up in 60 ecm of acetone, concentrated again at 20 ° C under 20 mmHg (2.7 kPa) to dryness and this procedure is repeated twice. The remaining solid is treated with 15 ecm of acetone at 40 C, allowed to cool and filtered. After filtration and drying, 0.65 g of 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido3-2-carboxy-3- (2-amino-4-thiazolyl) -3- {("1- (2,2-dimethoxyethyl) - 2-methoxycarbonyl-l, 3,4-triazol-5-yl3-2-thiovinyl-8-oxo-5-thia-1-aza-bicyclo / 4,2,2-octo-2-yne, syn isomer, Ε Shape, in the form of a cream-colored powder.

Infrared spectrum (KBr), characteristic bands (cm) 3200, 1775, 1735, 1680, 1620, 1535, 1385, 1050, 945

NMR proton spectrum

(350 MHz, CF ₃ COOD, </ in ppm, 3 in Hz) 3.65 (s, 6H,> 5 CH (OCH ₃ ) ₂ ); 4.21 (s, 3H, COOCH _3); 4.29 (s, 3H, = NOCH ₃ ); 5.38 (d, 0 = 4, IH, H in Figure 6); 6.08 (d, D = 4, IH, H in 7); 7.07 and 7.95 (2d, D = 16, 2H, -CH = CHS-); 7.48 (s, IH, H of the thiazole)

The 1- (2,2-dimethoxyethyl) -5-mereapto-2-methoxycarbonyl-1,3,4-triazole is obtained as a by-product in the preparation of 4- (2,2-dimethoxyethyl) -5,6-dioxo 3-thioxo-l, 2,4-perhydrotriazin described above in example 16 d _# h. in the condensation of 81.6 g of ethyl oxalate with 100 g of 4- (2,2-dimethoxyethyl) -thiosemicarbazide, in the presence of 44.0 g of sodium methylate in 440 ecm of methanol. At the end of

29.9.1980 AP C 07 D / 221 22 127 1 - iO8 .. 57 466/11

Reaction, the mixture is filtered, and you win 46.8 g of the matrial salt of triazine. The filtrate is at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness is taken up in 300 cc of ethyl acetate and acidified with stirring with 200 cc of 1 N hydrochloric acid. It is decanted, washed three times with 100 ml of sodium chloride.

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2 2 1 2 7 1 - v3oS> - 57.466 / n

water, dried over sodium sulfate, filtered and concentrated to dryness at 20 ^° C. under 20 mmHg (2.7 kPa). The residue is chromatographed on 200 g of silica gel Merck (0.06-0.2) (column diameter 4.5 cm, height 25 cm). It is eluted with 1 1 of a mixture of cyclohexane-ethyl acetate (30-70 vol.), Wins fractions of 100 ecm. The fractions 2-9 are concentrated to dryness at 20 ° C. under 20 mmHg (2.7 kPa) and 14.3 g of a white crystalline solid of mp = 123 ° C. are obtained.

Infrared spectrum (CHBr_), characteristic bands (cm) 3420, 3200, 2840, 2600, 1745, 1450, 1085, 1065, 980.

Example 31

To a solution of 2.37 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-8-oxo-3 - (2-tosyloxyvinyl) -5-thia-1-one aza-bicyclo f4.2.0j oct-2-ene, syn isomer, Ε-shape, in 75 cc of dry N ₁ N-dimethylformamide, heated to 60 C, is added 0.75 g of 1,4-dimethyl ~ 5, 6 ~ dioxo ~ 3 ~ thioxo ~ l, 2,4-perhydrotriazine and then, dropwise over 15 minutes, a solution of 0.42 ecm N, N-diisopropylethylamine in 25 ecm of dry N, N-dimethylformamide. The reaction mixture is stirred for 25 minutes at 60 C, then diluted with 400 ecm of ethyl acetate and washed with three times 200 ecm of distilled water and then 100 ecm of a saturated sodium? bicarbonate solution and with 200 ecm of a saturated sodium chloride solution. After drying over magnesium sulfate, the organic phase (30 mmHg; 4 kPa) under reduced pressure at 40 ⁰ C and concentrated to dryness. This gives 2 g of an orange meringue, which is chromatographed by chromatography on a column of silica gel Merck (0.04-0.06) (column diameter 4 cm, height 30 cm), with 2 1 of a mixture of cyclohexane and ethyl acetate (30 - 70 Vol.)

29.9.1980 AP C 07 D / 221 271 22 1 2 7 1, _ 340-. 57 466/11

elutes and collects fractions of 50 ecm. Fractions 15-40 are combined and concentrated under reduced pressure (30 mmHg; 4 kPa) at 40 ^° C. This gives 0.85 g of 2-Benzhydryloxycarbony1-3- C [ l, 4-dimethyl-5,6-dioxo-l, 4,5 _f 6-tetrahydro-l ₁ 2 _# 4-triazin-3-yl) -2 -thiovinyl-3-7-r2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnido} ~ 8-oxo-5-thia-1-aza-bicyclo-≤ 4.2.03 oct-2-ene (50 / 50 mixture of syn and anti isomers, the E form). <

Infrared spectrum (KBr), characteristic bands (cm) 3400, 1790, 1720, 1680, 1585, 1520, 1506, 1450, 1035, 1025, 945, 760

NMR proton spectrum

(350 MHz, CDCl ₃ , egg in ppm, 0 in Hz)

syn isomer:

3.43 and 3.58 (2 s, 2 χ 3H, 2CH of the triazine); 3.61 and 3.70 (2d, 0 = 18, 2H, -SCH ₂ -); 4.08 (s, 3H ₁ = NOCH ₃ ); 5.12 (d, 0 = 4, IH, H in 6); 5.95 (dd, 3 = 4 and 9, IH, H in Figure 7); 6.77 (S, IH, H-thiazole); 6.81 (d, 0 = 16, IH, -CKh = CH-S-); 6.98 (s, IH, -CO ₂ CH (C ₆ H ₅ J ₂ ), 7.0 (s wide, IH, NH, trityl); 7.2-7.50 (solid, 27H, aromatic, CONIH-C ₇ , -CH = CH-S-).

anti-isomer:

3.43 and 3.50 (2 s, 2 χ 3H, 2CH _{3 of} the triazine); 3.50 and 3.58 (2d, 0 = 18, 2H ₁ -SCH ₂ -); 4,12 (s, 3H, SNOCH ₃ ); 5.13 (d, 0 = 4, IH, H in 6); 6.08 (dd, 0 = 4 and 9, IH, H in 7); 6.75 (d, 0 = 16, IH, -CH = CH-S-); 6.98 (s, IH, -CO ₂ CH (C ₅ H ₅ J ₂ ); 7.18 (s broad, IH, -NH-trityl); 7.2-7.50 (solid, 26H, aromatic, -CH = CIH-S-); 7.42 (s, IH, H, thiazole); 9.60 (d, 0 = 9, -CONH-C ₇ ).

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2 2 12 7 1 - ^ ~ ^{57 4} J ^5/11

Add 10 eq of distilled water to a solution of 0.8 g of 2-benzhydryloxycarbonyl-3- (1,4-dimethyl-5,6-dioxo-1,4,5,6-tetrahydro-l, 2,4- triazine-3-yl) -2-thiovinyl] -7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-thia-1-aza-bicyclo ^ 4,2.0 ^ oct-2-ene (50/50 mixture of syn and anti isomers

29.9.1980 AP C 07 D / 221 271 22 127 1. - ^ a- 57 466/11

of the Ε-form) in 20 ecm of 98% formic acid and then heated the reaction mixture for 25 minutes at '60 C, After concentration under reduced pressure (10 mmHg, 1.33 kPa) at 40 C, the residue is triturated with 25 ecm of absolute Ethanol and the solvent is concentrated to dryness under reduced pressure (30 mmHg; 4 kPa) at 40 ° C. This procedure is repeated twice more and then takes up the solid residue in 20 ecm boiling ethanol. The residue is filtered off with suction in the heat and dried under reduced pressure (10 mmHg, 1.33 kPa) * at 25 ° C. This gives 0.345 g of 7-r2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido3-2-carboxy-3-l (1,4-dimethyl-5,6-dioxo-l, 4,5,6- tetrahydrol, 2 _{L of} 4-triazin-3-yl) -2-thiovinyl J-8-oxo-5-thia-1-aza-bicyclo. 4,2.03 oct-2-ene, (50/50 mixture of the syn- and anti-isomers of the E-form),

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2.300, 1770, 1710, 1670, 1575, 1530, 1030, 940

NMR proton spectrum

(350 MHz, DMSO _dβ , cf in ppm, D in Hz)

syn isomer:

3.35 and 3.48 (2s, 2χ3H, 2-CH- of the triazines); 3.66 and 3.90 (2d, 0 = 18, 2H, -SCH ₂ -); 3.87 (s, 3H, = NOCH ₃ ); 5.18 (d, 0 = 4, IH, H in Figure 6); 5.82 (dd, 0 = 4 and 9, IH, H in 7); 6.74 (s, IH, H thiazole); 6.95 and 7.14 (2d, 0 = 16, 2H, -CH = CH-S-); 7.18 (s wide, 2H, -NH ₂ ); 9.64 (d, 0 = 9, IH, -CONiH-),

anti-isomer:

3.35 and 3.48 (2s; 2 χ 3H, _2-CH3 of the triazine); 3.66 and 3.90

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57 466/11

(2d, D = 18, 2H, -SCH ₂ -); 3.98 (s, 3H, = NOCH ₃ ); 5.19 (d, 0 = 4, IH, H in 6); 5.81 (dd, 3 = 4 and 9, IH, H in Figure 7); 6.95 and 7.15 (2d, 3 = 16, 2H, -CH = CH-S-); 7.09 (s wide, 2H, -NH ₂ ); 9.48 (d, 0 = 9, IH, -CONH-).

The l, 4-dimethyl-5 _f 6-dioxo-3-thioxo-l, 2,4 ~ perhydrotriazine can

29.9.1980 AP C 07 E / 221 271 2 2 1 2 7 \ i -3 / n -. ·. 57 466/11

be prepared according to the method described in BE-PS 830 455,

Example 32

A mixture of 1 g of 2-benzhydryloxycarbonyl-7 - / 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-8-oxo is stirred at 23 ^° C. under nitrogen for 1 h 20 min. 3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo f4.2.0j oct-2-ene, syn-isomer, E-form, 10 ecm dimethylformamide, 0.345 g 5,6-dioxo-l-ethyl 3-thioxo-1, 2,4-perhydrotriazine and 0.35 ecm Ν, Ν-diisopropylethylamine. The mixture is poured into 100 eq of a 2% sodium bicarbonate solution, extracted with 2 × 30 ecm of ethyl acetate, the organic phase washed with 50 ecm of 0.05N hydrochloric acid and 50 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C below 20 mmHg (2.7 kPa) to dryness. The residue is chromatographed on a column of silica gel Merck (0.04-0.06) (column diameter 1.5 cm, height 30 cm). It is eluted with 0 _f 5 l of ethyl acetate under a pressure of 40 kPa, collecting fractions of 25 ecm. The fractions 4-15 are evaporated to dryness at 20.degree. C. under 20 mmHg (2.7 kPa) and 0.75 g of 2-benzhydryloxycarbonyl-3-f (5,6-dioxo-1-ethyll, 4.5, 6-tetrahydro-l, 2,4-triazin-3-yl) -2-7- thiovinyl3 ~ £ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido] -8-oxo-5-thia -l-aza-bicyclo f4.2,0j oct-2-ene, syn isomer, Ε-form, in the form of a yellow meringue.

- 1 infrared spectrum (CHBr,), characteristic bands (cm) 3410, 1795, 1720, 1625, 1605, 1560, 1505, 1455, 1245, 1205, 1045, 940, 760, 745

NMR proton spectrum

(350 MHz, DMSO d, J "in ppm, D in Hz)

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1.25 (t, 0 = 7, -CH ₂ CH ₃ ); 3.68 and 3.88 (2d, 3 = 18, 2H, -SCH ₂ -); 3.80-3.90 (solid, 5H, -CH ₂ CH ₃ and -OCH ₃ ); 5.22 (d, 0 = 4, IH, H in 6); 5.74 (dd, 0 = 4 and 9, IH, H in Fig. 7); 6.75 (s, IH, H of the thiazole); 6.94 (s, IH, -COOCH-); 6.95 (d, 0 = 16, IH, -CH = CHS-); 8.80 (s, IH ₁ -NHC (C ₅ H ₅ J ₃ ); 9.60 (d, 0 = 9, IH, -CONH-).

A mixture of 0.72 g of 2-benzhydryloxycarbonyl-3-f (5,6-dioxo-1-ethyll, 4,5,6-tetrahydro-1, 2,4-triazine) is treated at 50 ° C. for 45 minutes *. 3-yl) -2-thiovinyl J -7- (2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido) -8-oxo-5-thia-1-aza-bicyclo r4,2.0j-oct -2-ene, syn-isomer, E-form, 12 cc formic acid and 6 cc water. Filter the cooled mixture, concentrate to dryness at 35 C below 0.05 mmHg (0.007 kPa) and take up with 20 cm 2 of ethanol , wherein each time at 20 C under 20 mmHg (2.7 kPa) evaporated to dryness * The solid residue is triturated in 10 ecm of ethanol at 60 ⁰ C for 10 min, filtered the cooled suspension, washed with twice 5 ecm diethyl ether and dry. 0.39 g of 7-f 2 - (2-amino-4-thiazolyl) -2-methoxyimino-acetarnido-2-carboxy-3- [( 5,6-dioxo-1-ethyl-1,4,4,5, 6-1-tetrahydro-1,2,4-triazin-3-yl) -2-thiovinyl J-8-oxo-5-thia-1-aza-bicyclo ¢ 4.2.Oj oct-2-ene, syn isomer, Ε- Form, in the form of a yellow powder,

Infrared spectrum (KBr), characteristic bands (cm) 3700, 2200, 1770, 1720, 1665, 1630, 1590, 1040, 945

NMR proton spectrum

(350 MHz, DMSO dg, <f in ppm, 0 in Hz) 1.25 (t, 0 = 7, 3H, -CH ₂ CIH ₃ -); 3.71 and 3.88 (2d, 0 = 18, 2H ₁ -SCH ₂ -); 3.80-3.90 (solid, 5H,., CH ₂ CH ₃ and -OCH ₃ ); 5.19 (d, 0 = 4, IH, H in 6); 5.75 (dd, 0 = 4 and 9, IH, H in 7); 6.77 (s, IH, H of the thiazole); 7.10 (s wide, 2H, -CH = CH-); 7.20 (s, 2H, -NH ₂ ); 9.62 (d, 0 = 9, IH, -CONH -) *

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The 1-ethyl-5 _/ 6 ⁱ -dioxo-3-thioxo-l, 2 _f 4-perhydrotriazine can be prepared in the following manner:

Prepare a solution of 1.15 g of sodium in 25 cc of methanol forth added 11 g of 1-ethyl-l-ethoxalyl-thiosemicarbazide and heated to reflux for 1 hour, the reaction mixture is concentrated at 20 ⁰ C under 20 mmHg (2, 7 kPa) to dryness, triturated in 50 ecm diethyl ether and filtered. The resulting yellow solid is dissolved in 15 ecm of water, acidified by the addition of 2 η-hydrochloric acid to pH 2, initiates the crystallization by scratching, left for 1 h at 4 ⁰ C and filtered. 5 g of 1-ethyl-5,6-dioxo-3-thioxo-l, 2,4-perhydrotriazine are obtained in the form of a pale yellow solid of melting point 214 ° to 216 ° C. _#

The 1-ethyl-1-ethoxalyl-thiosemicarbazide can be prepared in the following ways:

To a solution of 20 C of 11.9 g of i-ethylthiosemicarbazide in 200 ecm of acetone is added dropwise over 10 min. 10.6 ecm of ethoxalyl chloride, the temperature rises to 43 C, it is stirred for 1 h, without warming concentrated 20 C under 20 mmHg (2.7 kPa) to dryness, takes up in 30 ecm of methanol and initiates the crystallization After filtration and drying, 13.2 g of 1-ethyl-lethoxalyl-thiosemicarbazide in the form of a white solid from the FP 170 ° C «

The 1-ethylthiosemicarbazide is prepared by reducing 52 g of thiosemicarbazone of the acetaldehyde in 2 liters of ethanol with 26 g of sodium borohydride. The product obtained melts at 143 ° C.

29.9o3.980 AP C 07 D / 221 271 2 2 127 1. - · b / ft ' ^! - 57 466/11,

The thiosemicarbazone of acetaldehyde (52.2 g) is obtained by condensation of 45.5 g of thiosemicarbazide and 42.4 ecm of acetaldehyde in 1 liter of ethanol. The product crystallizes by partial concentration of the reaction mixture, mp = 153 ⁰ C.

29.9.1980 AP C 07 D / 221 271 1271 -3 / IS-57 466/11

Example 33

The mixture is heated at 60 C under nitrogen with stirring for 20 h, a mixture of 7.03 g of 2-Benzhydryloxycarbonyl-7-p> methoxyimino ~ 2- (2-tritylamino-4-thiazolyl) acetamido} - ^ - oxo-5 ~ Oxy-3- (2-tosyloxyvinyl) ~ 5-thia-1-aza-bicyclo / 4,2,0JoCt-2~en, syn-isomer, E-form, 70 ecm of dimethylformamide, 1.23 g of 5,6-dioxo 2-Methyl-3-thioxo-l, 2,4-perhydrotriazine and 1,34 ecm Ν, Ν-diisopropylethylamine, poured into 300 eq of ethyl acetate, washed with four times 150 eq of water, dried over sodium sulphate, filtered and concentrated The product is purified by chromatography on a column of 200 g of silica gel Merck (0.04-0.06) (column diameter 6 cm, height 30 cm) and eluted with 20 .mu.Hg (2.7 kPa) 3.5 1 of a cyclohexane-ethyl acetate mixture - fractions 17 (20. 80 volume) under a pressure of 40 kPa in order to recover fractions of I25ccm -. 25 are at 20 ⁰ C under 20 mmHg (2.7 kPa) concentrated to dryness, 0.50 g of 2-benzhydryloxycarbonyl-3 is obtained. r (5,6-dioxo-2-methyl-l, 2 _t 5,6-tetrahydro-l, 2,4-triazin-3-yl) - 2- thiovinyl] J-7- [z-me thoxyimino-2 - (2-tritylamino-4-thiazolyl) acetamidoj-S-oxo-S-oxide-S-thia-1-aza-bicyclo [4.2.o3oct-2-ene, syn isomer, Ε form, in Form of a cream meringue.

Infrared spectrum (CHBr ₃ ), characteristic bands (cm) 1800, 1725, 1685, 1595, 1515, 1495, 1450, 1040, 750, 700

NMR proton spectrum

(350 MHz, CDCl ₃ , J in ppm, 0 in Hz) 3.24 and 3.88 (2d, 0 = 18, 2H, -SCH ₂ -); 3.80 (s, 3H, -CH ₃ ); 4.09 (s, 3H, -OCH ₃ ); 4.60 (d, 0 = 4, IH, H in 6); 6.15 (dd, 0 = 4 and 9, IH, H in Fig. 7); 6.74 (s, IH, H of the thiazole); 6.95 (s, IH, -COOCH = C); 7.73 (d, 0 = 9, IH, -CONH-).

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A solution of 0.5 g of 2-benzhydryloxycarbonyl-3-r (5 _/ 6-dioxo-2-methyl-1,2,5,6-tetrahydro-1,2-one at -9 C for lh 40 min. 4-triazine-3-yl) -2-thiovinyl-3-7-C2-methoxyimino-

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2- (2-tritylamirio-4-thiazolyl) -acetamido} -8-0X0-5-OX10-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn-isomer, E-form , in 30 ecm methylene chloride and 0.192 ecm dimethylacetamide with D _t l76 ecm phosphorus trichloride. The mixture is diluted with 250 cc of ethyl acetate, washed twice with 100 cc of water, 100 cc of a saturated sodium bicarbonate solution and 100 cc of water, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. The product is purified by chromatography on a column of 50 g silica gel Merck (0.06-0.2) (column diameter 2.5 cm, height 15 cm). It is eluted with 500 ecm of ethyl acetate to give fractions of 30 ecm, the fractions 6-10 are concentrated to dryness at 20 ° C. under 20 mmHg (2.7 kPa) and 0.4 g of 2-benzhydryloxycarbony1-3- (5 , 6-dioxo-2-methyl-1, 2,5,6-tetrahydrol, 2 _{l of} 4-triazin-3-yl) -2-thiovinyl] -7-f2-methoxyimino-2- (2-t-ritylamino-4 -r thiazolyl) -α-ce tarn ido} · 8-oxo-5-thia-1-azabicyclo £ 4.2.Oj oct-2-ene, syn isomer, Ε form, in the form of a yellow orange meringue.

1 infrared spectrum (CHBr,), characteristic bands (cm) 3400, 1780, 1725, 1680, 1595, 1520, 1495, 1450, 1040,

NMR proton spectrum

(350 MHz, _CDCl3, <f in ppm, D in Hz) 3.52 and 3.61 (2d, D = 18, 2H, -SCH ₂ -); 3.84 (s, 3H, -CH _3); 4.08 (s, 3H, -OCH ₃ ); 5.12 (d, 0 = 4, IH, H in 6); 5.84 (dd, 0 = 4 and 9, IH, H in 7); 6.78 (s, IH, H of the thiazole); 6.81 (d, 0 = 9, IH, -CONH-); 6.98 (s, IH, -COOCH = CI); 7.18 (d, 0 = 16, IH, -CH = CHS-); 7.20 (s, IH, -NHC (C ₆ H ₅ J ₃ ).

29.9.1980 AP C 07 D / 221 2 2 12 7 1 - W - 57 466/11

Treated at 50 ⁰ C for 30 min. A mixture of 0.18 g of 2 ~ Ben2hydryloxycarbonyl-3 ~ £ (5,6-dioxo-2-methyl-1,2,5,6-tetrahydro-1,2,4 -triazin-3-yl) -2-thiovinyl] -7- [2- methoxyimino-2- (2-tritylamino-4-thiazolyl) -aeetamidoj-8-oxo-5-thia-1-aza-bicyclo f4.2 , 0] oct-2-ene, syn-isomer, E-form, 15 ecm of formic acid and 15 ecm of water. The mixture is filtered and concentrated at 30 ⁰ C under 0.05 mm Hg (0.007 kPa) to dryness, taken up with four times 25 cc of ethanol,

29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 - 3 $ 2 - 57 466/11

each time (at 20 C under 20 mmHg, 2.7 kPa) evaporated to dryness, the residue triturated in '10 ecm of ethanol at 60 C, allowed to cool and filtered. After drying, 0.062 g of 7- (2-aminog-4-thiazolyl) -2-methoxyiminoacetamido-J-2-carboxy-3-one (5,6-dioxo-2-methyl-1,2,5, 6-tetrahydro-1,2,4-triazin-3-yl) -2-thiovinyrj-8-oxo-5-thia-1-aza-bicyclo [4.2.2. Octo-2-ene, syn-isomer, e. Form, in the form of a yellow powder,.

Infrared spectrum (KBr), characteristic bands (cn ") 3600, 2300, 1765, 1720, 1670, 1600, 1525, 1280, 1075, 1040, 930

NMR proton spectrum

(350 MHz, CF ₃ COOD, cT in ppm, 0 in Hz) 3.77 and 3.88 (2d, 0 = 18, 2H, -SCH ₂ -); 4.0 (s, 3H, -CH ₃ ); 4.30 (s, 3H, -OCH ₃ ); 5, 41 (d, 0 = 4, IH, H in 6); 6.0 (d, 0 = 4, IH, H in 7); 7.50 (s, IH, H of the thiazole).

The 5,6-dioxo-2-methyl-3-thioxo-l, 2,4-perhydrotriazine can be prepared in the following manner:

A solution of 4.6 g of sodium with 200 eq of methanol is prepared under nitrogen and 21.03 g of 2-methylthiosemicarbazide are added at 40 ° C. to this solution, and 27.1 ecm of diethyl oxalate are added dropwise over 10 minutes. The mixture is then heated under reflux with stirring for 5 h and cooled to 5 C for 1 h. The mixture is filtered, and the resulting white crystals are washed with 25 ecm of methanol and three times 25 ecm of ether. The resulting sodium salt is stirred in the presence of 50 ecm 2 η-hydrochloric acid for 15 min. At 20 ⁰ C and then for 1 h at 5 ° C.

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Filter and recover 10.7 g of a white solid consisting of the expected product, the starting thiosemicarbazide and S-mercapto-S-methoxycarbonyl-1-methyl-1,2,4-triazole. After dissolution under reflux in 200 ecm of methylene chloride, cooling and filtration, 9.63 g of a mixture of the expected product and of 2-methylthiosemicarbazide are obtained. The final cleaning of the product is done by

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Transfer to the sodium salt (in 200 ecm of methanol, add 10 ecm of a 4N sodium 2-ethylhexanoate solution and filter), then acidify (10 ecm of water through 20 ecm of 2N hydrochloric acid). 5.5 g of 5,6-dioxo-2-methyl-3-thioxo-l, 2,4-perhydrotriazine are obtained in the form of a white powder of mp = 185 ° C.

The 2-methylthiosemicarbazide is prepared according to K, A. Oensen, Acta Chem. Scand. 22, 1-50 (1968).

Example 34

To a solution of 6.92 g of 2-benzhydryloxycarbonyl-7 - [2- methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamidoJ-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5 -thia-1-aza-bicyclo £ 4.2.OJ oct-2-ene, syn isomer, Ε-form, in 35 ecm dry N, N-dimethylformamide is added dropwise at 65 C under nitrogen for 40 min, a solution of 1.21 ecm Ν, Ν-diisopropylethylamine and 2.2 g of an equimolecular mixture of 3-methoxycarbonyl-1-methyl-5-thioxo-l, 2,4-triazoline and 5,6-dioxo-2-methyl-3- thioxo ~ l, 2,4-perhydrotriazine ^ prepared according to M. Pesson and M. Antoine, CR Acad. Be., Ser. C 267, 25, 1726 (1968) 3 in 35 cm dry N, N-dimethylformamide. The reaction mixture is stirred for 5 h 30 min. At 65 ⁰ C and then diluted with 200 ecm.Ethylacetat and washed with twice 100 ecm of distilled water After drying over magnesium sulfate and filtration, the organic phase under reduced pressure (30 mmHg, 4 kPa) concentrated at 40 ⁰ C to dryness. The residue is chromatographed on a column (height 35 cm, diameter 4 cm) of silica gel (0.02-0.04 mm) eluting under a pressure of 40 kPa

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4.5 L of a mixture of cyclohexane and ethyl acetate (30-70 vol.) And recovering fractions of 100 ecm. Fractions 2, 3 and 4 are combined and concentrated under reduced pressure (30 mmHg; 4 kPa) at 40 ° C. You win like that

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1- &> 6 - 57 466/11

2.1 g of unchanged Ausgangstosylats, Fractions 17-42 are combined and concentrated under reduced pressure (30 mm Hg; 4 kPa) at 40 ⁰ C to dryness. 3 g of 2-benzhydryloxycarbonyl-3-fCS-methoxycarbonyl-methyl-1,2,4-triazol-5-yl-J-2-thiovinyl-7-8-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) are obtained. -acetarnidoj-8-oxo-5-oxide-5-thia-1-aza-bicyclo- / 4.2.0j-oct-2-ene, (syn isomer, Ε-form) in the form of a yellow meringue.

Infrared spectrum (CHBr.,),), Characteristic bands (cm) 3380, 1800, 1730, 1670, 1515, 1495, 1450, 1210, 1040, ₁₇₅₅ 95O, 740

NMR proton spectrum

(350 MHz, CDCl ₃ / ppm in, 0 in Hz)

3.30 and 4 (2d, ö = 18, 2H, -S (O) CH ₂ -); 3.84 (s, 3H, NCH ₃ ^ triazole); 3.97 (s, 3H, -CO ₂ CH ₃ ); 4.07 (s, 3H, = NOCH ₃ ); 4.63 (d, D = 9, IH, H in Figure 6); 6.13 (dd, 0 = 4 and 9, IH, H in Figure 7); 6.72 (s, IH, -CH (C ₆ H ₅ J ₂ ), 7.0 and 7.50 (2d, 0 = 16, 2H,

-CH = CH-S-); 7.09 (s, IH, (C ₆ H ₅ J ₃ CNH-); 7.15-7.45 (Mt, 26H, aromatic and -CONH-C ₇ ).

A solution of 3 g of 2-benzhydryloxycarbonyl-3-β-f3-methoxycarbonyl-1-methyl-1,2,4-triazol-5-ylJ-2-thiovinylj-7- / 2-methoxyimino-2- (2-tritylamino) 4-thiazolyl) -acetamidoJ-8-oxo-5-oxide-5-thia-1-aza-bicyclo Γ4.2.0] oct-2-ene (syn isomer, Ε-form) in a mixture of 30 ecm of dry methylene chloride and 1.2 ecm Ν, Ν-dimethylacetamide is cooled to -25 C and treated with 0.57 ecm of phosphorus trichloride. After stirring for 30 minutes at a temperature of -25 to -10 C, the reaction mixture is washed with 150 ecm of ethyl acetate

29.9.1980 AP C. 07 D / 221 271 2 2 12 7 1 - 3λ> - 57 466/11

diluted and washed with 100 ecm saturated Natriumbicarbonatiösung and then 100 ecm of saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (30 mmHg; 4 kPa) at 40 ° C. The residue is filtered on a column (height 25 cm, diameter 4 cm) of silica gel (0.02-0.04 mm),

22 1 2 71

/ 221

under a pressure of 40 kPa 2.5 1 n:... of cyclohexane and ethyl acetate (50-50 by volume fractions of 100 cc wins The Fr. are combined and concentrated under reduced .- at 40 ⁰ C. This gives 2.3 b carbonyl-3-f3-methoxy-carbonyl-1-methyl-2-thiovinyl-7- / 2-methoxyimino-2 - (2-tr: acetamido-S-oxo-S-thia-1-aza-bicyclo- I - Isomeric, E-form _r in the form of a yellow.

Infrared spectrum (CHBr ₃ ), characteristic 1. 3490, 1785, 1735, 1685, 1515, 1495, 14L.-740

NMR proton spectrum

(350 MHz, CDCl ₃ , S in ppm, D in Hz) 3.62 and 3.72 (2d, D = 18, 2H, -SCH ₂ -), 4.0 (s, 3H,;> NCH _3- triazole ); 4.08 (s, 30 = 9, 1H, H in Figure 6); 5.98 (dd, 3 = 4 and (s, IH, H thiazole); 6.96 (s, IH, -CH (C: (2d, D = 14, 2H, -CH = CH-S-); 7.15 - "- 7, i

+ -CONH-O ₇ + (CH _c ), CNH-) "7. 6 5 3 - '

A solution of 2.3 g of 2-benzhydryloxyc; 1-carbonyl-1-yne] 1-1,2,4-1-riazol-5-yl] -: - '' - methoxyimino-2 - (2-t-ritylamino-4-thiazoi-5-thia-1-aza-bicyclo In 40 ecm of formic acid is diluted with 25 ecm C and finally distilled for 20 minutes at 50 with 15 ecm., ::: the filtration of the insoluble product mixture under reduced pressure (5 mml-icj

ahs of ind

24

lg; 4 kPa)

iryloxy-

; Ol-5-ylJ-

hiazolyl) - -en, syn-

(cm ^"1) 'rO, 755,

1, -COOCH ₃ ); 5,12 (d, 1 7); 6.78 and 7.03 aromatic

-methoxy-7-Γ2-

JOJ-8-oxo-

3, E-shape,

Jin water

ind

it. To

oaktions-

) at

29.9.1980 AP C 07 D / 221 271 '221271 - 3 ^ S - 57 466/11

40 C concentrated »The residue is triturated with 50 ecm of ethanol, which is then evaporated under reduced pressure (30 mmHg, 4 kPa) at 40 ° C. This procedure is repeated twice, and the residue is taken up in 50 ecm of ethanol. The solid

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is filtered off and washed with 10 ecm of ethanol and twice with 25 ecm of isopropyl ether. After drying, 1.1 g of 7-f2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-J-2-carboxy-3-i-3-methoxycarbonyl-1-methyl-1,2,1 'are obtained - triazole ~ 5-yl3-2-thiovinyl3-8-oxo-5-thia-1-aza-bicyclo f4.2.0j oct-2-ene (syn isomer, Ε-form) in the form of a cream-colored powder.

-1 Infrared Spectrum (KBr) ₁ characteristic bands (cm) 345O ₁ 3320, 2200, 1770, 1735, 1660, 1630, 1535, 1385, 1220, 1040, 945

NMR proton spectrum

(350 MHz, DMSO d, <Γ in ppm, D in Hz) 3.66 and 3.90 (2d, D = 18, 2H, -SCH ₂ -); 3.85 (s, 3H, = NOCH ₃ ); 3.87 (s, 3H, -CO ₂ CH ₃ ); 3.90 (s, 3H, ^ NCH ₃ triazole); 5.20 (d, 0 = 9, IH, H in 6); 5.79 (dd, 3 = 4 and 9, IH, H in Figure 7); 6.74 (s, IH, H thiazole); 6.98 and 7.03 (AB, Ό = 14, 2H, -CH = CH-S-); 7.20, (s wide, 2H, -NH ₂ ); 9.63 (d, Ό = 9, IH, -CONH-C ₇ ).

Example 35

The mixture is stirred at 60 ^° C. under nitrogen for 2 hours 30 minutes. A mixture of 6.02 g of 2-benzhydryloxycarbonyl-7-f 2 -methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidoj-8-oxo-5 is stirred -oxide-3- (2-tosyloxyvinyl) -r5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, E form, 60 cm2 dimethylformamide, 2.27 g Z- acetamidomethyl S-mercapto-1S-thiadiazole and 1.15 ecm of diisopropylethylamine Dilute the cooled mixture with 250 eq of ethyl acetate, wash with 150 eq of water, 100 ecm of 0.1 N hydrochloric acid, 100 eq of a saturated sodium bicarbonate solution and 100 ecm twice Water, dried over sodium sulfate, filtered and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 20 ° C. The residue, fixed to 20 g of silica gel Merck (0.05-

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0.2) is applied to a column of 70 g of silica gel (0.05-0.2) (column diameter 2.5 cm). It is eluted with 2.5 L of ethyl acetate, collecting fractions of 100 ecm. Evaporate fractions 9-23 at 20 ^° C. under reduced pressure (20 mmHg) to dryness and recover 3 g of 3- (2-acetamidomethyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl-3-one £ -benzhydryloxycarbony1-7- "2-methoxyimino-2- (2-1 ritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5- _{<oxide-5-thia-l- (aza-bicyclo«} £ 4.2,0 } oct-2-en, syn-isomer, E ~ "form in the form of a brown meringue.

Infrared spectrum (KBr), characteristic bands (cm ") 3400, 1795, 1720, 1670, 1525, 1495, 1450, 1370, 1040, 940, 750, 700

NMR proton spectrum

(350 MHz, CDCl, cf in ppm, D in Hz)

1.97 (s, 3H, -COCH _3); 3.30 and 4.15 - (2U, 3 = 18, 2H, -SCH ₂ -); 4.08 (s, 3H, -OCH ₃ ); 4.64 (d, D = 4, IH, H in Figure 6); 4.72 (AB, 2H, -CH ₂ NHCO-); 6.14 (dd, 0 = 4 and 9, IH, H in 7); 6.72 (s, IH, H of the thiazole); 6.97 (s, IH, -COOCH-).

To a cooled to -10 C solution of 3 g of 3 ~ £ (2-acetamidomethyl-l, 3,4 ~ thiadiazol-5-yl) -2-thiövinyl3-2 ~ benzhydryloxycarbonyl-7-C2-methoxyimino-2- (2 -t ritylamino-4-thiazolyl J-acetamido J-S-oxo-S-oxide-S-thia-1-aza-bicyclo f4.2.0j oct-2-ene, syn isomer, Ε-form, in 29 ecm methylene chloride to 1.1 cc of dimethylacetamide, and 0.519 cc of phosphorus trichloride and then stirred for lh at -10 ⁰ C, the mixture is poured into 250 cc of ethyl acetate, washed with saturated 25Q cc * a ¥ Natrilimbicarbonatlö'sung * and twice with 100 cc of water, dried over sodium sulfate , filtered

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and concentrated to dryness at 20 C under reduced pressure (20 mmHg). Dissolve the residue in 10 ecm of methylene chloride and chromatograph the solution on a column of silica gel Merck (0.04-0.06) (column diameter 4 cm). It is eluted with 2.5 l of a mixture of ethyl acetate-cyclohexane

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(80-20 vol.) Under a pressure of 40 kPa, yielding fractions of 100 ecm. The fractions 11-21 and obtains 2.1 g of 3- £ (2-acetamido ~ l, 3,4-thiadiazol-5 ~ yl; (2.7 kPa 20 mmHg) is evaporated to dryness at 20 ⁰ C under reduced pressure ) -2-thiovinyl]] - 2-benzhydryloxycarbonyl-7-p-2-methoxyimino-2 ~ (2-tritylamino-4-thiazolyl) acetamido]] e-oxo-S-thia-1-aza-bicyclo £ 4.2, 0j oct ~ 2 ~ en, syn-isomer, Ε-form, in the form of a yellow meringue.

Infrared spectrum (KBr), characteristic bands (cm) 3400, 3280, 1785, 1720, 1670, 1530, 1495, 1450, 1370, 1040, 945, 755, 700

NMR proton spectrum

(350 MHz, CDCl ₃ , / in ppm, 0 in Hz) 2.0 (s, 3H, -COCH ₃ ); 3.58 and 3.68 (2d, 0 = 18, 2H, -SCH ₂ -); 4.08 (s, 3H, -OCH ₃ ); 4.75 (d, 0 = 5, 2H, -CH ₂ NHCO-); 5.10 (d, 0 = 4, IH, H in 6); 5.97 (dd, 0 = 4 and 9, IH, H in 7); 6 _r 55 (t, 0 "= 5, IH, -rJHCO-); 6.76 (s, 1Ή, H of thiazole), 7.0 (s, IH, -COOCH ^ :); 7.05 (s, IH, -NH-C (C ₅ H ₅ J ₃ ); 7.18 (d, 0 = 16, IH, -CH = CHS-).

Dissolve 2.1 g of 3- (2-acetamidomethyl) -1,3,4-thiadiazol-5-yl) -2-thiovinyl J-2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4- thiazolyl) acetamido] -8-0x0-5-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn-isomer, Ε-form, in 21 ecm of formic acid, add 12 eq of water and heat 30 min. at 50 ⁰ C. the cooled to about 20 ⁰ C mixture is then filtered and dried at 50 C under reduced pressure (0.05 mmHg; 0.007 kPa) concentrated to dryness, the residue is taken up in 50 cc of ethanol, and the solvent is at 20 ⁰ C under reduced pressure

29.9.1980 AP C 07 D / 221 12 7 1, ... 33f - 57 466/11

(20 mmHg; 2.7 kPa); Repeat this procedure twice and then take the residue in 50 ecm of ethanol under reflux. It is filtered under heat to remove a small amount of insoluble material, concentrated to 20 cc under reduced pressure (20 mml-lg; 2.7 kPa) at 20 ⁰ C and filtered. After drying, 0.75 g of 3-f (2-acetamido) are obtained.

29.9.1980 AP C 07 D / 221 271 22 127 1 - 33fc>. 57 466/11

methyl-l, 3,4-thiadiazol-5-yl) -2-thiovinylJ-7-f2- (2-arnino-4-thiazolyl) -2-methoxyimino-acetamido] -2-carboxy-S-oxo-5- thia-1-aza-bicyclo Ϊ, Α ^ Ζ. Oj oct-2-ene, syn isomer, E-form, in the form of a cream-colored powder,

Infrared spectrum (KBr), characteristic bands (cm) 3320, 1770, 1660, 1540, 1380, 1040

NMR proton spectrum. '

(350 MHz, DMSO d _& ><Γ in ppm, 0 in Hz) 1.90 (s, 3H, -COCH ₃ ); 3.68 and 3.92 (2d, 0 = 18, 2H, -S-CH ₂ -); 3.87 (s, 3H, -OCH ₃ ); 4.22 (d, 0 = 4, IH, H in 6); 4.60 (AB limit 2H ₁ -CH ₂ NHCO-); 5.82 (dd, 0 = 4 and 9, IH, H in 7); 6.75 (s, IH, -OCH ₃ ); 7.15 (d, 0 = 16, IH, -CH = CHS-); 7.20 (s, 3H, -NH ₃ ⁺ ); 7.25 (d, 0 = 16, IH, = CHS-); 9.63 (d, 0 = 9, IH, -CONH-).

The 2-acetamidomethyl-5-mercapto-l, 3,4-thiadiazole can be prepared by the method of OA patent application 51 80857 (Derwent 65961-X).

Example 36

Mari 'works as ^{4 described} in Oenice 35, and "4 g of 2-benzhydryloxycarbonyl-7-r2-methoxyimino-2- (2-trityl-amino-4-thiazolyl) -acetarnido J-8-oxo-5-oxide 3- ( Z -tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, with 1.86 g of 2-t-butoxycarbonylamino-5-mercapto l, 3,4-thiadiazole in 50 ecm of dimethylformamide in the presence of 0.83 ecm Ν, Ν-diisopropylethylamine. Chromatography on silica gel [eluent cyclohexane-ethyl acetate (40-60 vol.)] gives 2.6 g of 2-benzhydryloxycarbonyl -3-r (2-t-butoxycarbonylamino-l, 3,4-thiadiazol-5-yl) -2-thiovinylJ-7-Z "2-methoxyimino-2- (2-tritylamino-4-thiazolyl-acetamido] - 8-oxo-5-oxide-5-thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene,

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syn isomer, Ε-form, in the form of a cream-colored meringue.

* -l infrared spectrum (CHBr,), characteristic bands (cm) 338O ₁ 2820, 1800, 1720, 1530, 1490, 1445, 1390, 1370, 1050, 940, 760, 605

NMR proton spectrum

(350 MHz ₁ CDCl, cT in ppm, 0 in Hz) 1.43 (s, 9H, -C (CH ₃ ) ₃ ); 3.24 and 4.46 (2d, D = 19, 2H, * CH ₂ -); 4.04 (s, 3H, -OCH ₃ ); 4.64 (d, 0 = 4, IH, H in 6); 6.14 (dd, 0 = 4 and 9, IH, H in 7); 6.70 (s, IH, H of the thiazole); 6.94 (s, IH, -COOCH-); 7.11 (d, 0 = 16, IH, -Cu = CHS-); 7.34 (d, 0 = 9, IH, -CONH-); 7.37 (d, D = 16, IH, = CHS-).

Under the conditions described in Example 35, 2.55 g of 2-benzhydryloxycarbonyl-3- (2-t-butoxycarbonylamino-1,3,4-thiadiazol-5-yl) -2-thiovinyl] -7- 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-8-oxo-S-oxide-S-thia-1-aza-bicyclo [4.2.0]} oct-2-ene, syn-Isorneres , Ε-form with 0.46 ecm of phosphorus trichloride in the presence of 0.95 ecm of dimethylacetamide in 50 ecm of methylene chloride. Chromatography on silica gel, cyclohexane-ethyl acetate (30-70 vol.)] Gives 2.1 g of 2-benzhydryloxycarbonyl-3-r (2-t-butoxycarbonyl-10-amino, 3,4-thiadiazol-5-yl). 2-thiovinyl J -7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido J-8-oxo-5-thia-1-azabicyclo / 4,2,0J oct-2-ene, syn isomer, Ε shape, in the form of a cream-colored meringue.

- 1 infrared spectrum (CHBr,), characteristic bands (cm) 3400, 1785, 1725, 1685, 1530, 1495, 1450, 1250, 1210, 1050, 940, 755, 740

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NMR proton spectrum

(350 MHz, CDCl ₃ , / in ppm, 0 in Hz) 1.53 (s, 9H, -C (CH ₃ J ₃ ); 3.52 and 3.62 (2d, 0 = 18, 2H, -SCH ₂ -), 4.06 (s, 3H, -OCH ₃ ), 5.06 (d, 0 = 4, IH, H in 6), 5.92 (dd, 0 = 4 and 9, IH, H in 7); 6.72 (s, IH, H of the thiazole); 7.03

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(d, D = 16, IH ₁ -CH = CHS-); 7.07 (d, 0 = 9, IH, -CONH-).

Under the conditions described in Example 35, 2 g of 2-benzhydryloxycarbonyl-3-r (2-t-butoxycarbonylamino-l, 3,4-thiadiazol-5-yl) -2-thiovinyl-J-2-methoxyimino are treated ~ 2- (2-tritylamino-4-thiazolyl) -acetamido J-8-oxo-5-thia-1-azabicyclo ε 4.2, Oj oct-2-ene, syn isomer, Ε-form, with a mixture of 40 ecm Formic acid and 15 ecm of water. 0.74 g of 3 ^ώ l of (2-amino-l, 3,4-thiadiazol-5-yl) -2-thiovinyl-3-7-C2- (2-amino-4-thiazolyl) -2 is obtained. methoxyimino-acetamido} -2-carboxy-e-oxo-S-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn isomeric, Ε-form, in the form of a yellow powder.

1 Infrared Spectrum (KBr), characteristic bands (cm) 3320, 3200, 3100, 2820, 2000, 1770, 1670, 1610, 1380, 1040, 940

NMR proton spectrum

(350 MHz, DMSO d, <f in ppm, 0 in Hz) 3.83 (s, 3H, -OCH ₃ ); 5.12 (d, 0 = 4, IH, H in 6); 5.76 (dd, 0 = 4 and 9, IH, H in Figure 7); 6.74 (s, IH, H of the thiazole); 6.95 (d, 0 = 16, IH, -CfH = CHS-); 7.02 (d, 0 = 16, IH, = CHSt); 7.18 (s wide, 2H, -NH _{2 of} the thiazole); 7.48 (s broad, 2H, _£ -ΝΗ thiadiazole); 9.60 (d, 0 = 9, IH, -CONH-).

The 2-t-butoxycarbonylamino-5-mercapto-l, 3,4-thiadiazole is prepared by condensation of t-butyl dicarbonate with 2-amino-5-mercapto-l, 3,4-thiadiazole, prepared according to V. Petrow, 0 Chem. Soc. 1508 (1958) in the presence of sodium carbonate in a mixture of water-dioxane for 24 h at 25 ⁰ C.

Bas product is recrystallized from acetonitrile. Fp. Inst. (Kofler) = 200 ⁰ C.

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Infrared spectrum (KBr), characteristic bands (cm **) 1725, 1390, 1370, 1240, 1170, 1070

NMR Prοtoneηspektrum

(60 MHz, DMSO d, <f in ppm, O in Hz) 1.53 (s, 9H, -C (CH ₃ J ₃ ).

Example 37

Under the conditions described in Example 35, 1.3 g of 2-dimethylaminomethyl-5-mercapto-l, 3,4-thiadiazole are admixed with 6.02 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino) 4-thiazolyl) acetamido3-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo f4.2.03 oct-2-ene, syn isomer, Ε-form in 60 ecm of dimethylformamide in the presence of 1.15 ecm Ν, Ν-diisopropylethylamine. Chromatography on silica gel [ eluent cyclohexane-ethyl acetate (20-80 vol.)] Gives 2.7 g of 2-benzhydryloxycarbonyl-3-f (2-methoxyimino-2- (2-tert-rylamino-4-thiazolyl) acetamido-3-yl). 8-oxo-5-oxide-5-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn isomer, Ε-form, in the form of an orange meringue.

Infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3380, 2820, 2780, 1790, 1715, 1665, 1515, 1445, 1200, 1040, 940, 750, 735

NMR proton spectrum

(350 MHz, CDCl ₃ , <f in ppm, 0 in Hz) 2.34 (s, 6H, -N (CH ₃ J ₂ ), 3.28 and 3.98 (2d, 0 = 18, 2H, - SCH ₂ -); 3.85 (s, 2H,;> NCH ₂ -); 4.07 (s, 3H, -OCH ₃ ); 4.62 (d, 0 = 4, IH, H, ifi 6); 6.15 (dd, 0 = 4 and 9, IH, H in 7); 6.71 (s, IH, H of thiazole); 6.96 (s, IH, -COOCH <:).

22127 1

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The reduction of 2.7 g of 2-benzhydryloxycarbonyl-3 - / (2-dimethylaminomethyl-1, 3,4-thiadiazol-5-yl) -2-thiovinyr) ~ 7-f 2 -methoxyimino-2- (2-tritylamino 4-thiazolyl) -acetamido J-8-oxo-S-oxide-S-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, as described in Example 35 Conditions, with 0.468 ecm of phosphorus trichloride in 27 ecm of methylene chloride in the presence of 0.995 ecm of dimethylacetamide, results after chromatography on silica gel eluting with cyclohexane-ethyl acetate (30-70 vol. To 1.6 g of 2-BBnZhYdTyIoXyCaTbOnYl-S- £ (2-dimethylaminomethyll , 3,4-thiadiazol-5-yl) -2-thiovinyr] -7-r2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-8-oxo-5-thia-1-azabicyclo £ 4.2 , Oj oct-2-en, syn isomer, Ε-form, in the form of a rose-colored meringue.

Infrared spectrum (CHBr ₃ ) I characteristic bands (cm) 3400, 2820, 2780, 1780, 1715, 1685, 1515, 1450, 1205, 1040, 755, 740

NMR proton spectrum

(350 MHz, CDCl ₃ , <f in ppm, 0 in Hz) 2.35 (s, 6H, -N (CH ₃ J ₂ ), 3.62 and 3.72 (2d, D = 18, 2H,

-SCH ₂ -); 3.86 (s, 2H, -NCH ₂ -); 4.09 (s, 3H, -OCH ₃ ); ' 5.12 (d, 0 = 4, IH, H in 6); 5.95 (dd, 0 = 4 and 9, IH, H in 7); 6.76 (s, IH, H of the thiazole); 6.88 (s, IH, -COOCHcC); 6.88 (d, 0 = 9, IH, -CONH-); 7.22 (d, 3 = 16, IH, -ChI = CHS-); 7.42 (d, 3 = 16, IH, = CHS-)

Under the conditions described in Example 35, 1.6 g of 2-benzhydryloxycarbonyl-3- (2-dimethylaminomethyll, 3,4-thiadiazol-5-yl) -2-thiovinyl-7-8-2-methoxyimino-2 are treated - (2-tritylamino-4-thiazolyl) -acetamid0 ^ -8-0x0-5-thia-1-aza-

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bicyclo £ 4.2.OU oct-2-ene, syn-isomer, Ε-form, with a mixture of 16 ecm of formic acid and 8 ecm of water. 0.92 g of 7-f2- obtained (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido ^ -S-carboxy-S- £ (2-dimethylaminomethyl - l, 3 _f 4-thia-5- · dia2ol yl) -2-thiovinyl] -e-oxo-S-thia-1-aza-bicyclo ε4,2,03 oct-2-ene syn isomer, E ~ form, in the formate state, in the form of a yellow powder.

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Infrared spectrum (KBr), characteristic bands (cm) 3400, 3330, 3250, 2000, 1765, 1665, 1600, 1530, 1035, 960

NMR proton spectrum

(350 MHz, DMSO d _& , <T in ppm, D in Hz) 2.36 (s, 6H, -N (CH ₃ J ₂ ), 3.67 and 3.92 (2d, 0 = 18, 2H, -SCH ₂ -), 3.88 (s, 3H, -OCH _3); 5.28 (d, D = 4, IH, H in 6); 5.80 (dd, 0 = 4 and 9, IH, H in 7), 6.76 (s, IH, H of the thiazole), 7.10 (d, D = 16, IH ₁ -CH = CHS-) 7.20 (s, 2H, -NH ₂ ) 7 , 25 (d, 3 = 16, IH, = CHS-), 9.60 (d, 0 = 9, IH, -CONH-).

Example 38

The mixture is stirred at 60 ⁰ C under nitrogen for 2 h, a mixture of 4 g of 2-benzhydryloxycarbonyl-7 £ 2-methoxyimino ~ 2- (2-tritylamino-4-thiazolyl) -acetamido3-8-oxo-5-oxide ~ 3 - (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, E form, 1.05 x g SM

diazole, 0.83 ecm N, N-diisopropylethylamine and 50 ecm dimethylformamide. The cooled to about 20 ⁰ C mixture is diluted with 600 cc of ethyl acetate, and the organic phase is washed with 100 cc distilled water, 150 cc of 0.1 N hydrochloric acid, twice 150 cc of a 5% sodium bicarbonate solution and twice 150 cc water, saturated washed with sodium chloride, dried over sodium sulfate, filtered and concentrated to dryness at 20 C under reduced pressure (20 mmHg, 2.7 kPa). The brown residue is taken up in 10 ecm of a mixture of cyclohexane-ethyl acetate (40-60 vol.) And the solution is chromatographed on a column of 150 g of silica gel Merck (0.04-0.06) (column diameter 4 cm). It is eluted with 3 l of a mixture of cyclohexane-ethyl acetate (40-60 vol.) Under a pressure of 40 kPa to yield fractions of 50 ecm. It is evaporated at 20 ° C. under reduced pressure (20 mmHg; 2.7 kPa). fractions 24-60 and recover 1.8 g of 2-benzhydryl-T

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oxycarbonyl-7- 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -3-C (3-methyl-l _# 2 _/ 4-thiadiazol-5-yl) -2-thiovinyl-3-8 -oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn-isomer, E-form.

NMR proton spectrum

(350 MHz, CDCl ₃ , cT in ppm, 0 in Hz)

2.63 (s, 3H, -CH ₃ ); 3.29 and 4.07 (2d, 0 = 18, 2H, -SCH ₂ -);

4.08 (s, 3H, -OCH ₃ ); 4.61 (d, 0 = 4, IH, H in 6); 6.18 (dd,

0 = 4 and 9, IH, H in 7); 6.71 (s, IH, H of the thiazole); 6.89

(s, IH, -COOCHCL); 7.05 (d, 0 = 14, IH, -CH = CHS-); 7.48 (d,

0 = 9, IH, -CONH-); 7.58 (d, 0 = 14, IH, = CHS-).

To a cooled to -10 ⁰ C solution of 1.75 g of 2-ßenzhydryloxycarbonyl-7- / 2-methoxyimino-2 ~ (2-tritylamino-4-thiazolyl) acetamido) -3-r (3-methyl-l, 2,4-thiadiazol-5-yl) -2-thiovinyl3,8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene. syn isomer, Ε-form, and 0.72 ecm of dimethylacetamide in 40 ecm of methylene chloride are added at once 0.35 ecm of phosphorus trichloride. The mixture is stirred for 1 h at -10 ⁰ C, again adds 0.17 ecm phosphorus trichloride, stirred for 10 min. And then treated in the following manner:

It is diluted with 500 ml of ethyl acetate, washed twice with 150 ml of a 2% sodium bicarbonate solution, and twice 150 ml of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ° C. under reduced pressure (20 mmHg, 2.7 kPa ) to dryness. The residue is taken up in 15 ecm of a cyclohexane-ethyl acetate mixture (30-70 vol.) And the solution is chromatographed on a column of 60 g silica gel Merck (0.05-0.2) (column diameter 4 cm). One elutes with

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300 ecm of the above mixture, collecting fractions of 20 ecm. Fractions 6-13 are combined and concentrated at 20 C under reduced pressure (20 mmHg). 1.18 g of 2-benzhydryloxycarbonyl-7-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido3-3-C are obtained (3-methyl-1,2,4-thiadiazol-5-yl) ) -2-thiovinylJ-8-oxo-5-thia-l-aza-

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bicyclo f4.2.0] oct-2-ene, syn-isomer, E-form _#

NMR proton spectrum

(350 MHz, CDCl ₃₁ (f in ppm, 0 in Hz) 2.62 (s, 3H, -CH ₃ ); 3.60 and 3.68 (2d, 0 = 18, 2H, -SCH ₂ -); 4.07 (s, 3H, -OCH ₃ ), 5.11 (d, 0 = 4, IH, H in 6), 5.95 (dd, 0 = 4 and 9, IH, H in 7), 6 , 75 (s, IH, H of the thiazole), 6.88 (d, 0 = 9, IH, -CONH-), 6.98 (d, 0 = 16, IH, -CH = CHS-), 6, 99 (s, IH, -COOCH <:); 7.0 (s, IH, -NH-).

Dissolve 1.1 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido J-3-C (3-methyl-1,2,4-thiadiazol-5-yl) 2-thiovinyl-3-oxo-5-thia-1-aza-bicyclo Γ4.2.0} oct-2-ene, syn isomer, Ε-form, in 30 ecm of formic acid, add 13 eq of distilled water and heat The suspension is cooled to about 20 ^° C., filtered, and the filtrate is concentrated at 20 ° C. under reduced pressure (0.05 mmHg; 0.007 kPa). The residue is taken up in 30 eq of ethanol, concentrated at 20 C under reduced pressure and this procedure is repeated three times. The solid residue is refluxed with 100 eq of ethanol and a small insoluble portion is filtered off, and finally the filtrate is concentrated to 5 ecm, diluted with 20 ecm of diethyl ether and cooled to + 4 ° C. After filtering and drying, 0.44 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamidoj-2-carboxy-3-Γ (3-methyl-1,2,4-thiadiazole -5-yl) -2-thiovinyl-3-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, in the form of a yellow powder.

NMR Prοtonenspektrum

(350 MHz, DMSO d, cT in ppm, 0 in Hz)

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2.57 (S, 3H, -CH ₃ ); 3.65 and 3.95 (2d, 0 = 18, 2H, - ₂ 3.86 (s, 3H, -OCH _3); 5.23 (d, 0 = 4, IH, H in 6); 5, 82 (dd, 0 = 4 and 9, IH, H in 7); 6.75 (s, IH, H of the thiazole); 7.04 (d, O = 16, IH, -ChI = CHS-); 7 , 36 (d, O = 16, IH, = CHS-), 9.63 (d, O = 9, IH, -CONH-).

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The S-mercapto-S-methyl-l ^^ thiadiazole can be prepared according to the method described in Chem. Ber. 90, 184 (1957).

/ Example 39

To a solution of 4.0 g of 2-benzhydryloxycarbonyl-7-p-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-8-oxo-5-oxide-3- (2-tosyloxyvinyl) - 5-thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene, syn isomer, Ε-form, and 1.4 g of 2-mercapto-5-phenyl-1,3,4-oxadiazole in 40 ecm dry dimethylformamide is added 1.4 ecm of N-ethyl-N, N-diisopropylamine. The resulting solution is heated to 60 ° C. for 6 hours. After cooling, it is diluted with 500 ml of ethyl acetate and then washed successively with 150 ml of 0.1N hydrochloric acid, 150 ml of distilled water, 150 ml of a 3% sodium bicarbonate solution and finally 150 ml a saturated sodium chloride solution. Drying 'the organic extract over magnesium sulfate, filtered and concentrated under reduced pressure (25 ramHg; 3.3 kPa) at 30 ⁰ C. The product obtained is chromatographed on a column of silica gel Merck (.020-.063 mm) (column Mosser 45 mm, Height 300 mm) under a pressure of 50 kPa. It is eluted with 3 l of a cyclohexane-ethyl acetate mixture (50-50 vol.), Wins fractions of 50 ecm. Fractions 43-59 are combined and concentrated under reduced pressure (25 mmHg, 3.3 kPa). This gives 1.0 g of 2-benzhydryloxycarbonyl-7 - / "2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-S-oxo-S-oxide-S- t ( 5-phenyl, 3 , 4-oxadiazol-2-yl) -2-thiovinyl-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene (syn isomer, E form).

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To a solution of 2.1 g of 2-benzhydryloxycarbonyl-7-hexoxy-hoxyimino-2 - (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-oxide-3-f (5-phenyl-L _# 3, 4-oxadiazol-2-yl) -2-thiovinyl-5-thia-1-aza-bicyclo f4.2.0j oct-2-ene, syn isomer, E-form, in 20cm dry

29.9.1980 AP C 07 D / 221 271 221271 "- 57 466/11

Methylene chloride and 0.76 ecm N, N-dimethylacetamide, cooled to -15 ⁰ C, one adds 0.36 ecm phosphorus trichloride. The resulting solution is stirred for 1 h at -10 to -15 C, and then diluted with 500 ecm of ethyl acetate. It is washed successively with 200 ml of a 5% solution of sodium bicarbonate twice and with 200 ml of saturated sodium chloride solution twice. Dry the organic extract over magnesium sulfate, filter and concentrate under reduced pressure (25 mmHg, 3.3 kPa). The product is chromatographed on a column of silica Merck (0.020-0.063) (column diameter 15 mm, height 200 mm), under a pressure of 50 kPa, with 1 liter of a mixture of methylene chloride / ethyl acetate (95-5 vol. eluting and collecting fractions of 50 ecm. Combine fractions 5-16 and concentrate under reduced pressure (25 mmHg, 3.3 kPa) to obtain 1.2 g of 2-benzhydryloxycarbonyl ~ 7-l-2-methoxyimino-2 - (2-tritylamino-4-thiazolyl) -acetamido-8-oxo-3-E (5-phenyl-1,3,4-oxadiazol-2-yl) -2-thiovinyl] -5-thia-1-azabicyclo £ 4.2.0} oct-2-ene (syn-isomer, E-form),

A solution of 1.2 g of 2-benzhydryloxycarbonyl-7-ε-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamidoj-8-oxo-3-f is heated at 50 ° C. for 30 minutes (5 g). phenyll, 3,4-oxadiazol-2-yl) -2-thiovinyl-5-thia-1-aza-bicyclo [4.2 syn. octo-2-ene (syn isomer, .sup. form) in 10 cc formic acid and 3 ecm of distilled water. After cooling, the suspension was filtered, washing the cake twice with 3 cc of distilled water and concentrated daspiltrat under reduced pressure (0.5 mm Hg; 0.07 kPa) at 30 ⁰ C. The solid obtained is taken up in 40 cc of ethanol, and the resulting suspension is concentrated under reduced pressure (0.5 mmHg, 0.07 kPa) at 30 ^° C. One repeats

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - 350. 57 466/11

this operation twice. The resulting solid is triturated in a mixture of 10 ecm acetonitrile and 5 ecm ethanol. It is filtered, washed twice with 5 cc of acetonitrile and dried under reduced pressure (0.2 mm Hg; 0.03 kPa) at 20 ⁰ C. 0.25 g of so obtained 7- £ 2- (2-Amiηo ~ 4-thiazolyl ) -2-methoxyimino-acetamido3-2-carboxy-8-oxo-3- (5-phenyl-1,3,4-oxadiazole)

29.9.1980 AP C. 07 D / 221 271 12 7 1 - 554 - sy 466/11

2-yl) -2-thiovinyl} -5-thia-1-aza-bicyclo Γ4,2.θ} oct-2-ene (syn isomer, E form),

"-1 Infrared Spectrum (KBr) ₁ characteristic bands (cm) 3400-2000, 3330, 1760, 1630, 1540, 1380, 1055, 750, 710, 695

NMR proton spectrum

(350 MHz, DMSO d, <f In ppm, D in Hz) '

3.68 and 3.94 (2d, J = 18, 2H, -SCH ₂ -); 3.86 (s, 3H, SNOCH ₃ ); 5.22 (d, IH, H in Figure 6); 5.82 (dd, IH, H in 7); 6.74 (s, IH, H of the thiazole nucleus); 7.10 (d, 3 = 16, IH, -CH = CHS-); 7.18 (s, 2H, -NH ₂ ); 7.26 (d, D = 16, IH, -CH = ChIS-); 7.83 (mt, 3H, p and m protons of -CgH _1. ); 8.0 (d, 0 = 7, 2H, o protons of -C ₆ H ₅ ); 9.61 (d, 3 = 9, IH, -CONH-).

The mercapto-5-phenyl-l, 3,4-oxadiazole can be prepared by the method of E, Hoggarth, 0 ', Chem. Soc. 4811 (1952).

Example 40

To a solution of 4.0 g of 2-benzhydryloxycarbonyl-7-p-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5 -thia-1-aza-bicyclo "" 4.2.Oj oct-2-ene (syn isomer, Ε-form) "and 0.92 g of 2-mercapto-4-methyl-oxazole in 40 ecm of dimethylformamide are added to 1, 4 ml of N-ethyl-N, N-diisopropylamine The resulting solution is heated to 55 ° C. for 2 hours, then cooled, diluted with 500 ml of ethyl acetate and then washed successively with 150 ml of 0.1N hydrochloric acid, twice 150 ml 3 Sodium bicarbonate solution and finally 150 ml of saturated sodium chloride solution, the organic extract is dried with sodium sulphate, filtered and concentrated under reduced pressure (25 mmHg, 3.3 kPa) at 20 to 25 ^° C. The obtained

29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 - EAST ₃ _ ₅₇ 4 _55/11

The product is chromatographed on a column of 150 g of silica Merck (0.02-0.063 mm) (diameter of the column 3 cm) under a pressure of 50 kPa, eluting with .1.5 1 of a mixture of cyclohexane-ethyl acetate (40 -. 60 vol.), Winning fractions of 50 ecm. Fractions 14-23 are concentrated under reduced pressure (25 mmHg, 3.3 kPa) at 40 ° C. Drying is stopped below 0.2 mmHg (0.03 kPa) at 20 ° C. 1.15 g of 2-benzhydryloxycarbonyl-7-p-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido! thiovinyrj ~ 8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0] oct-2-ene (syn isomer, Ε-form) in the form of a yellow meringue.

To a solution of 1.1 g of 2-benzhydryloxycarbonyl-7-r2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-3... Ζ (4-methyl-2-oxazolyl) -2-thiovinyl. 8 ~ oxo-5-oxide-5-thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene (syn isomer, Ε-form) in 10 ecm dry methylene chloride and 0.43 ecm N _t N-dimethylacetamide , cooled to -12 C, add 0.202 ecm of phosphorus trichloride. The resulting solution is stirred for 1 h 30 min. At -15 C and then diluted with 250 ecm of ethyl acetate and washed successively with 250 ecm of a 3 iger sodium bicarbonate solution and then 250 ecm. a saturated sodium chloride solution. The organic extract is dried with sodium sulfate, filtered and then concentrated under reduced pressure (25 mmHg, 3.3 kPa) at 30 ° C. 1.08 g of 2-benzhydryloxycarbonyl-7-C2-methoxyimino-2- (2- tritylamino-4-thiazolyl) -acetamido3-3- (4-methyl-2-oxazolyl) -2-thiovinyl] -8-oxo-5-thia-1-aza-bicyclo C4.2.o3 oct-2-ene , syn isomer, E form.

29.9.1980 AP C 07 D / 221 271 - 353 -. 57 466/11

The mixture is heated for 45 minutes at 50 ⁰ C a solution of 1.08 g of 2-benzhydryloxycarbonyl-7-C2-methoxyimino ~ 2- (2-trityl · amino ~ 4-thiäzqlyl) -7acetamido] -3- f (4-methyl -2-oxazolyl) ~ 2-thiovinylo] -S-oxo-S-thia-1-aza-bicyclo [4.2.0] oct-2-ene {syn isomer, Ε-form) in 10 cc of formic acid and 6 ecm distilled water, After cooling, the suspension is filtered and the solid is washed

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with 3 ecm of distilled water. The filtrate is dried under reduced pressure (0.5 mmHg, 0.07 kPa) at 30 ° C. The resulting solid is taken up in 75 ecm of ethanol and the suspension is concentrated under reduced pressure (0.5 mmHg; 0.074 kPa) at 30 ^° C. The process is repeated twice. The solid obtained is triturated in 50 cc of acetonitrile, filtered, and then dried under reduced pressure (0.2 tnral-lg; 0.03 kPa) at 20 ⁰ C. There are thus obtained 0.41 g of 7-f 2 - (2-amino-4-thiazolyl) -2-methoxyiminoacetamido J-2-carboxy-3-ε (4-methyl-2-oxazolyl) -2-thiovinyl} -8-oxo -5-thia-1-azabicyclo Γ4.2.03 oct-2-ene (syn isomer, E form).

Infrared spectrum (KBr), characteristic bands (cm ") 3300, 2940, 1770, 1675, 1530, 1380, 1040, 940, 730, 700

NHR proton spectrum

(350.MHz, _CDCl3, </ "in ppm, 3 Hz) 2.10 (s, 3H, _-CH3), 3.66 and 3.90 (2d, ö = 18, 2H, -SCH ₂ 3.86 (s, 3H, = NOCH ₃ ), 5.19 (d, IH, H in 6), 5.78 (dd, IH, H in 7), 6.74) s, IH, H of the thiazole nucleus), 7.0 (d, Ό = 16, IH, -ChI = CHS-), 7.14 (d, D = 16, IH, -CH = CH ₁ S-), 7.20 (s , 2H, -NH ₂ ), 7.94 (s, IH, H of the oxazole nucleus), 9.72 (d, Ό = 9, IH, -CONH-).

The 2-mercapto-4-methyloxazole can be prepared by the method described by C, Bradsher, O, Org. Chem. 32, 2079 (1967).

Example 41

Under nitrogen at 60 C, a mixture of 0.57 g of 2-benzhydryloxycarbonyl-7-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido-8-oxo-3- (2- tosyloxyvinyl) -5-thia-laza-bicyclo-4,2-octo-2-ene, syn isomer, E form, 15 ecm dimethyl

29.9.1980 AP C 07 D / 221 271 12 7 1 - ffi - 57 466/11

• burner

formamide and 0.17 g of 1 ~ (2-hydroxyethyl) ~ 52mercaptotetrazole. A solution of 0.1 ecm of N-ethyl-N, N-diisopropylamine in 5 ml of dimethylformamide is added dropwise to this mixture with stirring during 15 min. After 3.5 h at 60 ⁰ C the mixture is diluted with 100 cc of ethyl acetate, washed five times with 50 cc of distilled water, dried over sodium sulfate, filtered and concentrated under reduced pressure (20 mmHg; 2.7 kPa) at 20 ⁰ C for dryness. (Column diameter 2 cm, height 15 cm) 'The column is eluted with 300 cc of cyclohexane - the residue in "solves 5 ecm Methylefichlorid and chromatogräphiert the solution on a column of 80 g silica gel Merck (0.06 mm 0.04).. Ethyl acetate mixture (25-75 vol.) Under a pressure of 40 kPa, yielding fractions of 60 ecm.

In the fraction 1, 0.06 g of the starting product is recovered. Fractions 2-4 are concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 20 ° C to give 0.4 g of 2-benzhydryloxycarbonyl-3-fluoro (2-hydroxyethyl) -5- tetrazolyl-2-thiovinyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnido} -8-oxo-5-thia-1-azabicyclo ^ 4.2.03 oct-2-ene (syn- Isomer, E-form).

Infrared spectrum (KBr), characteristic bands (cm) 3400, 1785, 1720, 1580, 1525, 1370, 1210, 1035, 940, 755, 700

NMR proton spectrum

(350 MHz, CDCl ₃ , <f in ppm, D in Hz) 3.57 and 3.67 (AB, 0 = 18, 2H, -SCH ₂ -); 4.07 (s, 3H, -OCH ₃ ); 4.1 and 4.35 (2t, 4H, -CH ₂ CH ₂ O-); 5.09 (d, 0 = 4, IH, H in Figure 6); 5.94 (dd, 0 = 4 and 9, IH, H in 7); 6.74 (s, IH, H in 5-position

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 ~ tt <0 - 57 466/11

development of the thiazole); 6.95 (s, IH, -COOCH-); 6.97 (s, IH, (CH) CNH-); 7.00 (d, D = 16, IH, -CH_ = CHS-).

Dissolve 0.39 g of 2-benzhydryloxycarbonyl-3- / 2- (2-hydroxyethyl) -5-tetrazolyl3-2-thiovinyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido03-8 -0x0-5-thia-1-azabicyclo [4, 2. 0 ') oct-2-ene

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OO 1 27 I ^ * ^ "· ^{57 465} Al

(syn isomer, Ε-form) in 7 ecm of formic acid, diluted with 4 ecm of water and heated for 30 min at 50 ° C, allowed to cool, filtered and concentrated under reduced pressure (0.05 mmHg, 0.007 kPa) at 20 ^° C to dryness. The residue is triturated in 10 ml of diisopropyl ether, and after filtration and drying, 0.2 g of the solvate with formic acid of 7-Γ 2- (2-methylbenzo-4-thiazolyl) -2-methoxyimino-acetamido-2-carboxy- is obtained. 3-l- (2-hydroxyethyl) -5-tetrazolyl-thiovinyl-S-oxo-S-thia-1-aza-bicyclo-ε4,2.0j oct-2-ene (syn isomer, Ε-form) in in the form of a pale yellow solid.

Man '* treated under reflux with 50 cc of ethanol 0.9 g of the above product (Solvatzustand) removed by filtration low insoluble fraction, stirred for 2 h at 20 ⁰ C for 2 hours to cool to 4 ⁰ C and filtered. 0.41 g of the above product is obtained in the form of its internal salt.

- 1 infrared spectrum (KBr), characteristic bands (cm) 3350, 1770, 1720, 1675, 1530, 1390, 1040, 940

NMR proton spectrum

(350 MHz, DMSO dg, S in ppm, 0 in Hz).

3.63 and 3.87 (AB, O = 19, 2H, -SCH ₂ -); 3.77 and 4.41 (2t, 4H, -CH ₂ CH ₂ O-); 3.84 (s, 3H, -OCH ₃ ); 5.19 (d, D = 4, IH, H in Figure 6); 5.89 (dd, 0 = 4 and 9, IH, H in 7); 6.73 (s, IH, H at the 5-position of the thiazole); 6.94 (d, D = 16, IH, -CH = CHS-); 7.25 (d, 0 = 16, IH, = CHS ~); 9.61 (d, 3 = 9, IH, -CONH-).

0.27 g of the internal salt are suspended in 2 eq of distilled water, 0.042 g of sodium bicarbonate are added

29.9.1980 AP C 07 D / 221 271 22 127 1. " ^ 5 & ~ 57 466/11

and stirred for 15 min. At 20 C. After lyophilization gives 0.27 g of the sodium salt of the product.

2-Benzhydryloxycarbonyl ~ 7- '£ 2 ~ methoxy in ino-2- (2-tri-la-la-ino-4-thiazolyl) -acetamido] -8-oxo-3- (2-tosyloxyvinyl) ~ 5-thia -l ~ aza-bicyclo £ 4.2.Oj oct-2-ene (syn-isomer, Ε-form) may be prepared according to the im

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2 2 12 7 1 - 359 _ _{57 466/11}

Example 3 method can be obtained.

Example 42 ». .

A mixture of 10.04 g of 2-benzhydryloxycarbonyl-7-ε-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido-8-oxo-5-oxide is stirred at 60 ° C. under nitrogen for 6 hours. 3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo Γ4.2.0! Oct-2-ene, syn isomer, E-form, 200 cc ^: dimethylformamide, 3.74 g! (Acetamidoethyl) S-mercaptotetrazole and 3.5 ecm of diisopropylethylamine,

It is diluted with 800 eq of ethyl acetate, washed with three times 400 eq of water, dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C under 20 mmHg (2.7 kPa). The product, previously fixed to 50 g of silica gel Merck (0x05-0.2), is applied to a column of 100 g of the same silica gel (diameter of the column 3 cm). It is eluted successively with mixtures of cyclohexane-ethyl acetate (50-50 vol.) 500 ecm, (25-75 vol.) 1 1 and with 3 1 of ethyl acetate to give fractions of 125 ecm. Fractions 19-30 are concentrated to dryness at 20 ° C under 20 mmHg (2.7 kPa). 5.05 g of 3-methyl-2-acetamidoethyl-5-tetrazolyl-3-2-thiovinyl-2-benzhydroloxycarbonyl-7- (2-methoxyimino-2- (2-t-ritylamino-4) are obtained -thiazolyl-J-acetamido-J-S-oxo-S-oxide-S-thia-1-aza-bicyclo f4.2.03 oct-2-ene, syn isomer, Ε-form, in the form of a brown meringue.

Infrared spectrum (CHBr _3), characteristic bands (cm) 3440, 3380, 1800, 1720, 1670, 1510, 1495, 1445, 1370, 1045, 940, 750, ⁷³⁵ '

29.9.1980 AP C 07 D / 221 22 127 1 - 3> kO - 57 455/11

NMR proton spectrum

(350 MHz, CDCl ₃₁ <Tin ppm, D in Hz) 1.84 (s, 3H, -COCH); 3, 27 and 4 (2d, D = 18, 2H, SCH ₀ -);

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2 2 12 7 1 " ^3ΌΑ " ^{57 466} Z ¹¹

3.62 (mt, 2H, -CH ₂ NHCO-); 4.05 (s, 3H, -OCH ₃ ); 4.35 (t, 2H, ^ = - N CH ₂ -); 4.62 (d, 0 = 4, IH, H in 6); 6.07 (dd, 0 = 4 and 9, IH, H in 7); 6; 50 (t, 0 = 7, IH, -NHCO-); 6.69 (s, IH, H of the thiazole); 6.93 (s, IH, '- COOCH-); 6.96 (d, O = 16, IH, -CH = CH-S-); 7,10 (s, IH, -!

To a cooled to -10 ⁰ C solution of 4.99 g of 3-acetamidoethyl) -5-tetrazolyl3 -2-thiovinyl) -2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) - acetamido-1-oxo-S-oxide-S-thia-1-aza-bicyclo f4.2.03 oct-2-ene, syn-isomer, Ε-form, in 49 ecm methylene chloride, adding 1.95 ecm dimethylacetamide and 0 , 86 ecm phosphorus trichloride. The mixture is stirred for 2 h at -10 ⁰ C and diluted with 300 ecm of ethyl acetate, washed with 200 ecm of a semigosaturated sodium bicarbonate solution and 200 ecm of a saturated sodium chloride solution, dried over NatTium'sulf at, filtered and concentrated at 20 ⁰ C under 20 mmHg (2 , 7 kPa) to dryness. Chromatograph on a column of silica gel Merck (0.04-0.06) (column diameter 6 cm). It is eluted with 5 1 of a cyclohexane-ethyl acetate mixture (20-80 vol.) Under a pressure of 40 kPa, to obtain fractions of 125 ecm. Fractions 19-32 are evaporated to dryness at 20 C under 20 mmHg,. and 2.36 g of 3- (1- (2-acetamidoethyl) -5-tetrazolyl] -2-thiovinyl J-2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidoj are obtained -8-0x0-5-thia-1-aza-bicyclo £ 4.2.Oj oct-2-ene, syn-isomeric, E-form, in the form of a yellow meringue.

Infrared spectrum (CHBr,), characteristic bands (cm) 3440, 3400, 1785, 1720, 1680, 1515, 1495, 1450, 1370, 1040, 945, 755, 740

29.9.1980 AP C 07 D / 221 271 22 1 27 1, - M, «57 466/11

NMR proton spectrum

(350 MHz, _CDCl3, <f in ppm, in ö Hz) 1.93 (s, 3H, -CH _3); 3.54 and 3.50 (2d, 0 = 18, 2H, -SCH ₂ -); 3.70 (m, 2H, -CH ₂ NHCO-); 4.04 (s, 3H, -OCH ₃ ); 4.35 (t, D = 5, 2H,> NCH ₂ -); 5.10 (d, 0 = 4, IH, H in 6); 5.94 (dd, D = 4 and 9,

29.9.1980 AP C 07 D / 221 271 127V '- % b - sy 466/11

IH, H in 7); 6.40 (t, 3 = 5, IH ₁ -NHCOCH ₃ ); 6.73. (s, IH, H of the thiazole); 6.93 (s, IH, -COO CH-); 7.00 (s, IH,

Dissolve 2.32 g of 3- (fl- (2-acetamidoethyl) -5-tetrazolyl-2-thiovinyl-2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido J-8 -oxo-5-thia-1-azabicyclp 04.2.03 0C; t-2-ene, syn-isomer, Ε-form, in 60 cc of formic acid, add 60 cc of water and heat to 50 C with stirring for 15 min. The mixture is filtered, cooled to about 20 ⁰ C, concentrated at 50 ⁰ C under 0.05 mmHg (0.007 lcPa) to dryness and the residue is taken up in three times 150 ecm of ethanol, each time the solvent under reduced pressure (20 mmHg) distributes at 20 C. the residue is taken up in 50 cc of ethanol, the suspension is stirred for 1 h at 40 ⁰ C, allowed to cool to 20 ⁰ C and filtered. so are recovered 0.86 g of 3-FCL ~ (2 ~ Acetamidoethyl) -5-tetrazolyl-2-thiovinyl-7- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido3-2-carboxy-8-oxo-5-thia-1-azabicyclo [4.2. o3-oct-2-ene, syn isomer, Ε-form, in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3500, 2500, 1775, 1660, 1540, 1040, 945

NMR proton spectrum

(350 MHz, DMSO d _β , cfm ppm, 3 in Hz) 1.90 (s, 3H, -CH ₃ ); 3.44 (t, 2H,:> N CH-), "3.6 O (q, 2H, -CH ₂ NHCO-); 3.64 and 3.76 (2d, 0 = 18, 2H, -S CH ₂ -), 4.0 (s, 3H, -OCH ₃ ), 5.16 (d, 0 = 4, IH, H in 6), 5.82 (dd,

0 = 4 and 9, IH, H in 7); 6,60 (s, 3H, -NH ⁺ ); 6.78 (s, IH, H of the thiazole); 6.96 (d, 0 = 16, IH, -ChI = CH-S-); 7.37 (d,

29.9.1980 AP C 07 D / 221 271 22 127 1 - <3fct - 57 456/11

D = 16, IH ₁ = CHS -); 7.86 (t _f 3 = 5, IH ₁ -NHCOCH ₃ ); 9.50 (d, 0 = 9, IH, -CONH-).

The l- (2-acetamidoethyl) -5-mercapto-tetrazole can be prepared by the method described in U.S. Patent 4,117,123 method.

29.9.1980 AP C 07 D / 221 22 127 1 - MS - 57 466/11

Example 43

A solution of 1.04 g of 2-benzhydryloxycarboyl-7- / 2-methoxyimino-2- (2-triylamino) -4-thiazolyl J-acetamido- ¹ -S-oxo-3 is stirred at 60.degree. C. under nitrogen for 5 hours - (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo / 4.2, OJ oct-2-eh, syn isomer, Ε-form, and 0.35 g of 1- (2-dimethylaminoethyl) -5-mercapto tetrazole (prepared according to DE-OS 2,733,711) in 15 ml of dimethylformamide, after extraction into ethyl acetate as described in Example 42, and chromatography on silica gel eluting with a mixture of cyclohexane-ethyl acetate (20-80 vol. there is obtained 0.3 g of 2-benzhydryloxycarbonyl-3-ε-fl- (2-dimethylaminoethyl) -5-tetrazolyl] -2-thiovinyl-7-f2-methoxyimino-2 - (2-tritylamino-4-thiazolyl) acetamidoJ. S-oxo-o-thia-1-aza-bicyclo f4.2.03 oct-2-ene, syn isomer, Ε-form, in the form of a light, brown meringue.

Infrared spectrum (CHBr, *), characteristic bands (cm) 3390, 2820, 2780, 1780, 1715, 1680, 1510, 1445, 1205, 1045, 940, 750, 735

NMR proton spectrum

(350 MHz, CDCl, d, <f in ppm, Ό in Hz) 2.25 (s, 6H, -N (CH ₃ J ₂ ); 2.73 (t, Ό = 7, 2H, -CH ₂ N (CH ₃ ) ₂ ); 4.3 (t, D = 7, 2H, -CH ₂ CH ₂ N (CH ₃ J ₂ ); 5.11 (d, 0 = 4, IH, H in Figure 6); 5.95 (dd, 0 = 4 and 9, IH, H in 7); 6.76 (s, IH, H of the fhiazole); 6.84 (d, D = 9, IH, -CONH-); 6 , 95 (s, IH, -COOCHC "); 6.99 (s, IH, -NHC (CgH ₅ J ₃ ); 7.07 (d, D = 16, IH,

-CH = CHS-); 7.42 (d, D = 16, 1H, = CHS-). ⁺ / 3.61 and 3.68 (2d, 0 = 18, 2H ₁ -SCH ₂ -); 4.08 (s, 3H, = NOCH ₃ ).

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As described in Example 42, a mixture of 30 cc of formic acid and 30 cc of water is used to treat 0.59 g of 2-benzhydryloxycarbonyl-3-O- (2-dimethylaminoethyl) -5-tetrazolyl] -2-thiovinyl $ -7 -f2-methoxyimino-2 ~ (2-tritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5-thia-l-aza-bicyclo /"4.2.O] oct-2-en _t syn isomer, Ε- shape, and obtains 0.38 g of 7- (2- (2-amino-4-thiazolyl) -2-carboxy-3- methoxyiminoacetamidoj -2- ^ fl- (2-dimethylaminoethyl) -5-tetrazolylJ-2-thiovinyl ^ -

29.9.1980 AP C 07 D / 221 271 22 1 27 1. - 3fc> - 57 466/11

e-oxo-S-thia-1-aza-bicyclo C4.2.0J oct-2-ene, syn isomer, Ε-form, in the form of the formate and in the form of a yellow powder,

-1 Infrared Spectrum (KBr), characteristic bands (cm) 3400, 3200, 2000, 1770, 1670, 1530, 1035

NMR proton spectrum

(350 MHz, DMSO d,><f in ppm, 0 in Hz) 2,70 ('s, 6H, -N (CH ₃ J ₂ ); 2,? 5 (t, 0 = 7, 2H, -Cl 3.85 (S, 3H, -OCH ₃ ); 3.95 (t, 0 = 7, 2H, -CH ₂ CH ₂ N (CH ₃ J ₂ ); 5.16 (d, 0 = 4, IH, H in 6), 5.85 (dd, 0 = 4 and 9, IH, H in 7), 6.74 (s, IH, H of the thiazole), 6.80 (d, 0 = 16, IH, -ChI = CHS-), 6.90 (d, 0 = 16, IH, = CHS-), 7.20 (s, 2H, -NH ₂ ), 9.63 (d, 0 = 9 , IH, -CONH-),

Example 44

A mixture of 10 g of 2-benzhydryloxycarbonyl-7-β-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-delta-5-oxide-3 is stirred at 50 ° C. under nitrogen for 2 hours - (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo / "4,2.Oj oct-2-ene, syn-isomer, E-form, 200 ml dimethylformamide and 5.75 g of the sodium salt of 1- (2 It is diluted with 200 ml of ethyl acetate and 200 ml of water, decanted, washed with three times 200 ml of water and 100 ml of water, saturated with sodium chloride, filtered and concentrated under 20 mmHg (2, 7 kPa) to dryness at 20 ° C. The residue is chromatographed on a column of silica gel Merck (0.04-0.06) (column diameter 6 cm, height 30 cm) and eluted with 3.8 g of a mixture of cyclohexane-ethyl acetate (50 -. 50 volume) and 4.6 1 of a mixture of 25 -. 75 in order to recover fractions of 120 cc concentrate the fractions 40-69 under 20 mmHg (2.7 kPa) at 20 ⁰ C to dryness and wins 3.4 g 2-ßenzh ydryloxycarbonyl-

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - ^ ^δ - δ ⁷ 466/11

3-fluoro [(2,2-dimethoxyethyl) -5-tetrazolyl] -2-thiovinyl] -7- / 2-methoxyimino-2- (2-tritylamino-4-thia2olyl) acetamido-8-oxo S-oxide-S-thia-l-aza-bicyclo £ 4.2.Oj oct-2-ene _f syn isomer, Ε-shape, in the form which is used as such in the following working steps of a brown meringue.

Are treated at -8 ⁰ C for 30 min. Under stirring a solution of 3.37 g of 2-benzhydryloxycarbonyl-3 / fl- (2,2-dimethoxyethyl) -5-tetrazolyl] -2-thiovinyl] ~ 7-, f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoj-8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn-isomer, E Form, in 25 ecm of methylene chloride and 1.31 ecm of dimethylacetamide with 0.58 ecm of phosphorus trichloride. It is diluted with 75 ecm of methylene chloride, washed with twice 50 ecm of a half-saturated sodium bicarbonate solution and twice 50 ecm of water, dried over sodium sulfate, filtered and concentrated under 20 mmHg (2.7 kPa) at 20 ° C to dryness. The residue is chromatographed on a column of silica gel. .r Merck (0.04 to 0.06) (column diameter 4 cm, height 20 cm). It is eluted with 1.8 1 of a cyclohexane-ethyl acetate mixture (50-50 vol.), In which one obtains fractions of 60 ecm, under a pressure of 40 kPa. Dry fractions 16-24 to dryness and recover 1.1 g of 2-benzhydryloxycarbonyl-3- {-1- (2,2-dimethoxyethyl) -5-tetrazolyl3-2-thiovinyl-7-r2-methoxyimino-2- ( 2-tritylamino-4-thiazolyl) ~ acetamidoj-S-oxo-S-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, in the form of a cream meringue.

Infrared spectrum (KBr), characteristic bands (cm) 3400, 1790, 1725, 1690, 1520, 1500, 1450, 1210, 1050, 1040, 945, 755 »705

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AP C 07 D / 221 2 2 1 2 7 1 ... 369 - 57 466/11

NMR proton spectrum

(350 MHz, DMSO dg, <f in ppm, 3 in Hz) 3.31 (S ₁ , 6H _1. , S C (OCH ₃ J ₂ ), ... 3 ', 65 and 3, 91- ( 2d, D = 18, 2H, -SCH ₂ -); 3.83 (s, 3H, = NOCH ₃ ); 4.48 (d, 0 = 6, 2H, ^ NCH ₂ CHc :); 4.70 ( t, 0 = 6, ^ 1 NCH ₂ CHcT )> 5.23 (d, 3 = 4, "H ₆ ); 5.78 (dd, 3 = 4 and 9, H ₇ ); 6.74 (s, H of the thiazole); 6.96 (s, -COOCh [C ^);

29.9.1980 AP C 07 D / 221 271 22 1 27 1 .370- 57 466/11

7.02 and 7.08 (2d, 0 = 16, 2H, -CH = CH-S-); 8.7 9 (s, -NH-);

9.60 (d, 0 = 9, -NHCO-).

The mixture is heated for 30 min. At 50 ⁰ C a solution of 1.06 g of 2-benzhydryloxycarbonyl-3-FRI (2,2-dimethoxyethyl) -5rtetrazolylJ-2-thiovinylJ-7-f2-methoxyimino ~ 2 ~ (2- tritylamino-4-thiazolyl) acetamido] -8-oxo-5-thia-1-aza-bicyclo Γ4.2.03 oct-2-ene, syn isomer, Ε form, in 42 ecm formic acid, Man concentrated below 0, 05 mmHg (0.007 kPa) at 30 C to dryness, taken up in 100 cc of acetone, re-concentrated under 20 mmHg (2.7 kPa) at 20 ⁰ C to dryness, and repeated this operation four times. The yellow solid is treated under reflux in 30 ecm of acetone, allowed to cool and filtered. After drying, one obtains 0.43 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido) -2-carboxy-3- {(1,2-dimethoxyethyl) -5- tetrazolyl J-2-thio-vinyl-3-S-oxo-S-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, E-Forn, in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3350, 1780, 1680, 1655, 1620, 1530, 1120, 1040, 940

NMR proton spectrum

(350 MHz, CF ₃ CO ₂ D, (f in ppm, 0 in Hz)

3.61 (s, 6H,> C (OCH ₃ ) ₂ ); 3.92 (s wide, 2H, -SCH ₂ -); 4.31 (s, 3H, = NOCH ₃ ); 4.73 (d, 0 = 6, 2H, J> NCH ₂ -); 5.0 (t, 0 = 6, IH, -CH ₂ -CHCT); 5.38 (d, 0 = 4, H ₅ ); 6.05 (dd, 0 = and 9, H ₇ ); 7.16 and 7.77 (2d, 0 = 16, -CH = CH-); 7.50 (s, H of the thiazole).

The sodium salt of 1- (2,2-dimethoxyethyl) -5-mercaptotetrazole can be prepared in the following manner:

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - W - 57 466/11

A solution of 65 g of sodium azide in 1680 eq of 95% ethanol is heated under reflux. It is added dropwise with stirring for 1 h 30 min. A solution of 147.2 g of 2,2-Dimeth'oxyethyl-isothiocyanate in 320 cc to 95 / pc alcohol of ethanol and heated 12 h under reflux, is concentrated at 40 ⁰ C under 20 mmHg (2.7 kPa) to dryness, taking the residue in 600 ecm of acetone,

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filtered and added 1 1 diethyl ether. The crystallization is initiated and 2.5 l of diethyl ether are added again. It is allowed to stand at 20 ⁰ C for 24 h and filtered. After drying, 208.2 g of the sodium salt of 1- (2,2-dimethoxyethyl) -5-mercapto-tetrazole are recovered as a hydrate.

Infrared spectrum (KBr), characteristic bands (cm) 4380, 3220, 2840, 1660, 1400, 1290, 1115, 1070, 1025, 790

Example 45

A mixture of 0.4 g of 2-benzhydryloxycarbonyl-8-oxo-5-oxide ~ 3- (2-tosyloxy-vinyl) ~ 7- iZ- (2-tritylamino-4-thiazolyl) is heated at 60 ° C. for 4 h. 2-vinyloxyimino-acetamido-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn-isomer, E-form, 5 ecm dimethylformamide, 0.1 g 5-mercapto-1-methyltetrazole and 0.15 ecm Ν, Ν-diisopropylethylamine. It is taken up in 50 ml of ethyl acetate, washed with 50 ml of water, 50 ml of 0.1 N hydrochloric acid, 50 ml of a half-saturated sodium bicarbonate solution and 50 ml of a saturated solution of sodium chloride, dried over sodium sulphate, filtered and concentrated under 20 mmHg (2 , 7 kPa) at 30 C to dryness. The residue is chromatographed on a column of 50 g of silica gel (0.06-0.02) (column diameter 1.5 cm, height 15 cm). It is eluted with 2.5 l of a mixture of methylene chloride-ethyl acetate (90-10 vol.), Under a pressure of 40 kPa, obtaining fractions of 25 ecm. Fractions 18-42 are concentrated to dryness below 20 mmHg (2.7 kPa) at 20 ° C. 0.15 g of 2-benzhydryloxycarbonyl-3-ε (1-methyl-5-tetrazolyl) -2-thiovinyIj-8-oxo-5-αα-7-ε2- (2-tritylamino-4-thiazolyl) is thus obtained. 2-vinyloxyimino-acetamido-S-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, the characteristics of which are given below:

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - 3? 3 - 57 466/11

Infrared Spectrum (KBr), characteristic bands (cm ~) 3340, 2940, 2860, 1800, 1730, 1690, 1640, 1575, 1525, 1500, 1450, 1215, 1045, 1005, 950, 765, 760

NMR proton spectrum

(350 MHz, _CDCl3), ppm CTin, 0 (in Hz) 3.31 and 4.05 2d, 0 = 18, 2H, -SCH ₂ -); 3.92 (s, 3H, -CH ₃ );

H H 4.26 (dd, 3 = 2 and 6, IH, ^> cC ~); 4.76 (dd, 0 = 2 and 14,

IH, ^ T C = C ^); 4.67 (d, 0 = 4, IH, H in 6); 6.18 (dd, -OH

0 = 4 and 9, IH, H in 7); 6.78 (s, 3H, H of the thiazole); 6.95 (s, IH, -COOCH ^); 7.0 (d, O = 15, IH, -CH = CHS-); 7.05 (dd, O = 4 and 6, IH, -OCH =); 7.10 (s, IH, rCNH-); 7.58 (d, O = 15, IH, -CH = CHS-).,

Treat at -10 C for 20, min. a solution of 3 g of 2-benzhydryloxycarbonyl-3-ε (1-methyl-5-tetrazolyl) -2-thiovinyl] -8-oxo-5-oxide-7-ε -2- (2-tritylamino-4-thiazolyl) - 2-vinyloxyimino-acetamidoj-S-thia-1-aza-bicyclo f4.2.03 oct-2-ene, syn isomer, Ε-form, in 31.7 ecm of methylene chloride and 1.22 ecm of dimethylacetamide with 0.554 ecm of phosphorus trichloride. Pour the mixture into 250 cc of ethyl acetate, a, washed with 250 cc of a saturated Natriumbicarbonatlösurig, 250 cc water and 250 cc of a saturated sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under 20 mmHg (2.7 kPa) at 20 ⁰ C to dryness , Fix the product to 10 g silica gel Merck (0.06-0.2) and chromatograph on a column of 30 g silica gel Merck (0.06-0 * 2) (1.5 cm column diameter). It is eluted with 250 ecm of a cyclohexane-ethyl

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - 3> * ί - 57 466/11

acetate mixture (80-20 vol.), 250 ecm of a 70-30 (vol.) mixture and 250 ecm. of a 60-40 (vol.) mixture, and recovering 60 ecm fractions. Concentrate fractions 5-10 20 mmHg (2.7 kPa) at 20 ⁰ C to dryness and obtains 1.92 g of 2-benzhydryloxycarbonyl-3- £ l [l-methyl-5-tet razolyl) -2-thiovinyl] -8-oxo-7- f2- (2-t ritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido J-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, in the form of a

29.9.1980 AP C 07 D / 221 2 2 12 7 1 -3 ^ - 57 466/11

cream meringue.

Rf = 0.58 silica gel chromatography plate, eluent: cyclohexane-ethyl acetate (50-50 vol.)

The mixture is stirred at 50 ^° C. for 15 minutes. A mixture of 1.92 g of 2-benzhydryloxycarbonyl-3-bis (1-methyl-5-tetrazolyl) -2-thiovinyl-8-oxo-7-β-2-tritylamino-4 -thiazolyl) -2-viny1oxyiminoacetamidoT-S-thia-1-aza-bicyclo f4.2,0j oct-2-ene, syn isomer, E form, 15 ecm formic acid and 7 ecm water. Filter and concentrate at 0.05 mmHg (0.007 kPa) at 30 ° C to dryness. It is believed the residual oil in 100 cc "ethanol, the solvent sells under * '20 mmHg, 2.7 kPa, at 20 ⁰ C, and repeats this operation a second time. It is taken up in 100 cc of ethanol is heated with stirring under Reflux, allowed to cool and filtered, after drying, 0.72 g 7f2- (2 ~

^ *

Amino-4-thiazolyl) -2-vinyloxyimino-acetamido J-2-carboxy-3-ε (1-methyl-5-tetrazolyl) -2-thiovinyl] -8-oxo-5-thia-1-azabicyclo ε 4.2. 0j oct-2-ene, syn isomer, Ε-form, in the form of a yellow powder.

- • I

Infrared spectrum (KBr), characteristic bands (cm) 3340, 1770, 1680, 1620, 1530 and 1380.

NMR proton spectrum

(350 MHz, DMSO d _& , <T in ppm, O in Hz) 3.64 and 3.89 (2d, 3 = 18, 2H, -SCH ₂ -); 4.0 (s, 3H, -9H _3);

4.22 (dd, Ο = 2 and 6, IH, ^ C = C); 4.65 (dd, 0 = 2 and

H . - -O

14, IH,> C = C); 5.22 (d, 0 = 4, IH, H in 6); 5.82 -OH

(dd, 0 = 4 and 9, IH, H in 7); 6.75 (s, IH, H of the thiazole); 6.95 (d, O = 16, IH, -CH = CHS-); 6.96 (dd, 0 = 6 and 14, IH, -OChI = CH ₂ ); 7.13 (d, O = 16, IH, "CHS-); 9.83 (d, O = 9, IH, -CONH-).

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12 7 1 - ^ k - 57 466/11

The 2-Benzhydryloxycarbonyl-8-oxo-5-oxide ~ 3- (2-tosyloxyvinyl) · 7- £ 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamidoj-5

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - 3 »- 57 466/11

thia-1-aza-bicyclo-4,2'-O-oct-2-ene, syn-isomer, E-form, can be prepared in the following manner:

To a cooled to -10 ⁰ C solution of 1.6 g of 2-benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl.) ~ 7-f2- (2-tritylammino-4-thiazolyl) -2-vinyloxyiminoacetamidoj-5 -thia-1-azabicyclo £ 4.2.03 ~ oct-2-ene and 3-enes, syn. isomeres, mixture of the E and Z forms, in 5 ecm of methylene chloride is added dropwise over 10 min. A solution of 0.33 g of m-chloroperbenzoic acid of 85 % in 7 ecm of methylene chloride. The mixture is stirred for 1 h at -10 C, diluted with 30 ecm of methylene chloride, washed twice with 50 ecm of a saturated sodium bicarbonate solution and 50 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 mmHg (2.7 kPa) at 30 ⁰ C. to dryness. The residue is chromatographed on a column of 20 g of silica gel Merck (0.06-0.2) (column diameter 1 cm, height 10 cm), eluting with 500 ecm of methylene chloride, 1 l of a methylene chloride-ethyl acetate mixture (97-3 Vol.) And 1.5 1 of a 95-5 (vol.) Mixture, obtaining fractions of 25 ecm. Fractions 14-24 are evaporated at 20 mm Hg, 2.7 kPa, at 20 ⁰ C to dryness. 0.45 g of 2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxyviny1) -7- ^ 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido-J-5-thia-1 is recovered -aza-bicyclo [4, 2.Ojoct-2-en, syn-isomer, E-form.

Infrared spectrum (KBr), characteristic bands (cm) 1800, 1725, 1690, 1635, 1520, 1495, 1450, 1195, 1180, 1070, 1050, 1000, 945, 740, 700

29.9.1980 AP C 07 D / 221 22 1 27 1 -M - 57 466/11

NMR proton spectrum

(350 MHz, CDCl ₃ , Jin ppm, 3 in Hz)

2.45 (s, 3H, -CH ₃ ); 3.19 and 3.77 (2d, 3 = 18, 2H, -!

H JA 4.27 (dd, 3 = 2 and 6, IH, ^ OC ^ J "); 4.62 (d, 3 = 4, IH,

H in 6); 4.76 (dd, 3 = 2 and 13, IH, ^. C = C); 6,20 (dd, 3 = 4 - ° ä

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and 9, IH ₁ H in 7); 6.80 (s, IH, H of the thiazole); 6.90 (s, IH, -COOCH: ^); 6.92 and 7.10 (2d, D = 12, 2H, -CH = CH-); 7.05 (dd, 0 = 6 and 13, IH, = NOCH =); 7.73 (d, 0 = 8, 2H, H in ortho to the group -OSO--).

The 2-Benzhydryloxycarbonyl-8-oxo-3- (2-tosyloxyvinyl) ~ 7-C2- (2-tritylarnino-4-thiazolyl) -2-vinyloxyimino-acetamido) ~ 5-thia-1-aza-bicyclo £ 4.2. Oj oct-2-ene and 37ene "mixture of E" and Z forms can be prepared as follows:

To a cooled to -15 C solution of 2.4 g of 2-Benzhydryloxycarbonyl'-3- (2-oxoethyl) -8-oxo-7-r2- (2-tritylamino-4-thiazolyl) -2 ^ - vinyloxyiminoacetamido} - 5-thia-f-aza-bicyclo £ 4.2.Oj oct-2-ene, syn isomer, in 30 ecm of methylene chloride, are added 0.65 g of p-toluenesulfonyl chloride followed by dropwise addition over 10 min of a solution of 0.44 ecm triethylamine in 5 cc of methylene chloride "it is stirred for 30 min. at -15 C and allowed for 1 h at 20 ⁰ C rise, the mixture was diluted by 50 cc of methylene chloride, washed three times with 50 cc of a saturated sodium bicarbonate solution, three times 50 cc of water, dried over sodium sulfate, filtered and concentrated at 20 mmHg (2.7 kPa) at 30 ⁰ C to dryness.

The residue is taken up in 5 ml of ethyl acetate, 50 ml of diisopropyl ether are added, the mixture is stirred for 10 minutes, filtered, and after drying, 1.6 g of a beige powder, mainly consisting of 2-benzhydryloxycarbonyl-8-oxo-3, are obtained - (2-tosyloxy-vinyl) -7-jf 2 - (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido 3 -5-thia-1-aza-bicyclo-4,2'-oo-3-octene and 3-ene, mixture of E and Z shapes.

Infrared spectrum (KBr), characteristic bands (cm ^-1 ) 1790, 1725, 1690, 1640, 1525, 1495, 1450, 1195, 1180, 1075, 1005, 950, 755, 705

29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 - 2> δΟ - 57 466/11

NMR proton spectrum

(350 MHz, _CDCl3, </ in ppm, D in Hz) 2.45 (s, 3H, -CH _3); 3.40 and 3.55 (2d, D = 18, 2H, -SCH ₂ -);

4.27 (dd, D = 2 and 6, IH, J ^ C = C); 4.77 (dd, Ό = 2 and

-0 ^ H ^V ä

16, IH ₁ ^ C = C _v "); 5.09 (d, 0 = 4, IH, H in 6); 5.94 (dd, 0 = 4 and 9, IH, H in 7); 6, 81 (s, IH, H of the thiazole), 6.91 (s, IH, -COOCH C ^), 7.07 (dd, δ = 6 and 16, IH, -CH = CH ₂ ), 7.74 ( d, 0 = 8, 2H, H of the sulfonyl group)

The 2-Benzhydryl oxy car bony 1-3- (2-oxoethyl) ~ 8-oxo-7 - / "2- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido-5-thia-1-aza bicyclo £ 4,2.0]] oct-2-ene, syn isomer, can be prepared in the following W _e ise:

A solution of 2.5 g of 2-benzhydryloxycarbony1-3- (2-dimethylaminovinyl) -8-oxo-7--2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetamido 3-one is stirred at 25 ° C. for 1 h. 5-thia-1-aza-bicyclo £ 4.2.0} oct-2-ene, syn-isomer, E-form in 70 ecm of ethyl acetate in the presence of 50 ecm of 1 N hydrochloric acid. After decanting, wash the organic phase with two times 50 ecm of a half-saturated sodium bicarbonate solution and 50 ecm of a half-saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate under 20 mmHg (2.7 kPa) at 20 ° C to dryness. 2.4 g of a brown meringue is obtained, which is mainly composed of 2-benzhydryloxycarbonyl-3- (2-oxoethyl) -8-oxo-7-2- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido ] -5-thia-1-aza-bicyclo £ 4.2.O] oct-2-ene, syn isomer.

- 1

Infrared spectrum (KBr), characteristic bands (cm) 1785, 1725, 1685, 1640, 1530, 1495, 1450, 1000, 950, 755,700

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2 2 12 7 1 _m 3B4 " _{57 456/11}

NMR proton spectrum

(350 MHz, CDCl ₃₁ S in ppm, D in Hz) 3.26 and 3.58 (2d, D = 18, 2H, -SCH ₂ -); 3.53 and 3.69 (2d O = 18, 2H, -CH ₂ -); 4.28 (dd, 'O = 2 and 6, IH,

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AP C 07 D / 221 271

2 2 1 2 7 1 - ^ - ⁵⁷ 466 / Ii

• 0. -OH

^, C = C ^); 4.78 (dd, 0 = 2 and 17, IH, ^, C = cC); 5,12 ^ H.

(d, 0 = 4, IH, H in 6); 6.0 (dd ^ O = 4 and 9, IH, H in 7); 6.8 (s, IH, H of the thiazole); 6.90 (s, IH, -COOCHiC); 7.08 (dd, O = 6 and 17, IH, -C] H = CH ₂ ); 9.55 (s, IH, -CHO)

The 2-Benzhydryloxycarbonyl-3- (2-dimethylaminovinyl) -3-oxo-7- [2- { 2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetothio] -5-thia-1-aza-bicyclo £ 4.2 OJ oct-2-en, syn isomer, E form, can be prepared as follows:

To a solution of 2.5 g of 2-benzhydryloxycarbonyl-3-methyl-8-OXO-7-T2- (2-t-ritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido J-5-thia-1-aza-bicyclo ^ 4.2 .03 oct-2-ene, syn-isomer, in 80 ml of dimethylformamide add 0.7 ecm of tert-butoxy-bis-dimethylaminomethane at 80 ° C. under nitrogen, stir for 10 minutes at 80 ° C., and pour the mixture into 250 ml of ethyl acetate 250 ecm of ice water. It is decanted, washed with three times 150 eq of water and 150 ecm of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under 20 mmHg (2.7 kPa) at 30 ° C to dryness. 2.5 g of a brown meringue is obtained, consisting mainly of 2-benzhydryloxycarbonyl-3- (2-dimethylaminovinyl) -8-0X0-7- 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetamido3- 5-thia-1-aza-bicyclo ^ 4.2.Oj oct-2-ene, syn isomer, E form.

Infrared spectrum (KBr), characteristic bands (cm) 1770, 1670, 1635, 1610, 1530, 1495, 1450, 1000, 945, 755, 700

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2 2 12 7 1 - 383. _{57 466 / αι}

NMR proton spectrum.

(350 MHz, _CDCl3, S in ppm, 3 in Hz)

2.90 (s, 6H, -N (CH ₃ J ₂ ); 4.25 (dd, 3, = 2 and 6, IH

/ C = cC); 4.73 (dd, 3 = 2 and 14, IH, ^ C = C ^); 5,18 -O-O H

(d, 3 = 4, IH, H in 6); 5.60, (dd, 3 = 4 and 9, IH, H in Fig. 7); 6.53 and 6.75 (2d, 3 = 16, 2H, -CH = CH-); 6.88 (s, IH, -COOCH ^); 7,10 (dd, 3 = 6

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2 2 12 7 1 -. ^ " ^{57 466} Z ¹¹

and 14, IH, = N0CH =).

The 2-benzhydryloxycarbonyl-3-methyl-8-oxo-7-f 2 - (2-t-ritylamino-4-thiazolyl) -2-vinyloxyiminoacetamido 3 -5-thia-1'-azabicyclo £ 4.2.o] oct-2 syn-isomer is prepared by condensation of 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyiminoacetic acid, syn isomer, (4.6 g) with the benzhydryl ester of 7-ADCA (3.8 g) in the presence of N, N'-dicyclohexylcarbodiimide (2.3 g) and 0.05 g of 4-dimethylaminopyridine in 40 ecm of methylene chloride, at 5 to 20 ⁰ C for 4 h. Chromatography on silica gel (200 g) with methylene chloride gives 5 g of the expected product as a yellow meringue.

Infrared spectrum (KBr), characteristic bands (cm) 3400, 1785, 1725, 1690, 1640, 1525, 1495, 1450, 1040, 1000, 940, 755, 700.

NMR proton spectrum

(350 MHz, CDCl, </ * in ppm, 0 Hz) 2.12 (s, 3H, -CH _3); 3.22 and 3.49 (2d, D = 18, 2H, -CH ₂ -);

4.25 (dd, 0 = 2 and 6, IH ^ C = C ^); 4.76 (dd, 0 = 2 and 14,

-0

IH, *> C = C ^); 5.08 (d, 0 = 4, IH, H in-6); 5.92 (dd, -OH

u = 4 and 9, IH, H in 7); 6.83 (s, IH, H of the thiazole); 6.93 (s, IH, '- COOO-K'); 7.0 (s, IH, -NH-C (C ₆ H ₅ J ₃ ).

The 2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetic acid, syn-form, is prepared according to BE-PS 869,079.

29.9.1980 AP C 07 D / 221 271 221271 -3 ^ -. 57 466/11

Example 46

To a cooled to 5 C solution of 7.81 g of 2-syn-methoxyimino-2- (2-t.ritylamino-4-thiazolyl) acetic acid in 30 ecm of methylene chloride is added 1.90 g of dicyclohexylcarbodiimide. It is stirred for 40 min. At 5 ⁰ C and then for 30 min. At 20 ⁰ C and the solution is filtered,

To this cooled to -30 C solution is added a solution of 4.32 g of 7-amino-2-benzhydryloxycarbonyl-3-C (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl 8-oxo-5-oxide-5-thia-1-aza-bicyclo 4.2.2Oct oct-2-ene (mixture of the E and Z forms) in 25 ecm of methylene chloride, added with 1.25 ecm of triethylamine. The cooling bath is removed and stirred for 1 h 50 min. At 20 C, then the mixture is concentrated under reduced pressure (20 mmHg) at 20 C, the residue is taken up in 300 ecm of ethyl acetate, washed successively with 300: ecm of water, 100 ecm 0.1 η-hydrochloric acid, γ 100 cam a l ^ sodium bicarbonate solution and twice with 100 cc of water, which is half saturated with sodium chloride, dried over sodium sulfate and concentrated under reduced pressure (20 mmHg) at 20 ⁰ C to dryness, the residue is 30 g silica gel Merck (0.05-0.2 mm) and the powder is applied to a column of 130 g silica gel Merck (0.05-0.2 mm) (column diameter 3 cm, height 54 cm). It is subsequently eluted with mixtures of cyclohexane-ethyl acetate: 500 ecm (80-20 vol.), 1000 ecm (60-40 vol.), 2000 ecm (40-60 vol.) And 3000 ecm (20-80 vol.), whereby one wins fractions of 125 ecm. After evaporation of fractions 32-49 under reduced. Pressure (20 mmHg, 2.7 kPa) at 20 C gives 3.2 g of 2-ßenzhydryloxycarbonyl-7- ^ 2-

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methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido3-3- 1 { 2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl-3-8-oxo-5-oxide-5 -thia-1-aza-bicyclo t4,2,0 " oct-2-ene, syn isomer, mixtures of the E and Z forms, in the form of a brown, light ring, * ^T

29.9.1980 AP C 07 D / 221 22 127 1. - 3δΚ 57 466/11

1 infrared spectrum (CH.sub.r), characteristic bands (cm) 3390 _f 1805/1725, 1685, 1520, 1375, 1050, 940, 755, 740

NMR proton spectrum

(350 MHz, CDCl ₃ , ^ T in ppm, 0 in Hz) The following main signals are detected:

2.74 and 2.75 (2s, total 3H, -CH _3); 4.09 (s, 3H, SNOCH ₃ ); 6.73 (s, IH, H in the 5-position of the thiazole).

ν. ·? <S * x 4 * '-' * To a cooled to -10 C solution of 2.99 g of 2-benzhydryloxycarbonyl-7 £ 2 ~ methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-3 -f (2-methyl-l, 3,4-thiadiazol-5-yl) -2-thioylinyl J-8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2- en (syn isomer, mixture of E and Z forms) in 30 ecm of methylene chloride and 1.25 ecm of dimethylacetamide, add 0.54 ecm of phosphorus trichloride and stirred for 30 min. At this temperature, diluted with 500 ecm of ethyl acetate, washed one after the other. Dissolve 100 eq of a 2 ^ 0 solution of sodium tri-sulphibicarbonate twice and 200 x ecm of a solution saturated with sodium chloride, dry over sodium sulphate, filter and concentrate under reduced pressure (20 mmHg, 2,7 kPa) at 20 ° ⁰ C. the residue is chromatographed on 10 g silica gel Merck (0,05 - 0,2 mm) is fixed, and the powder is applied to a column of Merck silica gel 50 g (0,05 - 0,2 mm) was applied (column diameter 3 cm Height 23 cm). Successively elute with cyclohexane-ethyl acetate mixtures: 500 ecm (75-25 vol.), 750 ecm (50-50 vol.), 1000 ecm (25x-75VOlT), obtaining fractions of 125 ecm. Fractions 9-14 are under reduced pressure (20 mmHg; 2.7 kPa) at 20 ⁰ C * 2UR dryness, obtaining 1.55 g of 2-benz-

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hydryloxycarbony1-7- ^ 2-methoxyimino-2- (2-1-ritylamino-4-thiazolyl) -acetamido] -3-C (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl-3-yl 8-oxo-5-thia-1-aza-bicyclo f4.2.0j oct-2-ene (syn isomer, mixture of E and Z forms) in the form of a yellow herrings.

- * 1 Infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3400, 1790, 1720, 1685, 1515, 1370, 1045, 755, 740

29.9.1980 AP C 07 D / 221 271 2 12 7 1 - ³ ^ - 57 466/11

NMR proton spectrum

(350 MHz, CDCl, / in ppm, O in Hz) The following main signals are detected:

2.77 (s, 3H, -CH ₃ ); 4.09 ('s, 3H, = NOCH ₃ ); 6.77 (s, IH, H in the 5-position of the thiazole).

Dissolve 1.47 g of 2α-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido] -3-C (2-methyl-1,3,4-thiadiazol-5-yl ) -2-thio-vinyl-3-8-oxo-5-thia-1-aza-bicyclic 4,2,0] oct-2-ene, syn-isomer, mixture of E and Z forms, in 8 ecm trifluoroacetic acid and 0 , 15 ecm anisole. The mixture is stirred for 1 h at +5 ⁰ C and 30 min. At 20 ⁰ C and then poured with stirring into 35 ecm diethyl ether. It is filtered, dried and replaced with 1 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido) -2-carboxy-3-f (2-methylthyl, 3,4-thiadiazole-5 ~ yl) -2-thiovinyl-8-oxo-5-thia-1-aza-bicyclo [4.2-octo-2-ene (syn-isomeres, mixture of E and Z forms) in the form of trifludracetate,

Rf = 0.50; ^ Silica gel chromatography plate, solvent: ethyl acetate-acetone-acetic acid-1 water (50-20-10-10 vol.)].

- 1 infrared spectrum (KBr), characteristic bands (cm) 3380, 3300, 1780, 1675, 1200, 1140, 1050, 945

NMR proton spectrum

(350 MHz, CDCl ₃ , cT in ppm, D in Hz) E-form:

2.74 (s, 3H, -CH _3); 3.69 and 3.83 (2d, D = 17, 2H ₁ -SCH ₂ -); 3.91 (s, 3H, -OCH ₃ ); 5.23 (d, 0 = 4, IH, H in 6); 5.82 (dd, 0 = 4 and 10, IH, H in 7); 6.85 (s, IH, - H in position 5 of the

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Thiazole); 7.16 and 7.32 (2d, D = 16, 2H, -ClH = Ch [S-); 9.75 (d, ö = 10, IH, -CONH-)

Z-form:

3.88 and 3.92 (2d, 3 = 17, 2H, -SCH ₂ -); 6.91 (AB limit, 2H,

-CH = CIH-). ",:

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J "

The 7-amino-2-benzhydryloxycarbonyl-3-f (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl] -8-oxo-5-oxide ~ 5-thia-1-aza ~ bicyclo / 44.2.0j oct-2-ene, mixture of E and Z forms, can be prepared in the following manner:

The mixture is stirred for 16 h at 20 C, a mixture of 7.67 g of 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-Γ (2-methyl-l, 3,4-thiadiazol-5-yl) -2-thiovinyl 8-oxo ~ 5-oxide ~ 5-thia-1-aza-bicyclo 14.2.0 "} oct-2-ene, (mixture of E * and Z forms), 120 ecm acetonitrile and 4.57 g p- Toluene sulfonic acid monohydrate, dilute the mixture with 300 ecm of ethyl acetate, wash with 200 ecm of a saturated sodium bicarbonate solution and three times 200 ecm of a half-saturated sodium chloride solution, dry over sodium sulfate, filter and concentrate under reduced pressure (20 / nmHg, 2.7 kPa) at 20 ⁰ C to dryness. This gives as 4.32 g of 7-amino-2-benzhydryloxycarbonyl-3 ~ / '(2 ~ methyl-l, 3,4-thiadiazol-5 ~ yl) ~ 2-thiovinylJ-8-oxo- 5-oxide-5-thia-1-aza-bicyclo ^s C4.2.0J oct-2-ene, in the form of a crude brown herrings.

Rf = 0.17, silica gel chromatography plate; Eluent, dichloroethane-methanol (85-15 vol.) J,

The 2-ßenzehydryloxycarbonyl-7-t-butoxycarbonylamino-3 - / (2-methyl-l, 3,4-thiadiazol-5-yl) -2-thiovinyl J-8-oxo-5-oxide-5-thia-1 -azabicyclo C4.2.0J oct-2-ene (mixture of E and Z forms) may be prepared in the following manner:

The mixture is stirred at 20 ⁰ C under nitrogen for 17 hours a mixture of 13.58 g of 2-ßenzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-l- aza-bicyclo £ 4.2.03 oct-2-ene (mixture of E and Z forms), 40 ecm diameter

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methylformamide, 0.13 ecm of trimethylchlorosilane, 2.91 g of 2-methyl-5-mercapto-l, 3,4-thiadiazole and 3.85 ecm of N-ethyl-N, N-diisopropylamine. The mixture is diluted with 500 ecm of ethyl acetate Wash successively with four times 250 eq. of water, 250 ecm. of 0.1 N hydrochloric acid, twice 250 eqm. of a 2% sodium bicarbonate solution, 500 ecm

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Water, and twice 250 ecm of water, saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure (20 mmHg, 2.7 l <Pa) at 20 ⁰ C to dryness. The residue is fixed to '50 g silica gel Merck (0.05-0.2 mm) and the powder is applied to a column of 200 g silica gel Merck (0.05-0.2 mm) (column diameter 4 cm, height 47 cm) applied. It is eluted with mixtures of cyclohexane-ethyl acetate £ 500 _v , ccm * (80-20 vol.), 2000 ecm (60-40 vol.) And 8000 ecm (40-60 vol.)] To yield fractions of 125 ecm , Fractions 38-80 are recovered and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 20 ° C. 7.91 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-C (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl-8-oxo-5-oxide-5 are recovered -thia-1-aza-bicyclo f4.2.0j oct-2-ene (mixture of E and Z forms) in the form of a light brown meringue.

1 infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3420, 1805, 1720, 1505, 1370, 1050, 940, 760, 745

NMR proton spectrum

(350 MHz, CDCl3, </ "in ppm, 3 in Hz)

E-shape:.

1.5 (S, 9H, (CH ₃ ) ₃ C-); 2.75 (s, 3H, -CH ₃ ); 3.30 and 4.15 (2d, Ο = 18, 2H, -SCH ₂ -); 4.55 (d, D = 4.5, IH, H in Figure 6); 5.7-5.9 (mt, 2H, -CONH- and H in Figure 7); 6.97 (s, IH, -COOCH-); 7.15 (d, D = 16, IH, -C = CHS-); 7.53 (d, D = 16, IH, = CHS-).

Z-form:

1.5 (s, 9H, (CH ₃ ) ₃ C-); 2.74 (s, 3H, -CH _3); 3.45 and 4.11

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(2d _f 3 = 18, 2H, -SCH ₂ -); 4.55 (el, 0 = 4.5, IH, H in 6); 5.7-5.9 (int, 2H, -CONH- and H in Figure 7); 6.78 (d, 0 = 10, IH, -CH = CHS-); 6.88 (d, 0 = 10, IH, = CHS-); 6.95 (s, IH, -CpOCH-).

The mixtures of E and Z forms of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-

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1-aza-bicyclo 4.2 4.2.oJoct-2-ene can be prepared by the method described in Example 47 below,

Example 47

To a cooled to 4 C solution of 2.89 g of 2-syn-methoxyimino-2- (2 ~ tritylamino-4-thiazolyl) acetic acid in 10 ecm of methylene chloride is added 0.71 g of dicyclohexylcarbodiimide. It is stirred for 40 min. At 4 ⁰ C and then for 30 min, at '20 C and filtered the solution,

To this filtered, cooled to -30 ⁰ C solution is added a solution of 1.55 g of 7 ~ amino-2-benzhydryloxycarbonyl-3-f (1-methyl-5-tetrazolyl-2-thiovinylj-8-oxo-5 Oxide-5-thia-laza-bicyclo [4.2.0] oct-2-ene (Z form) in 13 ecm methylene chloride, to which is added 0.46 ecm triethylamine, and the cooling bath is removed and stirred for 1 h 50 min. at 20 ⁰ C, it concentrate the mixture under reduced pressure (20 mmfrig; 2.7 kPa). at 20 ⁰ C and the residue is taken up in 100 cc of ethyl acetate, this organic phase is washed three times with 50 cc of water, 50 cc 0 , 05 n-Chlorvvasserstoffsäure, 50 cc of a l% sodium bicarbonate solution and two 50 cc of water, which is half saturated with sodium chloride, dried over sodium sulfate, filtered and concentrated under reduced pressure (20 mmHg; 2.7 kPa) at 20 ⁰ C to dryness , The concentrate is dissolved in 25 ecm of a mixture of cyclohexane-ethyl acetate (10 - 90 vol.) And the solution is chromatographed on a column of 300 g of silica oxide gel Merck (0.04-0.06 mm) (column diameter 5 cm, height 33 cm). It is eluted with 3 l of a mixture of cyclohexane-ethyl acetate (10 - 90 vol.) Under a nitrogen pressure of 0.4 bar, to obtain fractions of 110 ecm. After concentrating fractions 9-17 to dryness and drying, 0.98 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2-bis (2-tritylamino-4-) is obtained.

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thiazolyl) -acetamido3-3-r (1-methyl-5-tetrazolyl) -2-thio-4-pyrimido-S-oxo-S-oxide-S-thia-1-aza-bicyclo-4,2,3'Octo-2-ene _f syn isomer, Z-form, in the form of a yellow meringue,

Infrared spectrum (CHBr,), characteristic bands (cm) 3380, 1805, 1725, 1680, 1515, 1050, 755, 740

NMR proton spectrum

(350 MHz, _CDCl3, </ "in ppm, D in Hz) 3.81 (s, 3H, ^ NCH _3), 3.89 and 4.01 (2d, D = 19, 2H, -S-CH ₂ -); 4.10 (s, 3H, -OCH ₃ ); 4.66 (d, 0 = 4, IH, H in 6); 6.24 (dd, 0 = 4 and 10, IH, H in 6,72 and 6,76 (2d, 0 = 10, 2H, -CH = CIHS-), 6.98 (s, IH, -COOCH-), 6.72 (s, IH, H in 5 Position of the thiazole); 7.07 (s, IH, (CHJ ₃ C-NH-).

To a cooled to -1O C solution of 0.93 g of 2-Benzhydryloxycarbonyl-7-l-2-methoxyimino-2- (2-t ritylamino-4-thiazolyl) acetamido]) -3-C (l-methyl-5 razolyl) .- 2-thiovinyl-S-oxo-S-oxide-S-thia-1-aza-bicyclo Γ4.2.03 oct-2-ene (syn isomer, Z-form) in 10 ecm of methylene chloride and 0 , 39 ecm of dimethylacetamide add 0.17 ecm of phosphorus trichloride and stir for 45 min. At the same temperature. The mixture is diluted with 200 eq of ethyl acetate, washed with twice 50 eq of a 2% sodium bicarbonate solution and twice with 50 ecm of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure (20 mml-1g, 2.7 kPa) at 20 ° C to dryness. The residue is fixed to 5 g silica gel Merck (0.05-0.2 mm) and the powder is applied to a column of 15 g silica gel Merck (0.05-0.2 mm) (diameter 2 cm, height 8 cm ) applied. One elutes one after another

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100 ecm of a mixture of cyclohexane-ethyl acetate (75-25 vol.), 250 ecm of a mixture of 50-50 (vol.) And 250 ecm of a mixture of 25-75 (vol.), Whereby fractions of 60 ecm are recovered , Concentrate fractions 3-7 to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 25 ° C to give 0.74 g of 2-benzhydryloxycarbonyl-3,4-methoxyimino (2- (tritylamino-4-thiazolyl) Acetamido} - *

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3- (1-methyl-5-tetrazolyl) -2-thiovinyl-8-OX-O-5-thia-1-azabicyclo [4.2.0] oct-2-ene (syn isomer, Z form) in the form a yellow herrings. '

- 1 infrared spectrum (CHBr-), characteristic bands (cm) 3400, 1790, 1725, 1685, 1515, 1370, 1050, 755, 740

NMR proton spectrum (350 MHz, CDCl ₃ , (T in ppm, 0 in Hz) 3.56 and 3.69 (2d, 0 = 17.5, 2H, -SCH ₂ -); 3.81 (s, 3H,> HCH ₃ ), 4.09 (s, 3H, -OCH ₃ ), 5.13 (d, 0 = 4, IH, H in 6), 5.99 (dd, D = 4 and 10, IH , H in 7), 6.76 (AB, 0 = 11, 2H, -CH = CHS- ), 6.9 (d, Ό = 10, IH, -CONH-), 6.97 (s, IH , -COOCH-); 7.01 (s, IH, (CH) CNH-).

Dissolve 0.67 g of 2-benzhydryloxycarbonyl-7-r 2 -methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido! 3-ε (1-methyl-5-tetrazolyl) -2-thiovinyl-3-8 -oxo-5-thia-1-aza-bicyclo C4.2.07 oct-2-ene (syn isomer, Z form) in 3.6 ecm trifluoroacetic acid and 0.07 ecm anisole. The mixture is stirred for 1 h at 5 C and then for 30 min. At 20 ⁰ C and concentrated under reduced pressure (20mmHg, 2.7 kPa) at 20 ⁰ C to dryness. The residue is redissolved in 2 ecm of trifluoroacetic acid, and the solution is poured into 10cc of ethyl ether with stirring. After filtration and drying, 0.33 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-J-2-carboxy-3 - / (1-methyl-5-tetrazolyl) -2- thiovinyl] · S-oxo-5-thia-1-aza-bicyclo / "4,2.Oj oct-2-ene (syn isomer, Z-form) in the form of the trifluoroacetate.

Rf = 0.50 / "silica gel chromatography plate; solvent: ethyl acetate-acetone-acetic acid-water (50-20-10-10 vol.) J.

- 1 infrared spectrum (KBr), characteristic bands (cm) 3300, 1785, 1675, 1180, 1140, 1050

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2 2 12 7 1 _r ^ _{m 57 456 / ljL}

NMR proton spectrum

(350 MHz, DMSO d _g, <f in ppm, D in Hz) 3.8 and 3.85 (AB> D = 17.5, 2H, -SCH ₂ -); 3.93 (s, 3H,> -NCH ₃ ); 4.0 (S / 3H, -OCH ₃ ); 5.26 (d, CT = 4, ^J IH, H in Figure 6); 5.85 (dd, 0 = 4 and 10, H in 7); 6.75 (d, D = 11, IH, -ChJ = CH-S-); 6.87 (s, IH, H at the 5-position of the thiazole); 6.91 (d, O = 11, IH, = CH-S--); 9.34 (d, 3 = 10, IH, -CONH-).

The 7-amino-2-benzhydryloxycarbonyl-3 - ^ (1-methyl-5-tetrazolyl) -2-thiovinyl3-8-oxo-5-oxide-5-thia-1-aza-bicyclo / 4,2.07 oct -2-en, Z-form, can be prepared in the following way:

The mixture is stirred for 16 h at 25 ⁰ C a mixture of 3.11 g of 2-benzhydryloxycarbonyl ^ -t-butoxycarbonylamino-S- C {1-methyl-5-tetrazolyl) -2-thiovinyl3-8 ~ oxo-5-oxide 5-thia-1-aza-bicyclo [4,2,03 oct-2-ene (Z-form), 50 ecm acetonitrile and 1.9 g p-toluenesulfonic acid monohydrate. Subsequently, the mixture was concentrated under reduced Drück- (20 mmHg; 2 * 7 kPa) at 20 ⁰ C and the residue is stirred in the presence of 100 cc of ethyl acetate and 100 cc of a 5 / o sodium bicarbonate solution. It is decanted, washed with 50 ecm of a 5% sodium bicarbonate solution and twice 50 cm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure (20 mmHg, 2.7 kPa) at 20 ° C to dryness. This gives 1.55 g of 7-amino-2-benzhydryloxycarbonyl-3-C (1-methyl-5-tetrazolyl) -2-thiovinyl-8-oxo-5-oxide-5-thia-1-aza-bicycloe 4.2.0} oct-2-en (Z-form) in the form of a raw brown meringue.

Rf = 0.21, silica gel chromatography plate; Solvent: dichloroethane-methanol (85-15 vol.).

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2 2 1271. "^" ^{57 4} S ^5/1 *

The 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3 - / '(1-methyl-5-tetrazolyl) -2-thiovinyl] -8-oxo-5-oxide-5-thia-laza-bicyclo Γ4.2.03 oct. 2-en (Z-form) can be prepared in the following way:

The mixture is heated to 60 C with stirring under nitrogen for 1 h

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a mixture of 5.44 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo [4.2.O] oct-2 -en (Z-form), 40 ecm of dimethylformamide, 1.88 g of 1-methyl-2-mercaptotetrazole and 2.8. ecm 'N-ethyl-N, N-diisopropylamine. The mixture is then diluted with 250 ml of ethyl acetate, washed successively with three times 100 ml of water, 100 ml of 0.1 N hydrochloric acid, twice 100 ml of a 2% solution of sodium bicarbonate and twice 100 ml of a half-saturated sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure (20 mmHg; 2.7 kPa) at 20 ⁰ C to dryness. The residue is fixed to 20 g of silica gel and applied to a column of 80 ecm silica gel Merck (0.05 0.2 mm) (column diameter 3 cm, height 12 cm). It is eluted successively with 250 ecm of a mixture of cyclohexane-ethyl acetate (90-10 vol.), 500 ecm of an 80-20 mixture (vol.), 1000 ecm of a 70-30 mixture (vol.), 2000 ecm of a 60 40 mixture (vol.) And 2000 ecm. Of a 40-60 mixture (vol.), Yielding fractions of 125 ecm. The fractions 34-45 are collected and concentrated to dryness to give 3.44 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (1-methyl-5-tetrazolyl) -2-thiovinyl-8-oxo-5-one oxide 5-thia-1-azabicyclo ΖΓ4.2.03 oct-2-ene (Z-form) in the form of a light brown meringue.

Infrared spectrum (CHBr,), characteristic bands (cm) 3410, 1800, 1720, 1500, 1370, 1230, 1045, 755, 740 <·.

NMR proton spectrum

(350 MHz, CDCl ₃ , <f in ppm, 0 in Hz) 1.48 (s, 9H, (CH ₃ J ₃ C-), 3.81 (s, 3H,> NCH ₃ ), 3.38 and 4.03

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(2d, D = 18, 2H ₁ -SCH ₂ -); 4.58 (d, 0 = 4.5, IH, H in Figure 6); 5.75 (d, 0 = 9, IH, -CONH-); 5.85 (dd, 0 = 4.5 and 9, IH, H in Figure 7); 6.70 (d, 0 = 9.5, IH, -CH = CH-S-); 6.79 (d, J = 9.5, IH, = CHS-); 6.98 (s, IH, -COOCH-).

29.9.1980 AP C 07 D / 221 271 _ 12 7 1. - & 44 - 57 466/11

The 2α-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo Z * 4.2.0j oct-2-ene can be found in the following manner getting produced: ,..*,

In a cooled to -10 C solution of 180.55 g of 2-ßenzhydryloxycarbony1-7-t-butoxycarbonylamin0-8-oxo-3- (2-tosyloxyvinyl) -5-thia-l-aza-bicyclo £ 4.2.0} oct 2-ene or 3-ene (mixture of the E and Z forms) in 1.4 l of methylene chloride, a solution of 55.22 g of 85% m-chloroperbenzoic acid in 600 ecm of methylene chloride is added dropwise during 2 h . The mixture is washed with 1.5 1 of a 5 / jigen sodium bicarbonate solution and twice 1.5 1 of water, dried over sodium sulfate and at 20 ⁰ C under reduced pressure (20 MMBG; 2.7 kPa) to a volume of 300 cc This solution is chromatographed on a column of 3 kg of Merck silica gel (0.05-0.2 mm) (column diameter * 9.2 cm, height 145 cm), eluting with mixtures of cyclohexane-ethyl acetate, successively with 15 ( 80-20 vol.) And 32 l (70-30 vol.), Yielding fractions of 600 ecm., Fractions 27-28 are collected and concentrated to dryness to give 5.56 g of the 2-form de s 2-.beta.zydehydloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-azabicyclo [4.2. octo-2-ene].

Infrared spectrum (CHBr,), characteristic bands (cm) 3420, 1800, 1720, 1505, 1380, 1370, 1195, lf80, 1050, 1010, 730

NMR proton spectrum

(350 MHz, CDCl ₃ , S in ppm, D in Hz) 1.49 (s, 9H, -C (CH ₃ J ₃ ), 2.44 (s, 3H, -CH ₃ ), 3.36 and 4.04

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(2d, 3 = 19, 2H, -SCH ₂ -); 4.44 (d, 3 = 4.5H, H in 6); 5.73 (d, 3 = 9, IH, -CONH-); 5.81 (dd, 3 = 4.5 and 9, IH, H in Figure 7); 6.42 (d, 3 = 7, IH, -CH = CH OSO ₂ -); 6.46 (d, 3 = 7, IH, = CH 0 S0 _p -); 6.89 (s, IH, -COOCH-); 7.77 (d, 3 = 9, 2H, H in the ortho position of the tosyl).

In fractions 29-34, 26 g of the mixture of Z-

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - Ǥ? - 57 466/11

and E-forms. '.

Finally, in fractions 35-58, 43 g of the Ε-form of the product are obtained: '*. - · -

Infrared spectrum (CHBr,), characteristic bands (cm * ") 3420, 1800, 1720, 1505, 1380, 1370, 1195, 1180, 1075, 935, 745

NMR proton spectrum

(350 MHz, CDCl ₃ , <f in ppm, D in Hz) 1.48 (s, 9H, (CH ₃ J ₃ C-), 2.46 (s, 3H, -CH ₃ ), 3.16 and 3.81 (2d, 0 = 18, 2H, -SCH ₂ -); 4.46 (d, D = 4.5, IH, H in 6); 5.73 (d, D = 9, IH, - CONH-), 5.8 (dd, D = 9 and 4.5, IH, H in 7), 6.83 (d, D = 13, IH, -CH = CHO, SO ₂ ), 6.83 ( s, IH, -COOCH-); 7.08 (d, D = 13, IH, = CH OSO ₂ -); 7.73 (d, D = 9, 2H, H in the ortho position of the tosyl).

The 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo / T4.2.0 J oct-2-ene, (mixture of E and Z. Forms) can be prepared in the following manner:

To a solution of 113.7 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-aza-bicyclo C4.2.0 J oct-2-ene (Ε-form ) in 1 liter of tetrahydrofuran is added a solution of 50 cc of formic acid in 500 cc of water. . Homo go solution at 20 C for 20 min The mixture is stirred, and then is concentrated to a quarter of its volume under reduced pressure (20 mmHg; 2.7 kPa) at ^20-0 C. Take the concentrate in 2 1 of ethyl. acetate, washed twice with 500 ecm of a 5% sodium

29.9.1980 AP C 07 D / 221 271 127 1 "SSa - 57 456/11

bicarbonate solution, twice 500 ecm of water and twice 500 ecm of a saturated sodium chloride solution, dried over sodium sulfate, filtered and evaporated under reduced pressure (20 mmHg, 2.7 kPa) at 20 ⁰ C to dryness. 112.4 g of crude product are obtained, which are treated in solution in 250 ecm of anhydrous pyridine of 5 ° C. with 57.2 g of tosyl chloride.

29.9.1980 AP C 07 D / 221 271 221271-S ^ - 57 466/11

After 30 min. At 5 ° C and 1 h at 20 ⁰ C, the solution is poured into 1 1 of a mixture V / asser-broken ice. The aqueous phase is separated off and the insoluble portion is washed with 300 eq. Of distilled water. The paste-like product is dissolved in 200 ml of ethyl acetate, washed twice with 750 ml of 1N hydrochloric acid, twice 750 ml of a 5% sodium bicarbonate solution and four times 750 ml of water, dried over sodium sulphate and concentrated under reduced pressure (20 mmHg; 7 kPa) at 20 C to dryness, giving 121 g of a product consisting essentially of 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3 ~ (2 ~ tosyloxyvinyl) -5-thia-l-aza ~ bicyclo £ 4.2.0} oct-2-ene (mixture of E and Z forms), in the form of a raw brown meringue.

The 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (2-dimethylaminovinyl) -8-oxo-5-thia-1-aza-bicyclo-4,2,2,3-oct-2-ene (Ε form). Can be described below Way to be obtained:

Dissolve 90.5 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo [4.2.2O] oct-2-ene in 400 ecm of anhydrous Ν, Ν- dimethylformamide. The resulting solution is heated to 80 ^° C. under a nitrogen atmosphere. Then added raschfcine'Lösung of 36.1 g of bis-dimethylarnino-t-butoxymethane in 60 cc anhydrous N, N-Öimethylformamid to which has been preheated to 80 ⁰ C. The reaction mixture is held for 5 min. At 80 C and then poured into 3 1 of ethyl acetate. After the addition of 1 liter of distilled water, the organic phase is decanted off, washed with distilled water four times, dried over sodium sulphate and, in an ordinary condition

29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 - 246 «- 57 466/11

filtered by decolorizing carbon. It is concentrated under reduced pressure (20 mmHg; 2.7 kPa) at 30 ⁰ C to dryness to obtain 101 g of 2-benzhydryloxycarbonyl-7-t -butoxycarbonylamino-3- (2-dimethylamino-vinyl) -8-oxo-5-thia -l-aza-bicyclo £ 4.2.0} oct-2-ene (Ε-form) in the form of an orange herring.

Rf = 0.29; Silica Gel Chromatography Plate fCyclohexane

29.9.1980 ^ AP C 07 D / 221

2 2 1 2 7 1 - ^ ² " ¹ " ^{57 465} A ¹

Ethyl acetate (50-50 vol.)].

The 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-methyl-8-oxo-5-thia-1-aza-bicyclo ^ 4.2, OJ qct-2-ene can be prepared in the following manner:

To a solution of 188.6 g of 7-t-butoxycarbonylamino-2 ~ ca-boxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo f4.2.0j oct-2-ene in 2100 ecm acetonitrile Add dropwise during 45 * min. at a temperature of 25-30 C, a solution of 116.5% of diphenyldiazomethane in 800 ecm of acetonitrile. The reaction mixture is stirred at 22 C for 16 h and then concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa) at 40 ° C. The residue is dissolved in 2 l of ethyl acetate, and the solution is washed with 700 eq of 2N-hydrochloric acid, then with 700 eq of a saturated aqueous sodium bicarbonate solution and with 700 ecm of a saturated aqueous sodium chloride solution. The solution is dried over sodium sulfate, treated with decolorizing charcoal and filtered, and then under reduced pressure (20 mmHg; 2.7 kPa) at 40 ⁰ C to dryness. The residue is dissolved in 600 ecm of ethyl acetate while boiling. Add 1 1 of cyclohexane, heated to reflux and then allowed to cool. The resulting crystals are separated by filtration, washed with three times 250 ecm diethyl ether and then dried. This gives 191 g of 2-Benzhydryloxycarbonyl-7 ~ t ~ butoxycarbonylamino-S-methyl-S-oxo-S-thia-l-aza-bicyclo 4 4 ₀ 2.0j oct-2-ene in the form of white crystals of mp = 179 ⁰ C. upon concentration of the mother liquors to 500 cc is obtained a second fraction of the product of «32.6 g, mp 178 ⁰ C.

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The 7-t-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo-4-ol 4.2.0j oct-2-ene can be prepared in the following manner:

371 g of 7-amino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo

29.9.1980 AP C 07 D / 221 271 '221271. - *** ^Λ - 57 466/11

oct-2-ene is dissolved in a solution of 307 g of sodium bicarbonate in a mixture of 2 l of distilled water and 2 l of dioxane. A solution of 421 g of t-butyl dicarbonate in 2 l of dioxane is added over 10 min. The Reaktionsgemisc.h y / ird 48 h at 25 C stirred. The suspension obtained is concentrated under reduced pressure (20 mmHg, 2.7 l <Pa) at 50 ° C. to a residual volume of about 2 l and then diluted with 1 l of ethyl acetate * and 2 l of distilled water. The aqueous phase is decanted off, washed with 500 ecm of ethyl acetate and acidified to pH 2 with 6N hydrochloric acid in the presence of 1500 ecm of ethyl acetate. The aqueous phase is extracted twice with 1 l of ethyl acetate. The organic phases are combined and washed twice with 250 ecm of a saturated sodium chloride solution and dried over sodium sulfate. After filtration, the solvent is evaporated at 50 C under reduced pressure (20 mmHg). This gives 486 g of 7-t-butoxycarbonylamino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo-4,2'-O-oct-2-ene, in the form of yellow crystals of mp = 190 C (decomposition).

Example 48

To a cooled to 4 ⁰ C solution of 36.59 g. 2-Syn-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetic acid in 135 ecm of methylene chloride is added 8.90 g of dicyclohexylcarbodiimide. After 40 min. Stirring at 4 ⁰ C and 30 min. At 20 ⁰ C, the solution is filtered. To this filtered cooled to -30 ⁰ C solution is added with stirring, a solution of 19.59 g of 7-amino-2-benzhydryloxycarbonyl-3 - / * (l-methyl-5-tetrazolyl) -2-thiovinylJ-8-oxo -5-oxide-5-thia-1-aza-bicyclo 4.2 4.2.Oj oct-2-ene (Ε form) in 165 ecm methylene chloride, combined with 5.8 ecm triethylamine. Remove the cooling bath and continue stirring for 1.5 h. The mixture is concentrated at 20 C under reduced pressure

29.9.1980 AP C 07 D / 221 271 22127 1, - Ήλ- 57 466/11

Pressure (20 mmHg, 2.7 kPa), the residue is taken up in 1 liter of ethyl acetate, washed successively with 500 ml of water, 500 ml of 0.1N hydrochloric acid twice, 250 ml of a 2% sodium bicarbonate solution twice and then 500 cm / 2 twice Sodium chloride solution, dried over sodium sulfate and concentrated to dryness at 20 ° C. under reduced pressure (20 mmHg, 2.7 kPa). The residue is fixed to 100 g of silica gel Merck (0.05-0.2 mm) and the resulting product is obtained Powder on a column of 700 g of silica gel Merck (0.05 - 0.2 mm) (column diameter 6 cm, height 61 cm). The mixture is subsequently eluted with 1.5 l of a mixture of cyclohexane-ethyl acetate (80-20 vol.), 1.5 l of a mixture of cyclohexane / ethyl acetate (70-30% vol.), 3 l of a mixture of cyclohexane / ethyl acetate (60%). 40 vol.), 3 l of a mixture of cyclohexane-ethyl acetate (50.50 vol.), 6 l of a mixture of cyclohexane-ethyl acetate (40-60 vol.) And 7.5 l of a mixture of cyclohexane-ethyl acetate ( 30-70 vol.), Yielding fractions of 600 ecm. After evaporation of fractions 27-37 to dryness at 20 C under reduced pressure (20 mmHg, 2.7 kPa) and drying, 15.52 g of 2-benzhydryloxycarbonyl-7 - / 2-methoxy-2-yne (2-tritylamino-4-thiazolyl) -acetamido J-3 - / (1-methyl-5-tetrazolyl) -2-thiovinyl J-8-oxo-5-oxide ~ 5-thia-1-azabicyclo £ 4.2.01 oct -2-en (syn-isomer, E-form,

Infrared spectrum (CHBr,), characteristic bands (cm) 3390, 1805, 1725, 1685, 1520, 1375, 1210, 1050, 945, 755, 740

NMR proton spectrum

(350 MHz, _CDCl3, S in ppm, D in Hz) 3 ·, 28 and 4.06 (2d, D = 17.5, 2H, -SCH ₂ -); 3.91 (s, 3H,

29.9.1930 AP C 07 D / 221 271 2 2 12 7 1 - 413 - 57 466/11

> NCH ₃ ); 4.06 (s, 3H, -OCH ₃ ); 4.60 (d, 3 = 4 _f IH, H in 6); 6.14 (dd, 3 = 4 and 10, IH, H in Figure 7); 6.71 (s, IH, H at the 5-position of the thiazole); 6.94 (s, IH, -COOCH-); 6.99 (d, 3 = 16, IH, -CH = CHS-); 7.56 (d, 3 = 16, 1H, '= CHS-).

To a cooled to -10 ⁰ C solution of 15.17 g of 2-benzhydryl

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oxycarbonyl-7 ~ £ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido ^ -3-r (l-methyl-5-tetra2olyl) -2-thiovinylJ-8-oxo-5-oxide 5 -thia-1-aza-bicyclo £ 4.2.O ^ oct-2-ene, syn isomer, Ε-form, in 160 ecm of methylene chloride and 6.4 ecm of dimethylacetamide is added 2.8 ecm of phosphorus trichloride and stirred for 1 h in the same temperature. Concentrate the mixture (at 20 ⁰ C under 25 mm Hg; 3.3 kPa) ecm to about 20, diluted with 1 1 ethyl acetate and washed successively twice with 500 cc of a 5 / o sodium bicarbonate solution and twice 500 cc of a half-saturated sodium chloride solution. After drying over sodium sulfate and filtering, it is concentrated under reduced pressure (20 mmHg, 2.7 kPa) at 20 ^° C. The residue is fixed to 50 g of silica gel Merck (0.05-0.2 mm), which becomes the resulting powder onto a column of 250 g of silica gel Merck (0.05-0.2 mm) (column diameter 6 cm, height 37 cm), which is eluted successively with 1 l of a mixture of cyclohexane-ethyl acetate (75-25 vol. , 2 l of a 50-50 mixture and 2 l of a 25-75 mixture (vol.), Obtaining fractions of 600 ecm, after evaporation at 25 C under reduced pressure (20 mmHg, 2.7 kPa). of fractions 4-6, 9.8 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnidyl-3-Γ (1-methyl-5-tetrazolyl) -2- are obtained. thiovinyl3-8-oxo-5-thia-1-aza-bicyclo f4.2.03 oct-2-ene (syn isomer, Ε-form) in the form of a yellow meringue.

Infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3390, 1785, 1720, 1680, 1515, 1370, 1205, 1040, 940, 760, 735

29.9.19S0 AP C 07 D / 221 271 2 12 7 1 - tftS ~ 57 466/11

NMR proton spectrum

(350 MHz, CDCl ₃ , S in ppm, D in Hz) 3.60 and 3.70 (AB, D = 18, 2H, -SCH ₂ -); 3.95 (s, 3H, ^ NCH ₃ ); 4.10 (s, 3H, -OCH ₃ ); 5.10 (d, 0 = 4, IH, H in 6); 5.95 (dd, P = 4 and 10, IH, H in Figure 7); 6.72 (s, IH, H in the 5-position of the thiazole); 6.95 (s, IH, -COOCH-); 7.02 (d, D = 16, IH, -CH = CHS-); 7.04 (d, D = 10, IH, -CONH-); 7.05 (s, IH, -NH-); 7.37 (d, 3 = 16, = CHS-). , \

29.9.1980. AP C 07 D / 221 2 2 12 7 1 - ¹ Vk- 57 466/11

Dissolve 9.32 g of 2-benzhydryloxycarbonyl-7 - / "2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido3-3- / '(1-methyl-5-tetrazolyl) -2-thiovinyl } -8-oxo-5-thia-l ~ aza-bicyclo £ 4.2.0} oct-2-ene, syn isomer, Ε-form ECM in 50 cc trifluoroacetic acid and 1 anisole. The mixture is stirred for 1 h at 4 ⁰ C and 30 min. At 20 ⁰ C, then concentrated under reduced pressure (0.05 mmHg, 0.007 l <Pa) at 20 C. The concentrate is taken up with two times 200 ecm of ethyl acetate, each time at 20 ⁰ C under The residue is triturated in 100 ecm of diethyl ether, filtered and dried to give 4.87 g of a cream solid, the 80 % expected product and 20 % of the N-tritylated product (according to NMR).

Dissolve the above solid in 35 ecm of trifluoroacetic acid and pour the resulting solution with stirring into 175 ecm of diethyl ether. After filtration and drying, 4.57 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-J-2-carboxy-3-C (1-methyl-5-tetrazolyl) are obtained. 2-thiovinyl J-S-oxo-S-thia-1-aza-bicyclo C4.2.0 J oct-2-ene (syn isomer, Ε-form, in the form of the trifluoroacetate.

Rf = 0.49 f silica gel chromatography plate; Solvent: ethyl acetate-acetone-acetic acid-water (50-20-10-10)}.

-1 Infrared Spectrum (KBr), characteristic bands (cm) 3320, 1780, 1675, 1200, 1140, 1040, 950

NMR proton spectrum

(350 MHz, DMSO dg, <Γ in ppm, J- in Hz) ~

3.66 and 3.86 (2d, D = 17, 2H, -SCH ₂ -); 3.90 (s, 3H,> NCH ₃ );

29.9.1980 AP C 07 D / 221 22 127 1 " ¹ ^" ¹ "57 466/11

4.0 (s, 3H ₁ -OCH ₃ ); 5.20 (d, 0 = 4, IH, H in 6); 5.80 (dd, 0 = 4 and 9, IH, H in 7); 6.83 (s, IH, H at the 5-position of the thiazole); 7.0 (d, O = 16, IH, -CH = CHS-); 7.1 (d, O = 16, IH, = CHS-); 9.7 (d, 0 = 9, IH, -CONH-).

29.9.1980 AP C 07 D / 221 2 2 1271, r ¹ Mi- 57 466/11

The 7-amino-2-benzhydryloxycarbonyl-3-ε (1-methyl-5-tetra-2-olyl) -2-thiovinyl] -8-oxo-5-oxide-5-thia-1-aza-bicyclo £ 4.2.0.3 oct-2-ene (Ε-form) can be prepared in the following way:

The mixture is stirred for 16 h at 25 ⁰ C, a mixture of 34.87 g of 2-Benzhydryloxycarbonyl ^ -t-butoxycarbonylamino-Sf (l-raethyl-5-tetrazolyl) -2-thiovinyll-8-oxo-5-oxide-5-thia -l-aza-bicyclo C4.2.OJ oct-2-ene, E-form, 560 ecm acetonitrile and 21.31 g p-toluenesulfonic acid monohydrate, then concentrate the mixture at 20 C under reduced pressure (20 mmHg) and the residue is taken up in 1 1 of ethyl acetate. the mixture is neutralized with stirring with 500 cc of a 5 / o sodium bicarbonate solution, decanted, washed three times with 500 cc of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure (20 mmHg) at 20 ⁰ C. This gives 19.59 g of 7-amino-2-benzhydryloxycarbbnyl-3- (1-methyl-5-tetrazolyl) -2-thiovinyl-3-8-oxo-5-oxide-5-thia-1-aza-bicyclo f4.2.03 oct-2-en (Ε-form) in the form of a brown raw meringue.

Rf = 0.27 ^ silica gel chromatography plate, solvent: dichloroethane-methanol (85-15 Voi;)}.

The 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3 - / * (1-methyl-5-tetrazolyl) -2-thiovinyl3-8-oxo-5-oxide-5-thia-1-aza-bicyclo C4.2.0J oct- 2-en (Ε-form) can be prepared in the following way:

It is heated to 60 ° C with stirring and under nitrogen for 1.5 h, a mixture of 40.73 g of 2-Benzhydryloxy-

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - M ⁰ I - 57 466/11

carbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo f4.2,0j oct-2-ene (E-form), 300 ecm of dimethylformamide, 13.94 g of 1-methyl-5-mercaptotetrazole and 20.9 ecm of N-ethyl-N, N-diisopropylamine. It is then diluted with 2 1 of ethyl acetate, washed successively with 1 1 of water three times and then 1 1 0.1 η-hydrochloric acid, 1 1 of a 1% sodium bicarbonate solution and twice 1 1 of a half-saturated sodium

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - / ftO -. 57 466/11

chloride solution, dried over sodium sulfate, filtered and concentrated at 30 C under reduced pressure (20 mmHg, 2.7 kPa) to dryness. 35.7 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (1-methyl-5-tetrazolyl) -2-thiovinyl] -8-oxo-5-oxide ~ 5-thia-1α-aza- bicyclo £ 4.2.0.] oct-2-en, Ε-form, in the form of a brown meringue.

Infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3410, _ä 180Q, 1715, 1505, 1370, 1050, 945, 760, 745

NMR proton spectrum

(350 MHz, _CDCl3, <f in ppm, D in Hz) 1.47 (s, 9H, _(CH3 J ₃ C-), 3.32 and 4.15 (2d, D = 17.5, 2H , -SCH ₂ -), 3.94 (s, 3H, ^ NCH ₃ ), 4.56 (d, 0 = 4, IH, H in 6), 5.72 (d, Ό = 10, IH, 5.83 (dd, 0 = 4 and 10, IH, H in 7); 6.97 (s, IH, -COOCH-); 7.05 (d, D = 16, IH, - C ₁ H = CHS-), 7.58 (d, 0 = 16, IH, = CHS-).

The 2-benzhydryloxycarbony1-7-1-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo [4.2-octo-2-ene (Ε-form ) can be prepared by the method described in Example 47.

Example 49

The condensation of 8 g of 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetic acid, syn-form, and 9.43 g of 7-amino-2-benzhydryloxycarbony1-8-oxo-5-oxide-3 f2 ~ (1,3,4-thiadiazol-2-ylthio) -vinyl3-5-thia-1-aza-bicycloΓ4.2.0} oct-2-ene, E-form, in the presence of 4.12 g of N, N'-dicyclohexylcarbodiimide in 150 ecm of methylene chloride, leads, after chromatography on silica gel, to eluent: cyclohexane-ethyl acetate (30-70 vol.)] To give 6.7 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-t

ι. , 09/29/1980

AP C 07 D / 221 271

221271 '"- ^" ^{57 466} S ¹¹

amino-4-thiazolyl) -acetamidoJ-8-oxo-5-oxide-3- £ 2- (1,3,4-thiadiazol-2-yl-thio) -vinyl] -5-thia-l-aza-bicyclo f4.2.0j oct-2-ene, syn isomer, Ε form, in the form of an orange solid.

Infrared spectrum (CHBr_), characteristic bands (cm ") 3380, 1800, 1725, 1680, 1595, 1580, 1515, 1495, 1450, 1210, 1050, 940, 750

NMR proton spectrum

(350 MHz, CDCl ₃ , <f in ppm, Ό in Hz) 3.31 and 4.09 (2d, D = 18, 2H, -SCH ₂ -); 4.08 (s, 3H, -OCH ₃ ); 4.63 (d, 0 = 4, IH, H in 6); 6.18 (dd, 0 = 4 and 9, IH, H in Fig. 7); 6.72 (s, IH, H of the thiazole); 6.97 (s, IH, -COOCH-); 7.10 (s, IH, -NHC (C ₆ H ₅ J ₃ ); 7.57 (d, 0 = 14, IH, = CHS-); 9.05 (s, IH, H of the thiadiazole).

The reduction of 6.7 g of 2-benzhydryloxycarbonyl-7-naphthoimino-2 - (2-tritylamino-4-thiazolyl) -acetamido J-8-0x0-5-oxide-3-f2- (1,3,4-thiadiazole -2-yl-thio) -vinyl] -5-thiaza-bicyclo £ 4.2.03 oct-2-ene, syn isomer, Ε-form, with 1.21 ecm of phosphorus trichloride in 100 ecm of methylene chloride in the presence of 2 , 78 ecm of dimethyl acetate under the conditions described in Example 48 leads, after chromatography on silica gel [ eluent: cyclohexane-ethyl acetate (30-70 vol.)} To 5.05 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2 -tritylamino-4-thiazolyl) -acetarnido] -8-oxo-3-C2- (1,3,4-thiadiazol-2-yl-thio) -vinyl] -5-thia-1-aza-bicyclo £ 4.2. 03 oct-2-ene, syn isomer, E-form, in the form of an orange solid.

"λ

Infrared spectrum (CHBr ₃ ); characteristic bands (cm) .3400, 2820, 1790, 1725, 1685, 1495, 1450, 1040, 940

09/29/1980

; AP C 07 D / 221

2 1271 -W% "57 466/11

NMR proton spectrum

(350 MHz, CDCl, <f in ppm, Ό in Hz) 3 _f 59 and 3.70 (2d, 3 = 18, 2H, -SCH ₂ -); 4.07 (s, 3H, -OCH ₃ ); 5.11 (d, 0 = 4, IH, H in 6); 5.95 (dd, 3 = 4 and 9, IH, H in Figure 7);

09/29/1980

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6.74 (s, IH ₁ H of the thiazole); 6.98 (s, IH, -COO CH <^); 7.04 (s, IH, -NHC (CH ₅ J ₃ ); 9.04 (s, IH, H of the thiadiazole).

Under the conditions described in Example 50, 4.9 g of 2-benzhydryloxycarbonyl-7-O-2-methoxyimcine-2- (2-tritylamino-4-thiazolyl) -acetamido3-3-0X0-3 - / 2- (1 , 3,4-thiadiazol-2-y1-thio) -vinylJ-5-thia-1-aza-bicycle · /Γ4.2.ΌΤ oct-2-ene, syn isomer, Ε-form, with a mixture from 70 ecm of formic acid and 13 ecm of T / asser. After this treatment, 1.5 g of 7-f _p 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-J-2-carboxy-8-oxo-3-f 2 - (1,3,4-thiadiazole) are obtained. 2-ylthio) -vinyl3-5-thia-1-aza-bicyclo Γ4.2.0} oct-2-ene, syn isomer, Ε-form, in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 2820, 1775, 1675, 1630, 1530, 1490, 1450, 1370, 1040, 750, 700.

NMR proton spectrum

(350 MHz, DMSO d _& , <f in ppm, 3 in Hz) 3.68 and 3.96 (2d, 0 = 18, 2H, -SCH ₂ -); 3.84 (s, 3H ₁ -OCH ₃ ); 5.21 (d, D = 4, IH, H in Figure 6); 5.80 (dd, Ό = 4 and 9, IH, H in Figure 7); 6.73 (s, IH, H of the thiazole); 7.18 - 7.22 (solid, 4H, -NH ₂ and -CH = CH-); 9.03 (d, 0 = 9, IH, -CONH-); 9.60 (s, IH, H of thiadiazole).

The 7-amino-2-benzhydryloxycarbonyl-8-oxo-5-oxide-3-f2- (1,3,4-thiadiazol-2-yl-thio) -vinylJ-5-thia-1-aza-bicyclo Γ4. 2.03 oct-2-ene, Ε form, is obtained by treating p-toluenesulfonic acid hydrate in acetonitrile at 35 ° C with 2-benzhydryloxycarbony1 -7-t-butoxycarbonylamino-8-oxo-5-oxide-3-f2- ( l, 3,4-thiadiazol-2-thio) -vinylJ-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, E-form.

The resulting crude product is used subsequently without purification.

29.9.1980 AP C 07 D / 221 271 2 1 2 7 1 .. kW - 57 466 / 11-

Rf = 0.32 ^ silica gel chromatography plate; Eluent: 1,2-dichloroethane-methanol (85-15 vol.) 3.

Under the conditions described in Example 46, 15.3 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3 - (tosyloxy-vinyl) -5-thia-1-aza-bicyclo ≦ 4.2.0Jf oct-2-ene, syn isomer, Ε-form with 2.66 g of 2-mercapto-l, 3,4-thiadiazole in 100 ecm of dimethylformamide, in the presence of 3.93 ecm Ν, Ν-diisopropylethylamine. -

After this treatment and subsequent chromatography on silica gel / eluent cyclohexane-ethyl acetate (20-80 vol.) J, 7.2 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2 -tosyloxyvinyl) -5-thia-1-aza-bicyclo ^ 4.2.0J oct-2-ene, syn isomer, E-form, in the form of an orange solid.

Rf = 0.43 C silica gel chromatography plate, eluent: cyclohexane-ethyl acetate (20-80 vol.) 3.

The 2-Benzhydryioxycarbony1-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (tosyloxyvinyl) -5-thia-1-aza-bicyclo ≤ "4.2.03 oct-2-ens, syn-isomer, Ε Form, can be prepared as described in Example 47.

Example 50

To a solution of 4.4 g of 7-amino-2-benzhydryloxycarbonyl-3-C- (1-methyl-5-tetrazolyl) -2-thiovinyl3-8-oxo-5-oxide-5-thia-1-aza-bicyclo 6.2 g of 2-octene, Ε-form, in 100 ecm of methylene chloride, 6.2 g of 2- (2-tritylamino-4-thiazolyl) -2-trityloxy-imino-acetic acid, syn isomer, is cooled 4 C and stirring with stirring successively 0.1 g of 4-dimethylaminopyridine and 1.89 g of dicyclo-

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 ΐ - WS - 57 466/11

hexylcarbodiimide. Removing the cooling bath and stirred for 1.5 h at 20 ⁰ C. The mixture is filtered and the filtrate concentrated at 20 C under reduced pressure (20 mmHg; 2.7 kPa) and the residue is taken up in 500 cc of ethyl acetate, washed with 250 cc 1 N hydrochloric acid, with twice 100 ecm of a 2% sodium bicarbonate solution, twice 100 ml of water and 100 eq of water, which is saturated with sodium chloride, dried over sodium sulfate and concentrated at 20 C under reduced pressure (20 mmHg; kPa) to dryness. The residue is fixed to 20 g silica gel Merck (0.05 0.2 mm) and the powder is applied to a column of 70 g silica gel (column diameter 2.5 cm, height 30 cm), which was prepared from a mixture of Cyclohexane-ethyl acetate (80-20 vol.); 500 ecm of a mixture of cyclohexane and ethyl acetate (80-20 vol.), 1000 ecm of a 70-30 mixture and 1200 ecm of a 60-40 mixture are eluted successively, fractions of 60 eq are obtained.

Fractions 33-42 are concentrated under reduced pressure (20 mmHg; 2.7 kPa) at 20 ⁰ C to dryness. 2 g of 2-benzhydryloxycarbonyl-3-C (1-methyl-5-tetrazolyl) -2-thiovinyl] -8-oxo-5-oxide-7-f2- (2-tritylamino-4-thiazolyl) -2- trityloxyiminoacetamido} -5-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene (syn isomer, Ε-form) in the form of a cream-colored powder.

- 1 infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3390, 1800, 1720, 1680, 1655, 1525, 1490, 1450, 750, 700

NMR proton spectrum

(350 MHz, CDCl ₃ , cT in ppm ", 3 in Hz)

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3.72 and 3 (2d, 0 = 18, 2H, -S-CH ₂ -); 3.96 (s, 3H ₁ ^ NCH ₃ ); 4.44 (d, 3 = 4, IH, H in Figure 6); 5.35 (dd, 3 = 4 and 9, IH, H in Figure 7); 6.40 (s, IH, H at the 5-position of the thiazole); 6.95 (d, 0 = 16, IH, -ChI = CHS-); 6.97 (s, IH, -COOCH-); 7.60 (d, 3 = 16, IH, = CHS-).

To a cooled to -10 ⁰ C solution of 2 g of 2-ßenzhydryloxycar-

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bonyl-3-ε (1-methyl-5-tetrazolyl) -2-thiovinyr] -8-oxo-5-oxide-7 £ 2- (2-tritylamino-4-thiazolyl) -2-trityloxyimino-acetamido J -5 -thia-1-aza-bicyclo / 4.2.0J oct-2-ene, syn-isomeres, Ε-form, in 17 ecm of methylene chloride and 0.64 ecm of dimethyla.cetamide are added with stirring 0.302 ecm of phosphorus trichloride. After 10 minutes at the same temperature, dilute with 500 ml of ethyl acetate, wash with twice 100 ml of a 5% solution of sodium bicarbonate and 100 ml of saturated sodium chloride solution twice, dry over sodium sulfate, filter and concentrate at 20 ° C. under reduced pressure (20 mmHg 2.7 kPa) to dryness. The residue is taken up in 10 ecm of methylene chloride and the solution is applied to a column of 150 g of silica gel (0.04-0.06 mm) (column diameter 4 cm, height 20 cm) prepared with a mixture of cyclohexane-ethyl acetate (65-35 v / v) _1, eluting with 2 l of the same mixture under a pressure of 40 kPa, obtaining fractions of 120 ecm.

Fractions 6-21 are under reduced pressure (20 mmHg; 2.7 kPa) at 20 ⁰ C concentrated to dryness, obtaining 0.85 g of 2-Benzhydryloxyaarbonyl-3- £ "(l-methyl-5-tetrazolyl) -2-thiovinyl-3-8-oxo-7 - / * 2- (2-tritylamino-4-thiazolyl) -2-trityloxyiminoacetamidoj-5-thia-1-aza-bicyclo / 4,2.Oj oct-2-ene (syn- Isomeres, Ε-form) in the form of a cream-colored powder.

1 infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3400, 1790, 1715, 1690, 1510, 1490, 1450, 950, 750, 710

NMR proton spectrum. , _%,. , ., (350 MHz, CDCl ₃ , cTin ppm, D in Hz)

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3.43 and 3.50 (2d, 0 = 18, 2H, -S-CH ₂ -); 3.94 (s, 3H,> NCH ₃ ); 5.09 (d, D = 4, IH, H in Figure 6); 6,10 (dd, 3 = and 9, IH, H in '7); 6.41 (s, IH, H at the 5-position of the thiazole); 6.71 (s, IH,) C ₆ H ₅ ) ₃ CNhI-); 6.95 (s, IH, -COOCH-); 6.97 (d, Ο = 16, IH, -CH = CHS-).

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A solution of 0.85 g of 2-ßenzehydryloxycarbonyl-3-ε (1-methyl-5-tetrazolyl) -2-thiovinyl J-8-oxo-7-f 2 - (2-tritylamino-4-thiazolyl) -2-one is treated. Trityloxyimino-acetamidoj-5-thia-1-aza-bicyclo / "4,2.Ό3 oct-2-ene (syn isomer, Ε-form) in 10 ecm of tetrahydrofuran with 10 eq. of aqueous 50 vol. greasy formic acid for 30 min. at 50 C, concentrated under reduced pressure (20 mmHg, 2 _f 7 kPa) at 20 ⁰ C to dryness, the residue in 20 ecm of ethanol at 60 C aufi allowed to cool, the crystals isolated on the filter, washed with two times 10 1 ml of diethyl ether and dried, giving 0.24 g of 7- (2- (2-amino-4-thiazolyl) -2-hydroxyimino-acetamido3-2-carboxy-3-f (1-methyl-5-tetrazolyl) -) -thiovinyl-S-oxo-S-thia-1-aza-bicyclo £ 4.2. Oj oct-2-ene (syn isomer, Ε-form) in the form of a yellow powder,

Infrared spectrum (KBr), characteristic bands (cm) 3440, 3360, 3200, 1785, 1720, 1680, 1610, 1405

NMR proton spectrum

(350 MHz, DMSO d ₆ , tf in ppm, D in Hz)

3.65 and 3.91 (2d, D = 18, 2H, -S-CH ₂ -); 4.97 (s, 3H _f ;> NCH ₃ ) .5.25 (d, 3 = 4, IH, H in 6); 5.90 (dd / 3 = 4 and 9, IH, H in 7); 6.76 (s, IH, H at the 5-position of the thiazole); 6.96 (d, D = 14, IH, -CH = CHS-); 7.07 (d, D = 14, IH, = CHS-); 9.50 (d, 0 = 9, IH, -CONH-).

The 7-amino-2-benzhydryloxycarbonyl ~ 3 ~ C (1-methyl-5-tetrazolyl) -2-thiovinyl3-8-oxo-5-oxide-5-thia-1-aza-bicyclo C4.2.OJ oct. 2-ene, Ε-form, can be obtained starting from 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-f (1-methyl-5-tetrazolyl) -2-thiovinyl J-8-oxo-5-oxide-5 -thia-1-azabicyclo / 4,2,0J oct-2-ene, Ε-form, operating as described in Example 48 above.

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The 2-benzylhydryloxycarbonyl-7-t-butoxycarbonylamino-3- / T (1-methyl-5-tetrazolyl) -2-thiovinyl] -S-oxo-S-oxide-S-thia-1-aza-bicyclo-

29.9.1980 AP C 07 D / 221 271 22 127 1. - »^ 4» 57.466 / 11.,

oct-2-ene, Ε-form, can be prepared in the following manner:

Stir at 25 ° C for 3 h, a mixture of 0.8 g of 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (2-ethoxymalonyloxyvinyl) -8-oxo ~ 5-oxide ~ 5-thia-l-aza- bicyclo Γ4.2.0} oct-2-ene, E-form, 8 ecm dimethylformamide, 0.3 g 5-mercaptol methyltetrazole and 0.45 ecm Ν, Ν-diisopropylethylamine. It is diluted with 200 cc of ethyl acetate, washed * with twice 100 cc of water, 100 cc acid 0.1 η-hydrogen chloride, 100 cc of a 2 ^ sodium bicarbonate solution and 100 cc of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C below 20 mmHg (2.7 kPa) to dryness. The residue is chromatographed on a column of silica gel Merck (0.06-0.04) (column diameter 1.5 cm, height 15 cm), eluting with 0.5 l of a mixture of cyclphexane / ethyl acetate (50-50 vol.). .. under a pressure of 40 kPa, yielding fractions of 25 ecm.

ο Fractions 10 - 21 are concentrated to dryness at 20 C below 20 mmHg (2.7 kPa). 0.15 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-β1- (1-methyl-5-tetrazolyl) -2-thiovinyl-3-8-oxo-5-oxide-5-thia-1-aza is obtained. .bicyclo £ 4.2.0} oct-2-ene, Ε-form, in the form of a cream-colored powder,

The 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (2-ethoxymalonyloxyvinyl) -8-oxo-5-oxide-5-thia-1-azabicyclo-f4.2.0j oct-2-ene, Ε-form, can be produced in the following way:

To a cooled to -10 C solution of 1.65 g of 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (2-ethoxym.alonyloxy-

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vinyl) -8-oxo-5-thia-1-aza-bicyclo / '4.2.oj oct-2-ene, E-form, in 3 ecm of methylene chloride is added dropwise with stirring for 10 minutes a solution of 0.63 g 85% m-chloroperbenzoic acid in 8 ecm of methylene chloride, stirred for 1 h at -10 C to -15 C, the residue taken up in 50 ecm of methylene chloride, washed with twice 50 ecm of a saturated sodium bicarbonate solution and

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50 ecm of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 C under 20 mmHg (2, _f 7 kPa) to dryness. The residue is chromatographed on a column of silica gel Merck (0.04-0.06) (column diameter 1.5 cm, height 15 cm). It is eluted with 0.5 l of a methylene chloride-ethyl acetate mixture (95-5 vol.) Under a pressure of 40 kPa, to obtain fractions of 20 ecm., _? The ..Fraktionen 5 - 10 are concentrated at 20 ⁰ C under 20 mmHg F2.7 kPa) to dryness, and recovering 0.8 g of 2-ßenzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (2-ethoxymalonyloxyvinyl) - 8-oxo-5-oxide ~ 5 ~ thia-1-aza-bicyclo C4.2.0J oct-2-ene, Ε-form, in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3420, 1795, 1725, 1640, 1500, 1460, 1395, 1370, 1160, 1050, 940, 760, 750, 700

NMR proton spectrum

(350 MHz, CDCl ₃ , "Tin ppm, 0 in Hz) 1.29 (t, Ο = 7, 3H, -CH ₂ CH ₃ ); 1.48 (s, 9H, -C (CH ₃ J ₃ ), 3.24 and 3.95 (2d, D = 18, 2H, -SCH ₂ -); 3.45 (s, 2H, -OCOCH ₂ 4.23 (q, 0 = 7, 2H, -OCH ₂ -), 4.55 (d, D = 4, IH, H in 6), 5.76 (d, 3 = 9, IH, 5.83 (dd, 0 = 4 and 9, IH, H in 7), 6.98 (s, IH, -COOCHc = C), 7.61 (d, D = 11, IH, , -ChI = CHO-).

The 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- (2-ethoxymalonyloxyvinyl) -8-oxo-5-thia-1-aza-bicyclo f4.2.O} oct-2-ene, Ε-form, can be prepared in the following way:

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To a cooled to -30 ⁰ C solution under nitrogen of 5 g of 2-benzhydryloxycarbonyl ~ 7-t-butoxycarbonylamino-3- (2-oxoethyl) -8TOXo-5-thia-l-a2a-bicyclo £ oct 4,2,0j -2-en, in 50 ecm of methylene chloride are added 1.4 ecm of triethylamine and, dropwise during 10 min. A solution of 1.5 g Ethoxymalonylchlorid in 10 ecm of methylene chloride. The mixture is stirred for 1 h at -30 C, diluted with 50 ecm of methylene chloride, washed with three times 50 ecm of a saturated

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Sodium bicarbonate solution and three times 50 ecm of water, dried over sodium sulfate, filtered and concentrated to dryness at 20 ° C under 20 mmHg (2.7 kPa). The residue is taken up in 5 ml of ethyl acetate, the solution is introduced into 50 ml of diisopropyl ether and the supernatant liquid is decanted off. Taking the gummy product in 5 cc of methylene chloride and the solvent distributes at 20 ⁰ C under 20 mmHg (2.7 kPa), is recovered 2.4 g of a pale yellow meringue which mainly consists of 2-benzhydryloxycarbonyl-7-tbutoxycarbonylamino- 3- (2-ethoxymalonyloxyvinyl) ~ 8-oxo-5-thia-1-aza-bicyclo f4.2.0j oct-2-ene, E-form,

Infrared spectrum (KBr), characteristic bands (cm J 3380, 1785, 1720, 1635, 1510, 1500, 1455, 1395, 1370, 1160, 955, 760, 750, 700

NMR proton spectrum

(350 MHz, _CDCl3) <f in ppm, 3 in Hz)

1.29 (t, 0 = 7, 3H, -OCH ₂ CH ₃ ); 1.48 (s, 9H, -C (CH ₃ J ₃ ); 3.46 (s, 2H, -COCH ₂ CO-); 4.23 (q, 0 = 7, 2H, -OCH ₂ -); 5.02 (d, D = H, IH, H in 6), 5.22 (d, 0 = 9, IH, -CONH-), 5.64 (dd, 0 = 4 and 9, IH, H in 7), 6.95 (s, IH, -COOCHc), 7.05 and 7.60 (2d, 3 = 12, 2H, -CH = CH-).

Example 51

To a +5 C cooled solution of 4.37 g of 7-amino-2-benzhydryloxycarbonyl-3-ε (1-methyl-5-tet vinyl-S-oxo-S-oxide-S-thia-1-aza bicyclo 4.2.03 oct-2-en, Ε-form, in 100 ecm of methylene chloride, add 3.8 g of 2- (2-trityllam * lno-4-thiazoly!) - 2-vinyloxyimino-acetic acid, syn form, prepared according to the Belgian Patent No. 869,079;. 0.10 g of 4-dimethylaminopyridine and 2.06 g NiN'-dicyclohexylcarbodiimide is stirred for 2 h at 20 ⁰ C, diluted with 500 cc of ethyl acetate, washed with 200 cc 1N -Chlorwasserstoff-

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acid, twice 200 ecm of a 5 / oigsn sodium bicarbonate solution and 200 ecm of water, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness, the residue is chromatographed on a column of silica gel Merck (0 , 04-0.06) (column diameter 6 cm, height 35 cm). It is eluted with 4 l of a mixture of cyclohexane-ethyl acetate (50-50 vol.) And 2 1 of a 30-70 (VoI.) - Mixture, under a pressure of 40 kPa, collecting fractions of 120 ecm. The fractions are evaporated 32 - 39 at 20 ⁰ C under 20 mm Hg, 2.7 kPa to dryness and 3 g 2-benzhydryloxycarbonyl-3- £ (lmethyl-5-tetrazolyl) -2-thiovinyll-8-oxo-5- Oxy-7- (2- (2-tritylamino-4-thiazolyl) -2-vinyloxyimino-acetamido-J-5-thia-1-aza-b'icyclo £ 4.2.Oj oct-2-ene, syn isomer, Ε- Form, in the form of an orange meringue.

This product is treated as described above in the Example to give 7α / 2- (2-amino-4-thiazolyl) -2-vinyloxyimino-acetamido3-2-carboxy-3-r (1-methyl-5-tetrazolyl) -2 -thiovinyl] J-8-oxo-5-thia-1-aza-bicyclo f4.2.0j oct-2-ene, syn isomer, Ε-form, whose characteristics are identical to those described above in Example 45.

Example 52

Working in the same manner as described in Example 45, and condensing 3.45 g of 7-amino-2-benzhydryloxycarbonyl-3-r (1-methyl-5-tetrazolyl) -2-thiovinyl J-8-oxo-5-oxide -5-thia-1-aza-bicyclo C4.2.03 oct-2-ene, Ε-form, and 3.1 g of 2-cyanomethoxyimino-2- (2-tritylamino-4-thiazolyl) -acetic acid, syn isomer, (prepared according to DE-OS 28 12 625) in 200 ecm of methylene chloride in the presence of 100 mg of 4-dimethylaminopyridine and 1.48 g of N, N'-dicyclohexylcarbodiimide. Purify in an analogous manner and recover 2.01 g of 2-benzhydryloxycarbonyl-7-p-2-cyanomethoxyimino-2-

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(2-tritylamino-4-thiazolyl) -acetamido3-3-r (1-methyl-5-tetra-2-olyl) -2-thioeryraxyl-8-oxo-5-oxide-5-thia-1-a2a-bicyclo-4,2 , OJ oct-2-en, syn isomer, Ε form, in the form of an orange meringue,

Infrared spectrum (KBr), characteristic bands (cm) 3330, 1800, 1720, 1685, 1625, 1525, 1495, 1450, 1210, 1040, 750, 700

NMR proton spectrum

(350 MHz, CDCl ₃ , cT in ppm, 0 in Hz) 3.27 and 4.10 (2d, 0 = 18, 2H, -SCH ₂ -); 3.90 (s, 3H, -CH ₃ ); 4.62 (d, 0 = 4, IH ₁ H in 6); 4.86 (s, 2H, -OCH ₂ -); 6.08 (dd, 0 = 4 and 9, IH, H in 7); 6.76 (s, IH, H of the thiazole); 6.92 (s, IH, -COOCH); 6.99 (d, 0 = 16, IH, -CH = CHS-); 7.50 (d, 0 = 16, IH, = CHS-); 7.58 (d, 0 = 9, IH, -CONH-).

2-Benzhydryloxycarbony1-7-p-2-cyanomethoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-3-r (1-methyl-5-tetrazolyl) is treated as in Example 45.2. 2-thiovinyl-3-oxo-5-oxide ~ 5-thia-1-aza-bicyclo Γ4.2.03 oct-2-ene, syn isomer, Ε-form, in 21 ecm of methylene chloride and 0.78 ecm of dimethylacetamide at 0.365 ecm phosphorus trichloride. Purify by analogous chromatography to yield 1.14 g of 2-benzhydryloxycarbonyl-7-f2-cyanomethoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido} -3-ε (i-methyl-5-1-tetrazolyl) -2 -thiovinyl J-8-oxo-5-thia-1-aza-bicyclo Z * 4.2.o3 oct-2-ene, syn isomer, Ε-form, in the form of a cream meringue.

Rf = 0.32 f silica gel chromatography plate, eluent: cyclohexane-ethyl acetate (50-50 vol.) 3.

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If one proceeds as described in Example 45, starting from 1.13 g of 2-ßenzhydryloxycarbonyl-7- £ * 2-cyanomethoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido] -3- ε (l-methyl -5-tetrazolyl) ~ 2-thiovinyl]] ~ 8-oxo-5-thia-1-aza-bicyclo ^ 4.2.o3 oct-2-ene, syn isomer, Ε-form, to give 0.53 g 7-f2- (2-amino-4-thiazolyl) -2-

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cyanomethoxyimino-acetamido3-2-carboxy-3-f (1-methyl-5-tetrazolyl) -2-thiovinyl] -8-oxo-5-thia-1-aza-bicyclo / 4.1. oct-2-ene, syn-isomeric, Ε-form, in the form of a yellow powder.

Infrared spectrum (KBr) ₁ characteristic bands (cm) 1770, 168O ₁ 1620, 1530, 1380

NMR proton field around

(350 MHz, DMSO dg, ff in ppm, 0 in Hz) 3.66 and 3.88 (2d, D = 18, 2H, -SCHg-); 4.02 (s, 3H, -CH ₃ ); 5.0 (6, 2H, -OCH ₂ -); 5.22 (d, D = 4, IH, H in Figure 6); 5.80 (dd _# Ο =, 4 * and 9, IH, H in * 7); 6.89 (s, IH, H of the thiazole)); 6.99 (d, 0 = 16, IH, -CH = CHS-); 7.12 (d, 0 = 16, IH, = CHS-); 9.82 (d, 0 = 9, IH, -CONH-).

Example 53

The mixture is stirred for 1 h at 60 ⁰ C and under nitrogen, a mixture of 1.16 g of 7 ~ amino-2-benzhydryloxycarbonyl ~ 8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-l-aza-bicyclo C4.2.oJ oct-2-ene, E-form, 35 ecm dimethylformamide, 1.67 g 5-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetylthioJ-2-methyl-1,3 , 4-thiadiazole, syn-isomer, and 0.35 ecm Ν, Ν-diisopropylethylamine. Dilute the mixture with 140 eq of ethyl acetate, wash the solution with three times 70 eq of water, dry over sodium sulfate, filter and concentrate to dryness at 20 ° C under 20 mmHg (2.7 kPa). The residue is taken up in 25 ecm of methylene chloride, 5 g of silica gel Merck (0.06-0.2 mm) added, concentrated to dryness at 20 ^° C. under 20 mmHg (2.7 kPa) and the powder placed on a column of 35 g of silica gel Merck (0.06-0.2) (column diameter 2 cm). It is eluted successively with 100 ecm of a cyclohexane-ethyl acetate mixture (80-20 vol.), 250 ecm of a 60-40 mixture (vol.), 500 ecm of a 40-60 mixture

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(Vol.), 500 ecm of a 20-80 mixture (v / v) and 500 ecm. Of pure ethyl acetate, yielding fractions of 60 ecm. The fractions 17-26 are concentrated to dryness at 20 ° C under 20 mmHg (2.7 kPa) and 0.56 g of 2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J is obtained -3- (j2- (2-methyl-1,3,4-1-hiadiazol-5-yl-thio) -vinyl-3-8-oxo-5-oxide-5-thia-1-aza-bicyclo [4.2.2.13 octane] 2-en, syn isomer, Ε-form, in the form of a rose-colored meringue.

Infrared spectrum (CHBr ₃ ), characteristic bands (cm) 3380, 1800, 1725, 1680, 1515, 1490, 1445, 1045, 935, 750

NMR proton spectrum

(350 MHz, CDCl _3, J * in ppm, 3 Hz) 2.72 (s, 3H, -CH _3); 3.28 and 4.08 (2d, 0 = 18, 2H, -SCH ₂ -); 4.07 (s, 3H, -OCH ₃ ); 4.60 (d, 0 = 4, IH, H in 6); 6.16 (dd, 3 = 4 and 9, IH, H in Figure 7); 6.71 (s, IH, H of the thiazole); 6.95 (s, IH, -COOCH-); 7.07 (s, IH, -NhI C (CH ₅ J ₃ ); 7.23 and 7.33 (2d, D = 16, -CH = CH-).

To a solution of 5.11 g of 2-benzhydryloxycarbonyl-7-r2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido} -3- (2-methyl-1,3,4-thiadiazole-5 -yl) -2-thioquino13 ~ 8-oxo-5-thialazza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, and 2.1 ecm of dimethylacetamide in 50 ecm of methylene chloride are added at -8 ⁰ C and with stirring 0.93 ecm phosphorus trichloride. The mixture is stirred for 1 h at -8 C and the mixture is diluted with 1 1 of ethyl acetate, washed twice with 250 ecm of a half-saturated sodium bicarbonate solution and twice 250 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate and concentrated at 20 ⁰ C below 20 mmHg (2.7 kPa ) to

29.9.1980 AP C 07 D / 221 22 127 1 - ΛΗ4 - 57 466/11

Dryness. The product dissolved in 50 ecm of a mixture of cyclohexane-ethyl acetate (40-60 vol.) Is chromatographed on a column of 150 g silica gel Merck (0.04-0.06) (column diameter 5 cm). 3 is eluted with the above mixture under a pressure of 4 kPa to yield fractions of 125 ecm. The fractions will be 10

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at 20 C below 20 mmHg (2 _f 7 kPa) to dryness. 2.69 g of 2-benzhydryloxycarbonyl-7-p-2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido J-3-C (2-methyll, 3,4-thiadiazol-5-yl) are obtained 2-thiovinyl} -8-oxo-5-thia-1-azabicyclo 4,2,03 oct-2-ene, syn isomer, Ε-form, in the form of a yellow meringue.

- 1

Infrared spectrum (CHBr,), characteristic bands (cm)

3390, 1785, 1720, 1685, 1515, 1495, 1445, 1045, 940, 755

NMR proton spectrum

(350 MHz, _CDCl3, in ppm cf, 3 in Hz)

2.75 (s, 3H ₁ -CH ₃ ); 3.60 and 3.69 (2d, 0 = 18, 2H, -SCH ₂ -); 4.09 (s; 3H, -OCH ₃ ); 5.09 (d, 0 = 4, IH, H in Figure 6); 5.93 (dd, 0 = 4 and 9, IH, H in 7); 6.75 (s, IH, H of the thiazole); 6.98 (s, IH, -COOCH-); 7.0 (s, IH, -NH-C (C ₆ H ₅ J ₃ ); 7.22 (d, 0 = 14, IH, -CHI = CHS-).

The mixture is stirred at 50 C for 15 min. A mixture of 2.37 g of 2 ~ Benzhydryloxycarbonyl-7- / 2-methoxyimino-2- (2-t ritylamino-4-thiazolyl) acetamido] -3-f (2-methyl -1,3,4-thiadiazol-5-yl) - ^ -thiovinyl-S-oxo-S-thia-1-aza-bicyclo f4.2.0j oct-2-ene, syn isomer, Ε-form, in 30 ecm of formic acid, mixed with 14 eq. Of water. It is allowed to cool, diluted with 16 eq. Water and filtered. The filtrate at 30 ⁰ C. It is concentrated under 0.05 mm Hg (0.007 kPa) to dryness and the residue is taken up with three times 50 cc of ethanol to each concentrated to dryness. The resulting solid is stirred at 50 C in 35 ecm of ethanol for 25 min. It is filtered, washed with twice 20 ecm of ethyl ether and dried. 1.18 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-J-2-carboxy-3-r (2-methyl-1,3,4-thiadiazol-5-yl) are obtained ) -2-thiovinylJ-S-oxo-ö-thia-l-aza-bicyclo

29.9.1980 AP C 07 D / 221 2 2 1 27 1 - * Π3> - 57 466/11

£ 4.2.0j oct-2-ene, syn-isomer, E-form _{f. In} the form of a yellow powder.

* -I

Infrared Spectrum (KBr) ₄ characteristic bands (cm) 3400, 32.00, 3100, 2200, 1775, 1675, 1530, 1045,

29.9.1980 AP C 07 D / 221 271 127 1 - ^ ⁴ ^ * - 57 466/11

NMR proton spectrum

(350 MHz ₁ DMSO d _& , cT in ppm, D in Hz) 2.74 (s, 3H, -CH ₃ ); 3.67 and 3.94 (2d, ö = 18, 2H, -SCH ₂ -); 3.86 (s, 3H, -OCH ₃ ); 5.21 (d, J = 4, IH, H in Figure 6); 5.80 (2d, O = 4 and 9, IH, H in 7); 6.75 (s, IH, H of the thiazole); 7,12 and 7,17 (2d, D = 16, 2H, -CH = CHS-); 7.20 (s, 2H, -NH ₂ ); 9.63 (d, D = 9, IH, -CONH-).

The 7-amino-2-benzhydryloxycarbonyl-8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo C4.2.03 oct-2-ene, E-form, can be mentioned below Way to be obtained:

A solution of 54.3 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-1-aza-bicyclo is stirred at 35 ° C. for 2 hours £ 4.2.03 oct-2-ene, Ε-form, and 30.4 g of p-toluenesulfonic acid hydrate in 1.4 l of acetonitrile. Concentrate at 30 C under 20 mmHg (2.7 kPa) to dryness, take up in 1 L of ethyl acetate. Wash twice with 500 ecm of a half-saturated sodium bicarbonate solution and 500 ecm of a half-saturated solution of sodium chloride twice, dry over sodium sulfate and concentrate to dryness at 20 ⁰ C below 20 mmHg (2.7 kPa). The residue is triturated in 200 ecm of ether. This gives 28.13 g of 7-amino-2-benzhydryloxycarbonyl-8-oxo-5-oxide ~3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, Ε Shape, in the form of a light brown powder.

Rf = 0.32, silica gel chromatography plate, CMethylene chloride-methanol (85-15 vol.)].

The 5-f2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetylthiol-2-methyl-1,3,4-thiadiazole, syn isomer, can be prepared in the following manner:

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2 2 1271 "W * ~ ^{57 466} Z ¹¹

To a cooled 4 C solution of 8.88 g £ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl)] - acetic acid, syn isomer, and _f 2 64 g of 5-mercapto-2-methyl-l , 3,4-thiadiazole in 200 ecm ethyl acetate adds ".

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4.96 g of N, N'-dicyclohexylcarbodiimide are added at once with stirring. The mixture is stirred for 4 h at 4 C, the suspension is filtered, washed twice with 200 ecm of water, twice 100 ecm of a half-saturated sodium bicarbonate solution and 100 ecm of a saturated sodium chloride solution, dried over sodium sulfate, filtered, concentrated at 20 C under 20 mmHg (2.7 kPa ) to 20 ecm and filtered. The filtrate is diluted with 200 ml of petroleum ether, filtered, and 6.2 g of yellow powder are obtained, which gives the expected product.

The purification is carried out in the following manner: treating the above product with 200 cc of cyclohexane under reflux, filtered while hot, the filtrate concentrated to 30 cc (at 20 ⁰ C under 20 mm Hg; 2.7 kPa), filtered and wins 4, 5 g of 5-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetylthio3-2-methyl-1,3,4-thiadiazole, syn-Isotneres.

NMR proton spectrum

(80 MHz, _CDCl3, <Γ in ppm, 0 Hz) 2.85 (s, 3H, -CH _3); 4.08 (s, 3H, = NOCH ₃ ); 6.60 (s, IH, H of the thiazole)

Infrared spectrum (CHBr ₃ ); characteristic bands (cm ") 1695, 1605, 1580, 1530, 1490, 1450, 1050, 900

Example 54 .

The mixture is stirred for 5 h at 60 C and under nitrogen, a mixture of 0.23 g of 7-amino-2-benzhydryloxycarbonyl-8 ~ oxo-5-oxide-3- (2-tosyloxyvinyl) -5-thia-l-aza-bicyclo /14.2.03 oct-2-ene, E-form, 15 ecm dimethylformamide, 0.40 g 4- (2,2-dimethoxyethyl) -5,6-dioxo-3-C2-methoxyimino-2- (2-tritylamino -4-thia-zolyl) -acetylthioj-1, 4,5,6-tetrahydro-1, 2,4-triazine, syn-isomer, and 0.07 ecm

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2 12 7 1, "^ ⁴ ^" ⁵⁷

N ₁ N-diisopropylethylamine was diluted with 60 cc of ethyl acetate, then the solution is washed with three times 30 cc of water and 'two 30 cc of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa ) to dryness. The residue is taken in 10 cc methylene chloride, add 2 g of silica gel Merck (.06 to 0.2) to and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. The resulting powder is applied to a column of 8 g silica gel Merck (0.06-0.2) (column diameter 1.2 cm). Successively elute with 50 ecm of a mixture of cyclohexane-ethyl acetate (80-20 vol.), 100 ecm of a 60-40 (VoI.) Mixture, 100 ecm of a 40-60 (VoI.) Mixture, 200 ecm of a 20-80 (vol.) mixture and 200 eq. of pure ethyl acetate to yield fractions of 25 ecm. The fractions 12-19 are concentrated to dryness at 20 ^° C. under 20 mmHg (2.7 kPa) and 0.19 g of 2-benzhydryloxycarbonyl-3- {C ⁴ - (2 ', 2-dimethoxyethyl) -5,6- dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-YLJ-2-thiovinylj-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido} -S oxo-S-oxide-S-thia-1-aza. bicyclo £ 4.2.Oj odt-2-en, syn-isomer ", Ε-form, in the form of a beige meringue.

Infrared spectrum (KBr), characteristic bands (cm) 3380, 3250, 1795, 1720, 1685, 1520, 1490, 1445, 1040, 940, 760, 700

NMR proton spectrum

(350 MHz, _CDCl3, <f in ppm, D in Hz) 3.34 and 4.12 (2d, D = 18, 2H, -SCH ₂ -); 3.40 (s, 6H, -OCH ₃ ); 3.94-4.06 (m, 5H, -OCH ₃ and> NCH ₂ -); 4.60-4.68 (m, 2H, H in 6 and -CH (OCH ₃ J ₂ ); 6.07 (dd, D = 4 and 9, IH, H in 7);

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1,. ltft . 57 466/11 -

6.70 (s, IH, H of the thiazole); 6.82 (d, D = 16, IH, -ChI = CHS-); 6.96 (s, IH, -COOCH-).

The reduction of the sulfoxide and the removal of the protective groups are carried out as described above in Example 16. There is thus obtained 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -2-carbo-

29.9.1980 AP C 07 D / 221 22 127 1. - * - ^ tH9 - .57 466/11

oxy-3-T5,5-dioxo-4-fluoromethyl-1-yl-sj-tetrahydro-1-yl-triazine-S-yl-3-thiovinyl-S-oxo-S-thia-1-aza bicyclo £ 4.2.0 '] oct-2-ene, syn isomer, Ε-form, whose characteristics are identical to those of the product obtained in Example 16.

The 4- (2,2-dimethoxyethyl) -5,6 ^ 10X0-3- £ 2-methoxy in ino-2- (2-tritylamino-4-thiazolyl) -acetylthioJ-1,4,5,6- _tetrahydro-i 1,2,4-triazine, syn isomer, can be prepared in the following manner:

To a solution of 0.89 g of methoxy, imino-2- (2-tritylamino-4-thiazolyl) J-acetic acid, syn isomer, cooled to 4 ° C, and 0.47 g of 4- (2,2- Dimethoxyethyl) -5,6-dioxo-3-thioxo-l, 2,4 ·· perhydrotriazine in 20 ecm of dimethylformamide is added at once 0.50 g of N, N ¹ -Dicyclohexylcarbodiimid. The mixture is stirred for lh at 4 ⁰ C and then for 3 h at 20 ⁰ C. The filtered

«. :: &

Reaction suspension, the filtrate is diluted with 100 ecm of ethyl acetate, washed with twice 50 ecm of water, twice 50 ecm of a sodium bicarbonate solution and twice 50 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 ⁰ C under 20 mmHg (2, 7 kPa) to dryness. The residue is triturated in 10 ml of isopropyl ether and, after filtration and drying, 0.91 g of dimethoxyethyl O -dioxio-3-p-2-methoxyimino-2- (2-tritylamino-4-) is obtained. thiazolyl) -acetylthioj-l, 4,5,6-tetrahydro-l, 2,4-triazine, syn isomer, in the form of a yellow powder.

NMR proton spectrum

(80 MHz, CDCl ₃ , (T in ppm, D in Hz)

3.30 (s, 6H, -OCH ₃ ); 4.05 (s, 3H, = NOCH ₃ ); 4.28 (d, 0 = 5,

29.9.1980 AP C 07 D / 221 22 127 1 - ** 50 - 57 466/11

2H,> NCH ₂ -); 4.66 (t, 0 = 5, IH, -CH =); 6.68 (s, IH, H of the thiazole)

Infrared spectrum (CHBr ^); characteristic bands (cm) 3380, 1720, 1585, 1525, 1490, 1450, 1040 900, 750, 730

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - tel - 57 466/11

Example 55

The mixture is heated at 60 C for 6 h under nitrogen, a mixture of 0.614 g of 7-amino-2-benzhydryloxycarbonyl-8-oxo ~ 5 ~ oxide-3- (2-tosyloxyvinyl) ~ 5-thia-l-aza ~ bicyclo £ 4.2 .0 "oct-2" -ene, E-form, 50 ecm of dimethylformamide and 0.70 g of 4- (2-t-butoxycarbonylaminoethyl) -5,6-dioxo-3-f2-methoxyimino-2- (2-tritylamino 4-thiazolyl) -acetylthioJ-l, 4,5,6-tetrahydrol, 2 _#j 4-triazine, syn-lspm.ere.s. The mixture is diluted with ethyl acetate, washed twice with 120 ml / 100 ml of hydrochloric acid, 100 ml of water and 100 ml of water, saturated with sodium chloride, dried over sodium sulphate, filtered and concentrated The residue is chromatographed on a column of 40 g of silica gel Merck (0.06-0.2) (column diameter 2.5 cm, height 29 cm) at 20 ° C under 20 mmHg (2.7 kPa). It is eluted with 1 1 of ethyl acetate to yield fractions of 60 ecm. Fractions 3-6 are concentrated to dryness at 20 ° C under 20 mmHg (2.7 kPa).

0.21 g of 2-benzhydryloxycarbonyl-3-butoxycarbonylaminoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl-J-2-thiovinyl-J-7 are obtained - / ^# 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido} -8-oxo-5-oxide ~ 5-thia-1-aza-bicycle £ 4.2.0} oct-2-ene, syn-isomeros, Ε-shape, in the form of a brown meringue.

Treating this product as described in Example 28 above gives 7-f2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido3-3- {4,4- (2-aminoethyl) -5,6-dioxole , 4,5,6-tetrahydro-l, 2,4-triazin-3-yl] -2-thiovinyl J-2-carboxy-srthia-1-aza-bicyclo f4.2,0j oct-2-ene, syn- Isomer, Ε-form, as formate, whose characteristics are identical to those of the product of Example 28.

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2 2 12 7 1 "^^" ^{57 456/1 : L}

The thioloester used as the starting material can be prepared in the following manner:

To a cooled to +4 ⁰ C solution of 2.17 g of 2-methoxyimino-2

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2 2 12 7 1 "^ ^{'57 456} A ¹

(2-tritylamino-4-thiazolyl) -acetic acid, syn-isomeric, and 1.05 g of 4 ~ (2-t-butoxycarbonylamino-ethyl) -5,6-dioxo-3-thioxo-1,2,4-perhydrotriazine in 50 pcm of ethyl acetate, add 1.11 g of N, N'-dicyclohexylcarbodiimide. The mixture is stirred for 4 h at 20 C ₁ * filtered and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness. The residue is taken up in 20 ecm of methylene chloride and the solution is poured into 250 ecm of diisopropyl ether. After filtration and drying, 0.73 g of 4- (2-t-butoxycarbonylaminoethyl) ~ 5,6-dioxo-3-p-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetylthio} -l are recovered "4,5,6-tetrahydro-l, 2,4-triazine, syn-isomer, in the form of a yellow powder,

- 1 Infrared Spoktrum (CHBr,), characteristic bands (cm) 3440, 3390, 2820, 1710, 1585, 1530, 1450, 1390, 1370, 1050, 955, 900, 755

Example 56 .

0.18 g of thiourea is added to a solution of 1.4 g of 2-benzhydryloxycarbonyl-7- (4-bromo-2-hydroxyimino-3-oxobutyramido) -3 - / (2-methyl-1,3,4- thiadiazol-5-yl) -2-thiovinyl3-e-oxo-S-thia-1-aza-bicyclo ^ 4.2.Oj oct-2-ene, syn-isomeric, Ε-form in 25 ecm of ethanol, 25 ecm of tetrahydrofuran and Water and stirred for 4 h at 20 ° C. The solution is concentrated to dryness under reduced pressure (20 mmHg; 2.7 kPa), the residue is triturated with 10 eq. Of water, the pH is adjusted to 7 with a sodium bicarbonate solution , the precipitate is filtered off, washed with 5 eq of water and dried, giving 1.3 g of a pale beige solid which is dissolved in 10 ecm of chloroform, and the resulting solution is added dropwise to 100 e of isopropyl ether with stirring, the insoluble matter is filtered, redissolved in 25 ecm of tetrahydrofuran, the resulting solution is filtered in the presence of decolorizing carbon and filtered to a vacuum.

.29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - itfH-57 466/11

5 ecm concentrated under reduced pressure (20 mmHg, 2.7 kPa). 25 ecm of ethyl acetate are added to this solution. The resulting solid is filtered, washed with 10 ecm of ethyl acetate and dried. This gives 0.9 g of 2-benzhydryloxycarbonyl-7-C2-hydroxyimino-2- (2-amino-4-t hiazolyl) -acetamide o] -3-Γ (2-γ-triazole-1,3,4-thiadiazole -5-yl) -2-thiovinyl ^ JS-oxo-5-thia-1-aza-bicyclo / "4,2.03 oct-2-ene, syn isomer, Ε-form in the form of a beige solid.

., -. · -1

Infrared spectrum (KBr), characteristic bands (cm) 3380, 3200, 3100, 1785, 1720, 1685, 1630, 1535, 1500, 1445, 1210, 950, 760, 745, 705

NMR proton spectrum

(350 MHz, DMSO d, <f in ppm, 3 in Hz) 2.71 (s, 3H, -CH ₃ Het); 3.72 and 3.98 (2d, 0 = 18, 2H, -SCH ₂ -); 5.28 (d, 0 = 4, IH, H in 6); 5.90 (dd, 0 = 4 and 9, IH, H in 7); 6.80 (s, IH, H of the thiazole); 5.98 (s, IH, -COOCH, = r); 7.05 (d, 0 = 16, IH, -CH = CHS-); 7.26 (d, 0 = 16, IH, -CH = CfHS-); 9.65 (d, 0 = 9, IH, -CONH-); 11.85 (s wide, IH, = NOH-).

Dissolve 0.3 g of 2-benzhydryloxycarbonyl-7-p-2-hydroxy-imino-2- (2-amino-4-thiazolyl) -azecidene-3-ε-2-methyl-1,3,4- thiadiazol-5-yl) -2-thiovinyl-3-oxo-5-thia-1-aza-bicyclo & -. 2.01 oct-2-ene, syn isomer, Ε-form, in 6 ecm of formic acid , Is added 6 cc of distilled water and brings during 15 min at 60 ⁰ C. The cloudy solution is cooled, filtered in the presence of decolorizing carbon, and the filtrate concentrated under reduced pressure (20 mmHg; 2.7 kPa). Evaporated to dryness. Add 10 ecm of ethanol to the residue, concentrate to dryness under reduced pressure (20 mmHg, 2.7 kPa), repeat this procedure twice

29.9.1980 AP C 07 D / 221 2 2 1 2 7 1 - ^ 55 - 57 466/11

and then bring the suspension of the residue to reflux with 10 ecm of ethanol, cool, filter and dry under reduced pressure (0.5 mmHg, 0.07 kPa) to give 0.07 g of 2 ~ carboxy-7-7 / ^> 2-hydroxy-imino-2- (2-amino-4-thiazolyl) -acetamido) -3-r (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl-1-oxo S-thia-

29.9.1980 AP C 07 D / 221 2 2 1 2 7 1 - ¹ ^ ~ 57 466/11

1-aza-bicyclo £ 4.2.0j oct-2-ene, syn isomer, Ε-form, in the form of a yellow solid.

- 1 infrared spectrum (KBr), characteristic bands (cm) 3600, 2200, 177O ₁ 1660, 1630, 1530, 1390, 950

NMR proton spectrum

(350 MHz, DMSO d, (Γ in ppm, 0 in Hz) 2.74 (s, 3H, -CH ₃ Het); 3.64 and 3.90 (2d, 3 = 18, 2H, -SCH ₂ - 5.20 (d, 3 = 4, IH, H in 6), 5.80 (dd, 0 = 4 and 9, IH, H in 7), 6.65 (s, IH, H of the thiazole) 7.08 (s wide, 2H, -NH ₂ ), 7.10 and 7.20 (2d, 0 = 14, 2H, -CH = CH-S-), 9.46 (d, 0 = 9, IH, -CONH-); 11.28 (s wide, IH, = NOH).

The 2-Benzhydryloxycarbonyl-7- (4-bromo-j-2-hydroxy in ino-3-oxobutyramido) -3-C (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl 8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, can be prepared in the following manner:

1.8 g of 2-benzhydryloxycarbonyl-7- (4-bromo-3-oxo-butyramido) -3-f (2-methyl-1,3,4-thiadiazol-5-yl) -2-one are suspended at 10 ° C. thiovinyl} -8-oxo-5-thia-1-aza-bicyclo-4,2,0} oct-2-ene, Ε-isomer, in a mixture of 23 ecm of tetrahydrofuran and 4.7 ecm of water. It then adds 7.8 ecm of acetic acid, cooled to 0 C with ice, "adds a solution of 0.187 g of sodium nitrite in 2.3 ecm of water and the reaction mixture is allowed to rise for 4 h to 20 C. The resulting solution is washed with The precipitate is filtered, dissolved in 100 eq of ethyl acetate, and the organic phase is washed twice with 25 ecm of a saturated sodium bicarbonate solution, twice with 25 ecm of a saturated sodium chloride solution, over magnesium sulfate.

29.9.1980 AP C 07 D / 221 2 2 1 2 7 1 - 45? - - 57 466/11

dried, filtered and concentrated to dryness under reduced pressure (20 mmHg, 2.7 kPa). Then one "1.5 g of 2-benzhydryloxycarbonyl ~ 7- (4 ~ bromo-2-hydroxyimino-3-oxo-butyramido) -3- £ (2-methyl ~ l, 3 _J 4-thiadiazol-5-yl) -2 -thiovinyl-3-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε-form, in

29.9.1980 AP C 07 E / 221 • 2 2 12 7 1 _ * t5g _ 57 465/11

Shape of a brown solid.

- 1. Infrared spectrum (KBr), characteristic bands (cm) 1785, 1715, 1685, 1540, 1495, 1455, 1205, 950, 760, 745, 700

NMR proton spectrum

(350 MHz ₁ CDCl ₃ , (T in ppm, δ in Hz) 2.76 (s, 3H, -CH ₃ Het); 4.53 (s, 2H, -COCHgBr); 5.12 (d, 0 = 4, IH, H in 6), 5.85 (dd, D = 4 and 9, IH, H in 7), 7.01 (s, IH, -COOCH), 9.43 (d, 0 = 9, IH, -CONH -); 16.50 (s wide, IH, = NOH).

A solution of 5.79 g of bromine in 3.53 ecm of methylene chloride is added dropwise to a solution of 3.04 g of diketene in 3.53 ecm of methylene chloride at -30 C for 35 min. This solution is stirred at the same temperature for 30 min. Take one-tenth of this solution and add dropwise to a stirred solution of 1.38 g of 7-amino-2-benzhydryloxycarbonyl-3 - / (2-methyl-1,3,4-thiadiazol-5-yl) -2 -thiovinyl J-S-oxo-5-thia-1-aza-bicyclo f4,2.0j oct-2-ene, Ε-isomer, and 1,11 ecm of bis-trimethylsilylacetamide in 20 ecm of ethyl acetate at -15 C for 10 min. and the solution is stirred at the same temperature for 30 minutes, then 20 ecm of water are added, decanted, the organic phase is washed three times with 10 ecm of a saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure. 20 mmHg, 2.7 kPa) to give 1.9 g of 2-benzhydryloxycarbonyl-7- (4-bromo-3-oxobutyramido) -3-C (2-methyl-1,3,4-thiadiazole). 5-yl) -2-thiovinyl-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, E-isomer, in the form of a brown solid.

Infrared spectrum (KBr), characteristic bands (cm) 1780, 1720, 1535, 1490, 1450, 1250, 940, 760, 700

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22 127 1 ^ _57466/11

NMR proton spectrum

(350 MHz ₁ CDCl ₃₁ <f in ppm, D in Hz) 2.75 (s, 3H, -CH ₃ heterocyclic); 3.58 and 3.84 (2d, ö = 19, 2H, -SCH ₂ -); 3.75 (s, 2H, -COCH ₂ CO); 4.03 (s, 2H, -CH ₃ Br); 5.04 (d, D = 4, IH, H in Figure 6); 5.85 (dd, D = 4 and 9, IH, H in Figure 7); 6.98 (s, IH, -COOCH <).

The 7-amino-2-benzhydryloxycarbony1-3 - ^ (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl J -8-0x0-5-thia-1-a'za-bicyclo ε 4.2, O) oct-2-ene, Ε-isomer, can be prepared in the following manner:

To a suspension of 9.2 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-ol (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl-8-oxo-5-. a solution of 8.43 g of p-toluenesulfonic acid monohydrate in 45 ecm of acetonitrile is added at 35 ° C. for 3 minutes to a solution of 8.43 g of p-toluenesulfonic acid monohydrate in 138 ecm of acetonitrile. The mixture becomes homogeneous,

and holding for 40 minutes at 38 ° C., and then pouring this mixture into a solution of 7.44 g of sodium bicarbonate in 600 ml of water. The mixture is extracted with 300 ecm of ethyl acetate and then m-it three times 100 ecm of ethyl acetate. The organic phases are combined, with 100 ecm of a saturated sodium bicarbonate solution and then with. twice 100 ecm of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure (20 mmHg, 2.7 kPa) to dryness. This gives 6.8 g of 7-amino-2-benzhydryloxycarbonyl-3-r (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl-8-oxo-5-thia-1-one aza-bicyclo f4 _# 2.0H oct-2-ene, Ε-isomer, in the form of a brown gum-like product.

29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - ^ ⁰ - ⁵⁷ 466/11

•• I Infrared Spectrum (KBr) ₁ characteristic bands (cm) 3400, 3340, 17S0, 1720, 1670, 1560, 1500, 1455, 950, 760, 745, 700

NMR proton spectrum

(80 MHz, CDCl ₃ <f in ppm, 0 in Hz)

29.9.1980 AP C 07 D / 221 221271 -W- * 57 466/11

2.72 (s, 3H, -CH ₃ heterocyclic); 3.46 (s wide, 2H, -SCH ₂ -); 4.77 (d, 0 = 4, IH, H in 6); 5.00 (d, D = 4, IH, H in 7); 7.0p (s, IH, -COOCHxT); 7.18 (s wide, 2H, -CH = CH-).

The 2-Benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-f (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl3,8-oxo-5-thia-1-aza-bicycloe 4.2.O] oct-2-ene, Ε-isomer, can be prepared in the following manner:

To a solution of 17 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-r (2-methyl-1,3,4-thiadia2ol-5-yl) -2-thiovinyl J-S-oxo-S-oxide-S -thia-1-aza-bicyclo C4.2.03 oct-2-ene, Ε-isomer, and 10.9 ecm of dimethylacetamide in 170 ecm of methylene chloride are added at -10 C for 5 min, 4.7 ecm of phosphorus trichloride and kept for 1 h at -10 C, the reaction mixture is diluted with 2000 ecm of ethyl acetate, washed three times with 250 ecm of saturated sodium bicarbonate solution and with 250 ecm of a saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue is chromatographed on a column of 291 g of silica gel Merck (0.063-0.2) (column diameter 4.5 cm, height 37 cm), with 3 l of a methylene chloride-ethyl acetate mixture (92.5-7.5 vol. ) elutes and fractions of 100 ecm wins. Fractions 12-29 containing the product are evaporated to dryness under reduced pressure (20 mmHg; 2.7 kPa). This gives 9.25 g of 2 ~ 3enzehydryloxycarboroylamino-3-f (2-methyl-1,3,4-thiadiazol-5-yl) -2-thiovinyl] -8-oxo-5-thia-1 -aza-bicyclo £ 4.2.03 oct-2-ene, E-isomer, in the form of a light yellow solid.

29.9.1980 AP C 07 D / 221 2 2 1271- H (A - 57 465/11

-

Infrared spectrum (KBr), characteristic bands (cm) 3370, 1790, 1715, 1700, .1520, 1160, 945, 740, 700

NMR proton spectrum

(80 MHz, _CDCl3, in ppm cf, D in Hz) 1.50 (s, 9H ₁ (CI-L) C-); 2.75 (s, 3H, -CH heterocyclic);

29.9.1980 APC 07 D / 221 2 2 1 2 7 1 - ^ 3 ~ 57 466/11

3.68 (s wide, 2H, -SCH ₂ -); 5.03 (d, 3 = 4, IH, H in 6); 5.28 (d, 0 = 9, IH, -CONH-); 5.65 (dd, 3 = 4 and 9, IH, Hin 7); 7.00 (IH, s, -

The 2-benzhydryloxycarbonyl-7α-t-butoxycarbonylamino-3-ε (2-yl-ethyl, 3,4-thiadiazol-5-yl) -2-thiovinyl-1-oxo-5-oxide-5-thia-1-one aza-bicyclo £ 4.2.O ^ oct-2-ene, Ε-isomer, can be prepared in the following manner:

A solution of 20 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-oxide-3- (2-tosyloxy-vinyl) -5-thia-1-aza-bicyclo, 4.2 g, is heated at 60.degree. C. for 2 hours .0j oct-2-ene, E-isomer, 4.87 g of 2-methyl-l, 3,4-thiadiazoline-5-thione and 5.04 ecm of diisopropylethylamine in 200 ecm of dimethylformamide. The mixture is poured onto 2,000 eq of ice-water , extracted with 2000 ecm and then 500cc of ethyl acetate, the organic phases are combined, with 250 ecm of a saturated. Sodium bicarbonate solution, washed four times with 250 eq of distilled water and then with 250 ecm of a saturated sodium chloride solution, dried over magnesium sulfate, filtered in the presence of decolorizing carbon and concentrated to dryness under reduced pressure (30 mmHg, 4 kPa) at 30 ° C. This gives 17 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3 - / (2-methyll, 3,4-thiadiazol-5-yl) -2-thiovinyl-8-oxo-5-oxide-5-thia 1-aza-bicyclo £ 4.2.03 oct-2-ene, Ε-isomer, in the form of a brown-green gummy product. Dissolve again in 60 ml of ethyl acetate, precipitate with 600 ml of isopropyl ether, filter and dry. This gives the expected product in the form of a yellow powder.

29.9.1980 AP C 07 D / 221 22 127 1. - W - 57 466/11

- 1 infrared spectrum (KBr), characteristic bands (cm)

3410, 1795, 172O ₁ 1500, 1160, 1050, 940, 755, 740, 700

Proton spectrum (350 MHz, _CDCl3, </ in ppm, D in Hz) .1,50 (s, 9H, (CH-JC); 2.75 (s, 3H, -CH, Het), 3.30 and

ό ό Q ό

4.15 (2d, Ο = 18, 2H, -SCH ₂ -); 4.55 (d, 0 = 4, IH, H in 6);

29.9.1980 AP C 07 E / 221 271 • 2 2 1 2 7 1 - Hi ₀ ? - 57 466/11

5.9 (m, 2 H ₄ -CONH- and H in 7); 6.97 (s, IH, -COOCH <^); 7.53 (d, ö = 16, IH, -CH = CHS-).

Example 57

Dissolve 0.51 g of 7-amino-2-carboxy-3-f (1-methyl-5-tetrazolyl) -2-thiovinyl} -8-oxo-5-thia-1-aza-bicyclo / T4.2.0J oct-2-ene, Ε-form, in a mixture of 10 ecm of water, 0.63 g of sodium bicarbonate and 7.5 ecm of acetone. It is cooled to -8 C and added dropwise during 5 min. A solution of 0.363 g of 4-bromo-2-methoxyimino-3 ~ oxobutyryl chloride, syn-form, in 5 ecm of acetone to. It is stirred for 50 min, "wherein to warm from -8 C to +5 C läßt- * The mixture is filtered, the acetone is evaporated at 20 ⁰ C and 20 mmHg (2.7 kPa), diluted with 50 cc of water, washed with 50 cc Ethyl acetate, the aqueous phase is diluted with 100 ecm of water, added to 150 ecm of ethyl acetate and acidified to pH 2.3 with a 4N hydrochloric acid solution. Wash the organic layer with 100 cc of a half-saturated sodium chloride solution, dried over sodium sulfate and concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness,

The solution of the product so obtained in 5 ecm of ethanol is added at 20 C to a solution of 0.11 g of thiourea in 5 ecm of ethanol and 10 ecm of water. It is stirred for 35 min. At 20 ⁰ C, then the pH by addition of sodium bicarbonate to 6 and acidified by the addition of 1 ecm of formic acid, the mixture concentrated at 20 C under 20 mmHg (2.7 kPa) to dryness and the residue is taken up with three times 50 eq of ethanol, each time evaporating to dryness at 20 C under 20 mmHg (2.7 kPa). The residue is extracted with 250 ecm of ethanol at reflux, filtered, concentrated at 20 ⁰ C under 20 mmHg (2.7 kPa) to 25 ecm, left for 15 min. At 5 ⁰ C, filtered again and the solid is washed with 5 ecm of ethanol

29.9.1930 AP C 07 D / 221 271 221271 .. W> - 57 466/11

and twice 10 ecm of ether, yield 0.28 g of 7-f2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamide-2-carboxy-3 - / (1-methyl-5-tetrazolyl) -2 -thioviny13-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene, syn isomer, E + form, in the form of a yellow powder, whose characteristics are identical to those of Example 48 above described product. The 7-amino-2-carboxy-3-T (1-methyl-tetrazolyl) ^ -thiovinyl-S-oxo-S-tetrazolyl-1-aza-bicyclo [4.2.0] oct-2-ene, E- Form., Can be prepared in the following way:

A mixture of 3 g of 7-amino-2-benzhydryloxycarbony1-3-f (1-methyl-5-tetrazolyl) -2-thiovinyl3-S-oxo-5-thia- ^{1 is} treated at 50 ° C. for 30 minutes. aza-bicyclo £ 4.2.o3 oct-2-ene, E ~ form, with 105 ecm of formic acid and 40 ecm of water, concentrated to dryness at 20 ⁰ C below 0.05 mmHg (0.007 kPa), taken up again twice with 100 ecm Ethanol, each time at 20 ⁰ C under, 20 mmHg (2.7 kPa) concentrated to dryness, the resulting solid triturated in 50 ecm of ethanol, filtered and washed with twice 25 ecm diethyl ether.

1.5 g of "7-amino-2-carboxy-3-f (1-methyl-5-tetrazolyl) -2-thio-vinyl-3-oxo-5-thia-1-aza-bicyclo f4.2.0] oct. Are obtained -2-en, Ε-form, as formate.

NMR proton spectrum

(350 MHz ₁ DMSO dg, <f in ppm, D in Hz) 3.64 and 3.89 (2d, 0 = 18, 2H ₁ -SCH ₂ -); 4.02 (s, 3H, -CH-); 5.15 (d, D = 4, IH, H in Figure 6); 5.77 (dd, 0 = 4 and 9, IH, H in Figure 7); 6.97 and 7.13 (2d, D = 16, 2H, -CH = CH-); 9.07 (d, 3 = 9, IH, -CONH-),

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The 7-amino-2-benzhydryloxycarbonyl-3-ε (1-methyl-5-tetrazolyl) -2-thiovinyl J-8-oxo-5-.thia-1-aza-bicyclo L "4,2.0j oct. can be made in the following way:

Treat under the conditions described in Example 56

29.9.1980 AP C 07 D / 221 271 22 127 1 - ^ δ -. 57 466/11

8 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino ~ 3- C ( l-methyl-5-tetrazolyl) -2-thiovinyl-3-8-oxo-5-thia-i-aza-bicyclo-4,2,0} oct -2-ene, Ε-form, dissolved in 80 ecm of acetonitrile, with 4.9 g of p-toluenesulfonic acid hydrate. After this treatment, 5.7 g of 7-amino-2-benzhydryloxycarbonyl-3 - / (1-methyl-5-tetrazolyl) -2-thovinyl-8-oxo-5-thia-1-azabicyclo are obtained. "4,2, O] I oct-2-ene, Ε-form, in the form of a light brown solid,

- I

Infrared spectrum (KBr), characteristic bands (cm) 1775, 1710, 1495, 1455, 1210, 755, 705.

A solution of 13.8 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3- C (1-methyl-5-tetrazolyl) -2-thiovinyl-3-oxo-5 is treated at -20 ° C. for 10 hours. oxide 5-thia-1-aza-bicyclo f4.2.0} oct-2-ene, Ε-form in 250 ecm of methylene chloride and 7.65 g of dimethylacetamide with 11.9 g of phosphorus tribromide. The mixture is poured into 250 ecm of a saturated solution of potassium bicarbonate, while stirring vigorously, the organic phase is washed with 100 ecm of a saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to dryness at 20 C under 20 mmHg (2.7 kPa). The residue is chromatographed on a column of 260 g silica gel Merck (0.06-0.2) (column diameter 3 cm, height 32 cm). It is eluted with 1.5 l of a mixture of cyclohexane-ethyl acetate (70-30 vol .) in order to recover fractions of 100 cc. concentrate the fractions 7-14 at 20 ⁰ C under 20 mmHg (2.7 kPa) to dryness and obtains 8.5 g of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3 -r (1-n-3-yl-5-tetrazolyl) -2-thiovinyl3-3-oxo-5-thia-1-aza-bicyclo-4,2'-O-oct-2-ene, Ε-form, in the form a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3340, 1790, 1705, 1690, 1510, 1160, 940, 730, 700

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AP C 07 D / 221

2 2 1 2 7 1 - ^ " ^{57 456} A ¹

Example 58

A solution of 2.5 g of 2-benzhydryloxycarbonyl-3-f5,6-dioxo-4- (2-hydroxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl3- 2-t hiovinyl-7-f2-methoxy in ino-2- (2-tritylarnino-4-thiazolyl) acetamido J-S-oxo-S-thia-1-aza-bicyclo f4.2, o3 oct-2 en, syn isomer, Ε-form in 250 ecm of dry tetrahydrofuran, is cooled to -50 C and treated with 11 ecm of chlorosulfonyl isocyanate. The mixture is stirred for 55 minutes, while slowly allowing the temperature to rise to -5 C and then added 150 ecm of a saturated sodium bicarbonate solution and 250 ecm of ethyl acetate. The aqueous phase is extracted with 100 eq of ethyl acetate, and the combined organic extracts are washed twice with 100 ecm of a saturated sodium chloride solution and then filtered through magnesium sulfate and dried. After evaporation of the solvent under reduced pressure (30 mmHg; 4 ICPA) at 40 ⁰ C and drying, 2.6 g of 2-benzhydryloxycarbonyl-3-i / * 4- (2-carbamoyloxyethyl) -5,6-dioxo -l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl} -2-thiovinylJ-7- ^ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido ^ - S-oxo-S-thia-1-aza-bicyclo ζΑ, 2.θ} oct-2-ene, syn isomer, Ε-form, in the form of a yellow powder,

Infrared Spectrum (KBr), characteristic bands (cm) 3350, 2600, 1785, 1720, 1685, 1530, 1490, 1450, 755,

NMR proton _spectrum (350 MHz, DMSO d _βf S in ppm, D in Hz) 3.30 and 3.64 (2d, D = 18, 2H, -SCH ₂ -); 3.84 (s, 3H, = NOCH ₃ ); 4.03 and 4.11 (2t, 0 = 5, 2 X 2H,>NCHgCHgOCO-); 5.24 (d, Ό. = 4, IH, H in Figure 6); 5.77 (dd, ö = 4 and 9, IH, H in)); 6.71

22 127 1

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(S ₁ IH, H of the thiazole); 6.94 (s, IH, -CH (C ₆ H ₅ ) ₂ ); 6.93 and 7.02 (AB, D = 16, 2H, -CH = CH-S-); 7.15 - 7.60 (Mt, 25H, aromatis'ch); 8.25-8.80 (2s, 2H, -OCONH ₂ ); 9.60 (d, O = 9,

12.60 (s, IH, -N = C-OH or * = NHC-triazine)

, 29.9,1980

AP C 07 D / 221 2 1271 "" ^ ¹ - ⁵⁷ 466/11

A solution of 2.6 g of 2-ßenzehydryloxycarbonyl ~ 3 ~ lC4- (2- carbamoyloxyeth.yl) -5,6-dioxo-l, 4,5,5-tetrahydro-l, 2,4-traiazin-3-yl ] | -2-thiovinyl-3-7-f2-methoxy-imino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-8-oxo-5-thia-1-a2a-bicyclo [4.2.2.3 oct-2-ene, Syn isomer, Ε-form, in 47 ecm of formic acid is diluted with 20 eq of distilled water and heated at 50 C for 20 min, followed by further dilution with 27 eq of distilled water. After filtration of the insoluble material, the filtrate is concentrated to dryness under reduced pressure (5 mmHg, 0.67 kPa) at 30 ° C. The residue is triturated with 50 eq of anhydrous ethanol, which is concentrated under reduced pressure (30 mmHg; 4 kPa). evaporated at 40 ° C. This operation is repeated twice more, whereupon the residue is taken up in 40 ecm of ethanol, filtered off, washed with twice 50 ecm of ether and dried. This gives 1.5 g of 7- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-3-O-4-O- (2-carbamoyloxyethyl) -5,6-dioxo-1,4,5 , 6-tetrahydro-1,2,4-triazin-3-y13-2-thiovinyl J-2-carboxy-8-oxo-5-thia-1-azabicyclo / 4,2,0j oct-2-ene, syn isomer , Ε-shape, in the form of a cream-colored powder.

Infrared spectrum (KBr), characteristic bands (cm) 3550, 2200, 1770, 1710, 1680, 1050, 940

NMR proton spectrum

(350 MHz, DMSO _dβ , <f in ppm, O in Hz) 3.62 and 3.82 (2d, O = 1~8, 2H, -SCH ₂ -); 3.86 (s, 3H, = NOCH ₃ ); 4.06 and 4.15 (2t, O = 5, 2 χ 2H,> NCH CH ₂ O-); 5.21 (d, O = 9, IH, H in Figure 6); 5.78 (dd, 0 = 4 and 9, IH, H in 7); 6.50 (s wide, 2H, -OCONH ₂ ) ⁺ // -CH = CH-S-); 7 - 7.50 (s wide, 2H, -NH ₂ -thiazole); 9.66 (d, 0 = 9, IH, -CONH-C);

29.9.1980 AP C 07 D / 221 271 221271 -Ί Η -. 57 466/11

12.62 (s, IH, -N = C-OH or = NNH-C-) ⁺ // 6.75 (s, IH, H of

ti

Thiazole); 6.92 and 7.08 (2d, D = 16, 2H

The 2-benzhydryloxycarbonyl-3- { 5,6-dioxo-4- (2-hydroxyethyl) -1, 4,5,6-tetrahydro-1, 2,4-triazin-3-ylJ-2-thiovinyl J-7 -f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido3-8-oxo-

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5-thia-1-aza-bicyclo f4.2,0] oct-2-ene, syn isomer, E form, can be prepared in the following manner:

To a solution of 5.5 g of 2-benzhydryloxycarbonyl-7-r2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-8-oxo-3- (2-tosyloxy-vinyl) -5-thia-1-one aza-bicyclo C4.2.03 oct-2-ene, syn isomer, Ε-form and 2.08 g of 5,6-dioxo-4- (2-hydroxyethyl) -3-thioxo-l, 2,4-perhydrotriazine in 150 cc of dry N ₁ N-dimethylformamide are added at 60 C for 15 min., a solution of N, N-diisopropylethylamine in 50 cc of dry N, N-dimethylformamide. The reaction mixture is stirred for 3 h at 60 C and then diluted with 600 ecm of ethyl acetate. The organic phase is washed with 150 ecm of a saturated sodium bicarbonate solution and then with three times 150 eq of distilled water and finally dried over magnesium sulphate. After filtering and concentrating under reduced pressure (30 mmHg; .4 kPa) at 40 ⁰ C to dryness, the residue is chromatographed on silica gel Merck (.04-.06) (column diameter 30 cm 6 cm, height), eluting with 7.5 1 of a cyclohexane-ethyl acetate mixture (15-85 vol.) eluted under a pressure of 40 kPa. The eluate is collected in fractions of about 100 ecm. Fractions 24-70 are combined and concentrated to dryness under reduced pressure (30 mmHg; 4 kPa) at 40 ° C. 3.31 g of 2-ßenzhydryloxycarbonyl-3- {5,6-dioxo-4- (2-hydroxyethyl) -1, 4,5,6-tetrahydro ~, 2,4-triazin-3-yl3- 2-thiovinyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-S-oxo-S-thia-1-aza-bicyclo £ 4.2.03 oct-2-ene, syn isomer , Ε-shape, in the form of a bright yellow solid.

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Rf = 0.33 C silica gel chromatography plate; Eluent: cyclohexane-ethyl acetate (10 - 90 vol,) 3.

 * · - "i Infrared spectrum (CHBr ..), characteristic bands (cm) 3380, 1785, 1715, 1680, 1585, 1520, 1495, 1450, 1050, 940, 755, 740

29 * 9.1980 AP C 07 D / 221 22 127 1- W-. 57 465/11

NMR proton spectrum

(350 MHz, CDCl ₃ , <f in.ppm, D in Hz) 3.44 and 3.60 (AB, 0 = 18, 2H, -SCH ₂ -); 3.81 (mf, 2H, -CH ₂ OH); 4.00 (s, 3H, = NOCH ₃ ); 5.00 (d, 0 = 4, IH, H in 6); 5.90 (dd, O = 4 and 9, IH, H in 7); 6.70 (s, IH, H of the thiazole); 6.81 (d, D = 15, IH, -ChU = CH-S-); 6.90 (s, IH, -CH (CH ₅ ) ₂ ); 5.72-7.6 (mf, aromatic, -CONH-, -CH = CFIS-, (C ₆ H ₅ J ₃ CNH-).

Example 59

To a solution of 2.5 g of 2-benzhydryloxycarbonyl-3-f, 5,5-dioxo-4- (2-hydroxyethyl) -1, 4,5,6-tetrahydro-l, 2,4-triazine ~ 3 yl} -2-thiovinyl | -7- [] 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -J-acetamidoj-S-oxo-S-oxide-S-thia-1-aza-bicyclo f4,2. O3 oct-2-ene, syn isomer, Ε-form in 100 ecm of dry tetrahydrofuran, cooled to -10 ⁰ C, are added 0.38 ecm of triethylamine and 0.5 g of 4-N, N-dimethylamine.opyridine and then a solution of formic anhydride (4.9 mmol) in 10 ecm of methylene chloride (prepared according to G, A, Olah et al, Angew Chem 91, 949, 1979)

Stirred at about 20 C for 3 h and then after filtration with 450 ecm of ethyl acetate and washed successively with 50 ecm of 0.2N hydrochloric acid, 100 ecm of distilled water, 100 ecm of a saturated sodium bicarbonate solution and 100 ecm of a saturated sodium chloride solution Phase is dried over magnesium sulfate, filtered and concentrated under reduced pressure (30 mmHg;

4 kPa) at 40 ° C. This gives 2.7 g of 2-benzhydryloxycarbonyl-3-fjT5,6-dioxo-4- (2-formyloxyethyl) -

methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-8-0X0-5-oxide-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε- Form, in raw form, in the form of a brown powder.

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22 1 27 1. ^ u _ - _57466/11

Rf = 0.68 / 'silica gel chromatography plate; Eluent: ethyl acetate-methanol (80-20 vol.) 3.

3.35 g of the crude product obtained above are dissolved in 50 ecm of dry methylene chloride. Add 1.42 ecm of N, N-dimethylacetamide, then cool to -10 ° C. and add 0.67 ecm of phosphorus trichloride to r. Reaction mixture _r is stirred at about -10 ° C. for 1 h and then with 0.2 ecm of N _# N ~ dimethylacetamide and 0.1 ecm phosphorus trichloride treated. After 20 min at -10 C, the reaction mixture is diluted with 500 ecm of ethyl acetate and 150 ecm of a saturated sodium bicarbonate. The organic phase is decanted off and washed twice with 50 ecm of distilled water and 100 ecm of a saturated sodium chloride solution, then dried over magnesium sulfate and filtered. Evaporation of the solvent under reduced pressure (35 mmHg, 4.7 kPa) at 40 ° C gives 3.6 g of the residue which is collected on a column (column diameter 5 cm, height 30 cm) of Merck silica gel (0.3463 - 0.04), eluting under a pressure of 40 kPa with 4 l of a mixture of cyclohexane and ethyl acetate (40-60 vol.) And obtaining fractions of about 50 ecm. "Fractions 38-76 are subjected to reduced pressure ( 35 mmHg, 4.7 kPa) at 40 C to dryness. This gives 1.3 g of 2-benzhydryloxycarbonyl-3-fr5,6-dioxo-4- (2-formyloxyethyl ^Y ) -l, 4,5,6-tetrahydro-.l, 2,4-triazin-3-yl-y. 2 ~ 7 ~ ~ thiovinyl ^ £ 2 ~ methoxyimino-2 ~ (2-tritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5-thia-l-aza-bicyclo / 4 _e 2.0J oct-2-ene, syn isomer, E-form, in the form of a bright yellow powder.

NMR proton spectrum

(350 MHz, DMSO d _& , (f in ppm, Ό in Hz)

29.9.1980 AP C 07 D / 221 22 1 27 1 - ^> -. 57 466/11

3.65 and 3.88 (AB, Ό = 18, 2H, -SCH ₂ -); _ 3.84 (s, 3H, = N0CH ₃ ); 4.10 and 4.32 (2t, D = 5, 2 χ 2H, ^ NCH ₂ CH ₂ OCHO); 5.21 (d, α = 4, IH, H in 6j_, 5.75 (dd, 0 = 4 and 9, IH, H in 7), 6.72 (s, IH, H * of the thiazole), 6 , 95 (s, IH, -CH (C ₆ H ₅ J ₂ ); 5.93 and 7.02 (AB, D = 16, 2H, -CH = CH-S-); 7.1-7.5 (Mt, 25H, aromatic)

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22 Ί 2/1 _ _We 57 466/11

8.80 (s broad, IH, (C ₆ H ₅ J ₃ CNH-); 9.60 (d, 0 = 9, IH, -CONH-C ₇ ); 12.60 (s wide, IH, = NN = C-0H or = NNH-C-)

A solution of 1.25 g of 2-ßenzehydryloxycarbonyl-3-f / * 5,6-dioxo-4- (2-sulfyloxyethyl) -1, 4,5,6-tetrahydro-1,2,4-triazine-3 yl3-2-thiovinyl-7-C2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-S-oxo-S-thia-1-aza-bicyclo [4.2.2O3 oct-2-ene, sy. n-Isorneres, Ε-form, in 15 ecm of formic acid, is diluted with 4 eq of distilled water and warmed to 50 ° C. for 25 min and then diluted with 11 eq of distilled water After filtration of the insoluble material, the filtrate is distilled under reduced pressure ( 5 mmHg; 0.67 kPa) at 30 C concentrated the residue is triturated in 50 cc of ethanol, which is under reduced pressure (35 mmHg;.. vaporized 4.7 kPa) at 40 ⁰ C. This latter operation is repeated four times, whereupon the solid residue, taken up in 20 ecm of ethanol, filtered off with suction, then washed with twice 25 ecm diisopropyl ether and dried. The product is dissolved in 10 ecm of pure formic acid, and the solution is heated for 1 h 30 tiin, at 45 ° C and sch leaving under reduced pressure (5 mml-lg; 0.67 kPa) at 40 C to dryness. The residue is triturated in 30 eq. Of anhydrous ethanol, which is evaporated at 40 ° C. under reduced pressure (30 mmHg; 4 kPa). This operation is repeated twice more. This gives 0.54 g of 7-C2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -2-carboxy-3- {r5,6-dioxo-4- (2-formyloxyethyl) -1, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl] 1- "2-thio-vinyl-3-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene," syn isomer, Ε-form, in the form of a yellow powder.

29.9.1980 AP C 07 D / 221 2 2 1271'- W - 57 466/11

Infrared spectrum (KBr), characteristic bands (cm)

3400, 3200, 2200, 1775, 1710, 1580, 1530, 1040, 945

NMR proton spectrum.

(350 MHz, DMSO _dβ , (f in ppm, J in Hz) 3.62 and 3.82 (AB, D = 18, 2H, -SCH ₂ -); 3.84 (s, 3H, ^ 4, 15 and 4.32 (2t, D = 5, 2 χ 2H,> NCHgCHg-OCHO), 5.21 (d,

29.9.1980 AP C 07 D / 221 22 127 1 - ^ O- 57 466/11

0 = 4, IH, H in 6); 5.78 (dd, 0 => 4 and 9, IH, H in Figure 7); 6.73 (s, IH ₁ H of the thiazole); 6.89 and 7.10 (2d, 0 = 16, 2H, -CH = CH-S-); 7.16 (s wide, 2H, -NH ₂ ); 8.18 (s, IH, H [COO-]; 9.59 (d, 3 = 9, IH, -CONH-C ₇ ); 12.60 (s wide, IH,

= NN = COH or = NNH-C-I ~ II

The 2-Benzhydryloxycarbony1-3- {f5,6-dioxo-4- (2-hydroxyethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl3-2-thiovinyl} -7 -f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamidoJ-8-oxo-5-oxide-5-thia-1-aza-bicyclo [4. 2.Oj oct-2-ene, syn-isomer, E-form can be prepared in the following manner:

To a solution of 18 g of 2-benzhydryloxycarbonyl-7- (2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamidoj-8-oxo-5-oxide-3- (2-tosyloxyvinyl) -5- thia-1-aza-bicyclo / '4.2.Oj oct-2-ene, syn-isomer, Ε-form in 490 ecm dry N, N-dimethylformamide, adding 7 g of 5,6 * dioxo at 65 ° C -4- (2-hydroxyethyl) -1,4,4-perhydrotriazine and then, dropwise over 10 min, a solution of 2.32 g of Ν, Ν-diisopropylethylamine in 160 ecm of dry Ν, Ν-dimethylformamide.The reaction mixture is 3 h stirred at 65 C and then diluted with 2 L of ethyl acetate and washed with four times 500 eq of distilled water The organic phase is dried over magnesium sulfate and concentrated under reduced pressure (35 mmHg, 4.7 kPa) at 40 ^° C. The residue is obtained 200 g silica gel Merck (0.2-0.04) (column diameter 4 cm), eluting with a mixture of cyclohexane and ethyl acetate (20-80 vol.) And collecting fractions of about 250 ecm n 6-41 are applied under reduced pressure (35 mmHg; 4.7 kPa) at 40 C to dryness. 17.16 g of 2-benzhydryloxycarbonyl-3- / t5,6-dioxo-4- (2-hydroxy-

.29.9.1980

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ethyl) -l, 4 _f 5.6

7 ~ C2 ~ methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido I-e-oxo-S-oxide-S-thia-1-aza-bicyclo '£' 4.2, Oj oct-2-ene, syn - »Isomeric, Ε-form, in the form of a light brown powder.

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2 2 12 7 1. _ HS ^ - 57 466/11

Infrared spectrum (KBr), characteristic bands (cm) 1800, 1720, 1685, 1525, 1495, 1450, 1045, 945, 755, 700

NMR proton spectrum

(350 MHz, DMSO d, (T in ppm, 0 in Hz) 3.60 and 4.28 (2d, 0 = 17.5, 2 χ IH, -S (O) CH ₂ -); 3.57 and 3.88 (2m, 2 χ 2H, > NCHgCHgOH); 3.84 (s, 3H, = NOCH ₃ ); 5.04 (d, 0 = 4, IH, H in 6); 5.84 (d , 0 = 4 and 9, IH, H in 7), 6.77 (s, IH, H of the thiazole), 6.96 (s, IH, -CH (C ₆ H ₅ J ₂ ), 6.96 and 7.09 (AB, O = 16, 2X IH, -CH = CH-S-); 7.15-7.60 (mt, 25H, aromatic); 8.72 (s, IH, = NN = C -OH or ^ NNH-C-

Il

Example 60

To a solution of 2.05 g of 2-ßenzehydryloxycarbonyl-3- {4- (2-hydroxyethyl) -5,6-diox0-1,4,5,6-tetrahydro-1,2,4-triazine-3 yl3-2-thiovinyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazoyl) -acetamido] -8-oxo-5-thia-1-aza-bicycloe ≤4.2.03 oct-2-ene, syn isomer, Ε-form, in 25 ecm of dry tetrahydrofuran is added at 22 ⁰ C 0.64 g of sodium bicarbonate and then dropwise over 15 min. A solution of 0.4 ecm of acetic anhydride in 5 ecm of dry tetrahydrofuran. It then adds 0.05 g of 4-dimethylaminopyridine, dissolved in 1 ecm of dry tetrahydrofuran and stirred for 10 min. At 25 ° C. The reaction mixture is diluted with 50 eq of distilled water and 120 ecm of ethyl acetate. The organic phase is decanted off and washed successively with 80 ecm of 0.5 N hydrochloric acid, 80 eq of saturated sodium bicarbonate solution and then 100 ecm of saturated sodium chloride solution. After drying over magnesium sulphate and filtering, the solution is concentrated to dryness under reduced pressure (30 mmHg; 4 kPa) at 40.degree. This gives 2.05 g of crude product in the form of a yellow

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Powder.

2.5 g of the crude product obtained above are chromatographed on a column (column diameter 4 cm, height 30 cm) of silica gel Merck (0.04-0.06), with 3 l of a mixture of cyclohexane and ethyl acetate ( 40-60 vol.) Eluted under a pressure of 40 kPa and fractions of 100 ecm wins. The fractions 11-26 are concentrated to dryness under reduced pressure (30 mmHg; 4 kPa) at 40 ° C. There are obtained 1.84 g of 3-fluoro-1, 4, 4, 4, 5, 6, 1, 4, 5, 6, 1, 4, 1, 4, 1, 6, 1-yl] - 2-thiovinyl J-2-benzhydryloxycarbonyl-7-C2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido} -8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2 -en, syn-isomer, Ε-form, in the form of a yellow meringue.

Infrared spectrum (CHBr ₃ ), characteristic bands (cm J 3400, 2820, 1790, 1720, 1685, 1590, 1495, 1450, 1050, 940, 760, 740

NMR proton spectrum

(350 MHz, DMSO dg, ti in ppm, 3 in Hz) 1.97 (s, 3H, CH ₃ CO ₂ -); 3.63 and 3.88 (AB, 3 = 18, 2H, -SCH ₂ -); 3.83 (s, 3H, = NOCH ₃ ); 4.06 (t, '3 = 5, 2H, ^ n -CH ₂ CH ₂ OCOCH ₃ ); 4.23 (t, 3 = 5, 2H,> NCH ₂ -CH ₂ OCOCH ₃ ); 5.21 (d, 0 = 4, IH, H in 6); 6.76 (dd, 3 = 4 and 9, IH, H in Figure 7); 6.71 (s, IH, H of the thiazole); 6.91 (d, 3 = 16, IH, -CH = CH-S-); / ⁺ 7.2-7.5 (m, 25H, aromatic); 9.60 (d, 3 = 9, IH, -CONH-); 12.58 (s wide, IH, = NN = C-OH or = NNH-C-) / ⁺ 6.93 (s, IH, -CH (C ₆ H ₅ J ₂ , 7.0 (d, J = 16, IH,

1.8 g of 3 - ^ / T4- (2-acetoxy-ethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-t-riazin-3-yl3-2-thiovinyl J-2 -benzhydryloxycarbonyl-

29.9.1980 AP C 07 E / 221 271 2 2 1 2 7 1 - Η * Η -. 57 466/11

7- / 2-nitro-thio in ino-2- (2-1-ritylamino-4-thiazolyl) ace tarn idcQ-e-oxo-S-thia-1-aza-bicyclo f4.2.0]] oct-2 -en, syn-isomer, E-form _# are dissolved in 40 ml of formic acid and after adding 15 ml of distilled water, the reaction mixture is brought to 60 ° C.

29.9.1930 AP C 07 D / 221 271 22 1274 - ^ ⁸⁵ - 57 466/11

heated, filtered, and then concentrated to dryness under reduced pressure (5 mmHg, 0.67 kPa) at 40 ° C for 30 min. The residue is taken up in 50 ml of ethanol, which is then evaporated at 40 ° C. under reduced pressure (30 mmHg; 4 kPa). This operation is repeated twice. The residue is dissolved in 150 eq of boiling ethanol; After filtering the hot solution is allowed to cool and kept for 2 days at 5 ° C, the residue is filtered off and washed with 20 ecm diethyl ether.and finally dried. 0.65 g of 3-tert-2- (2-acetoxy-ethyl) -5,6-dioxo-1, 4,5,6-tetrahydro-1, 2,4-triazine-3-yl-2-thiovinyl-1-yl are obtained 7 ~ t2 ~ (2-amino-4-thiazolyl) -2-methoxyimino-acetamido-O-S-oxo-S-thia-1-aza-bicyclo / 4,2,0J oct-2-ene, syn isomer, Ε- Form, in the form of a bright yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3320, 3220, 3150, 2300, 1780, 1740, 1720, 1680, 1635, 1590, 1535, 1375, 1210, 1040, 950

NMR proton spectrum

(350 MHz, DMSO dg, cT in ppm, 0 in Hz) 2.0 (s, 3H, CH ₁₃ CO ₂ -), 3.63 and 3.82 (ΑΒ, Ο = 18, 2H, -SCH ₂ -); 3.85 (s, 3H, = NOCH ₃ ); 4.08 (t, O = 5, 2H,>NCHgCHgOCOCH); 4.25, (t, 0 = 5, 2H,;> NCH ₂ CH ₂ OCOCH ₃ ); 5.20 (d, 0 = 4, IH, H in 6); 5.78 (dd, 0 = 4 and 9, IH, H in 7); 6.73 (s, IH ₁ H of the thiazole); 6.90 (d, O = 16, IH, -ClH = CH-S-); 7.12 (d, O = 16, IH, -CH = CHS-); 7.18 (s wide, 2H, -NH ₂ ); 9.60 (s, O = 9, IH, -CONH-C ₇ ); 12.6 (s wide, IH, = NN = C-OH or = NNH-C-

Il

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Example 61

To 1.12 g of N-t-butoxycarbonylglycine, dissolved in 30 ecm of dry Methylenc.hlorid at 0 C is added over 5 min. A solution of 0.72 g of NjN'-dicyclohexylcarbodiimide in 20 ecm of methylene chloride. The reaction mixture is stirred for 30 min. At a temperature of 0 to 5 ° C and then quickly filtered. The filtrate is added dropwise over 10 min. To a solution of 3 g of 2-benzhydryloxycarbonyl-3- {ε5,6 ^ 10 ^ 0-4- (2-hydroxyethyl) -1,4,5,6-tetrahydro-1, 2,4-triazin-3-yr} -2-thiovinylJ-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidο3-8-oxo-5-oxide-5-thia-1-azabicyclo Γ4.2.01 oct-2-ene, syn isomer, Ε form, in 70 ecm of dry tetrahydrofuran cooled to 0 ° C. The reaction mixture is stirred at 20 C for 45 min, then diluted with 500 eq of ethyl acetate and washed successively with 200 eq of distilled water, 100 eq of saturated sodium bicarbonate solution, 100 eq of distilled water and 50 ecm 'of a saturated sodium chloride solution. The organic phase is dried over sodium sulfate, filtered and concentrated under reduced pressure (30 mmoles, 4 kPa) at 40 ° C. This gives 3.45 g of 2-Benzhyd_ryloxycarbonyl-3 - ^ / "4- (2-Nt-butoxycarbonylglycyloxyethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4 ~ triazine-3 -yl3-2-thiovinyl J -7- (2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-8-oxo-S-oxide-S-thia-1-aza-bicyclo [4.2.2.O.Oct -2-ene, syn isomer, Ε-form, in crude form, in the form of a brown powder.

3.3 g of this crude product are dissolved in 45 ecm of dry methylene chloride. The cooled to -10 ⁰ C solution is with

, · 29.9.1980

AP C 07 D / 221 271 22 1 27 V - lfg * - 57 466/11

1.24 ecm N, N-dimethylacetamide and then treated with O ₁ S ecm phosphorus trichloride. After 1 h 30 min. At -10 ⁰ C, the reaction mixture is diluted with 600 ecm of ethyl acetate and washed successively with 100 ecm of a saturated sodium bicarbonate solution, twice 100 ecm of distilled water and twice 200 ecm of a saturated sodium chloride solution. After drying over sodium sulfate and filtering, the organic solution

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2 2 12 7 1 "" ^{57 466} Z ¹¹

concentrated to dryness under reduced pressure (30 mmHg; 4 kPa) at 40 ° C. The residue is chromatographed on a column (column diameter 4 cm, height 30 cm) of silica gel Merck (0.04-0.062), under a pressure of 40 kPa with 1.5 1 of a mixture of cyclohexane-ethyl acetate (10-90 Vol.) Elutes and fractions of 50 ecm wins. Fractions 7-22 are combined and concentrated to dryness under reduced pressure (30 mmHg; 4 kPa) at 30 ° C. This gives 1.44 g of "2-ßenzhydryloxycarbonyl-3 ~ {C4- (2-Nt-butoxycarbonylglycyloxyethyl) -5,6-dioxo ~ l, 4,5,6-tetrahydro-l, 2,4 ~ tri. 3-yl3-2-thiovinyl-7-F2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido3-: 8-oxo-5-thia-1-aza-bicyclo C4.2.0D oct-2- en, syn isomer, Ε form, in the form of a yellow powder.

Infrared spectrum (K3r), characteristic bands (cm) 1785, 1715, 1685, 1530, 1495, 1445, 1160, 1030, 945, 755,

NMR proton spectrum

(350 mHz, DMSO ≥ _Q , cT in ppm, 0 in Hz)

1.36 (s, 9H, (CH ₃ J ₃ CO-); 3.25 and 3.86 (2d, 0 = 18, IH, -SCH ₂ -); 3.65 (d, 0 = 9, 2H , -COCH ₂ NH-); 3.84 (s, 3H,

-NOCH ₃ ); 4.05 and 4.26 (2t, 0 = 5, 2 χ 211,> NCH ₂ CH ₂ OCO-); 5.23 (d, 0 = 4, IH, H in 6); 5.50 (d, 0 = 9, IH, -CHgNHCO-); 5.76 (dd, 0 = 4 and 9, IH, H in Figure 7); 6.71 (s, IH, H of

Thiazole); 6.91 (s, IH, -CH (C ₆ H ₅ J ₂ ), 6.90 and 7 (2d, 0 = 16, 2H, -CH = CH-S-), 7.15 - 7.5 ( R, 25H ₁ aromatic); 8.78 (s wide, IH, (C ₅ H ₅ ^ ₃ CNH-); 9.60 (d, 0 = 9, IH, -CONH-); 12.60 (s, IH, = NN = C-OH or = NNH-C-

1 If

29.9.1980 AP C 07 D / 221 271 2 12 7 1 - f S - 57 466/11

A solution of 1.5 g of 2-ßenzehydryloxycarbonyl ~ 3-lb / * 4 ~ (2 ~ N'-t-butyl-oxycarbonyl-gyexyloxyethyl) -5.6 ^ 10X0-1, 4, 5, 6-te trahydrol, 2 , 4-t, riazin-3-yl3-2-thiovinyl J -7- 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido J-8-bxo-5-thia-1-azabicyclo f4,2.03 oct-2-ene, syn isomer, Ε-form, in 15 ecm of formic acid is diluted with 4 eq of distilled water and warmed to 50 C for 30 min and finally diluted with 11 ecm of distilled water.

29.9.1980 AP C 07 D / 221 2 2 I 2 7 1 - ^ O - 57 466/11

After filtering the insoluble material, the mixture is evaporated to dryness under reduced pressure (5 mmHg, 0.67 kPa) at 30 ° C. The residue is triturated with 60 cc of dry ethanol which is under reduced pressure (30 mm Hg; 4 kPa) at 40 ⁰ C. This last operation is repeated a total of three times, whereupon the solid residue is taken up in 50 ecm of isopropyl ether, filtered off with suction and then washed with three times 20 ecm of ethyl ether and dried. There are obtained 0.8 g of the formate of 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-CaTbOXy-S- {5,6-dioxo-4- (2-glycyloxyethyl ) ~ 1,4,5,6-tetrahydro-1,2,4-triazin-3-yl3-2-thiovinyl J-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2- syn-isomer, E-form, in the form of a bright yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3550, 2200, 1755, 1705, 1675, 1580, 1530, 1035

NMR Ppotonenspektrum

(350 MHz, DMSO d _gf (Tin ppm, 0 in Hz) 3.51 and 3.62 (AB, 0 = 18, 2H, -SCH ₂ -); 3.72 (mt, 2H, -COCH ₂ NH ₂ 3.82 (s, 3H, = NOCH ₃ ); 4.12 and 4.40 (2M, 2X 2H,> NCH ₂ CH ₂ OCO-); 5.10 (d, 0 = 4, IH , H in 6), 5.67 (dd, Ο = 4 and 9, IH, H in 7), 6.44 (d, 0 = 16, IH, -CH = CH-S-), 6.72 ( s, IH, H of the thiazole), 7.18 (s broad, 3H, -NH ₃ ⁺ thiazole), 8.12 (s, IH, HCO ₂ -), 9.56 (d, 0 = 9, IH, -CONH-C ₇ ).

Example 62

To a solution of 2 g of 3- / 4- (2-aminoethyl) -5,6-dioxole, 4,5,6-tetrahydro-l, 2,4-triazih-3-yl3-2-thiovinyl ^ -2 -benzhydryloxycarbonyl-7- £ 2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamidoj-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn Isomer,... Form, prepared as described in the example, in 25 ecm

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2 2 1 2 7 1 _ Η-βλ r. 57 466/11

Tetrahydrofuran is added at -20 ⁰ C 0.28 ecm methanesulfonyl chloride and 0.2 ecm of triethylamine and then allowed to stand for 1 h 30 min. To -5. C rise. The mixture is poured while stirring vigorously, in 500 ecm of water, filtered, the solid washed with 30 ecm of ethanol and 10 ecm of diethyl ether, dried and chromatographed the previously fixed to 5 g silica gel (0.06 - 0.2) product a column of 10 g silica gel Merck (0.06-0.2) (column diameter 0.5 cm, height 10 cm). It is eluted with 200 ecm of ethyl acetate, obtaining fractions of 15 ecm. The fractions 5-11 are evaporated to dryness and 0.3 g of 2-benzhydryloxycarbonyl-3-C5-C5,6-dioxo-4- (2-methylsulfonylaminoethyl) -1,4,5,6-tetra! ^ Ατοί, 2 , 4-riazin-3-yl3-2-thiovinyl J-7 - / 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-8-oxo-5-thia-1-azabicyclo £ 4.2 .0} oct-2-ene, syn isomer, Ε-form, in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3300, 1790, 1715, 1695, 1590, 1525, 1495, 1450, 1320 ,. 1160, 1035, 945, 755, 700.

Is treated at 50 ⁰ C for 30 min. 0.7 g of 2-ßenzhydryloxycarbonyl-3- £ f5,6-dioxo-4- (2-methylsulfonylaminoethyl) -1,4,5,6-tetrahydro-1,2,4 -triazin-3-yl} -2-thiovinyl-7- ^ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-8-oxo-5-thia-1-aza-bicyclo f4,2.0j oct-2-ene, syn-isomer, E-form, with a mixture of 10 ecm of formic acid and 5 ecm of water. It is filtered, concentrated under 20 mmHg; 2,7 kPa at 50 C to dryness, takes up with four times 50 ecm of ethanol, each time under 20 mmHg; (2.7 kPa) at 20 ⁰ C evaporated to dryness. The resulting solid is triturated

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2 2 12 7 1 .. Vft ... ₅₇ 4S ₆₇₁₁

in 50 ecm of ethanol, filtered and washed with twice 10 ecm of diethyl ether. 0.4 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido3-2-carboxy) -3- [alpha] -5,5-dioxo-4- (2-methylsulfonylaminoethyl) -l is obtained, 4,5,6-tetrahydro-1,2,4-triazin-3-yl-3-2-thiovinyl-8-oxo-5-thia-1-aza-bicyclo-4,2'-O-oct-2-ene, syn- Isomer, Ε-form, in the form of a yellow powder.

29.9.1980 AP C 07 D / 221 2 2 1 2 7 1 - W - 57 466/11

Infrared spectrum (KBr), characteristic bands (cm) 3400, 3300, 3200, 1775, 1710, 1680, 1590, 1530, 1320, 1150, 1140 and 945

NMR ProtoneηSpektrum

(350 MHz, DMSO dg, cf in ppm, O in Hz) 2.90 (s, 3H, -SO ₂ CH ₃ ); 3.20 (mt, 2H, -CH ₂ NH-); 3.61 and 3.78 (2d, Ο = 18, 2H, -SCH ₂ -); 3.96 (s, 3H, = NOCH ₃ ); 3.96 (t, 0 = 5, 2H, for N-CH ₂ -); 5.17 (d, U = 4, IH, H in Figure 6); 5.73 (dd, 0 = 4 and 9, IH, H in 7); 6.74 (s, IH, H of the thiazole); 6.79 (d, O = 16, IH, -CH = CHS-); 7.17 (s, 2H, -NH ₂ ); 9.60 (d _f 0 = 9, IH, -CONH-).

Example 63

To a cooled to +5 C solution of 0.84 g Nt-3utoxycarbonylglycine in 20 ecm methylene chloride, is added dropwise over 10 min. A solution of 0.5 N, N ¹ -Dicyclohexylcarbodiifnid in 10 ecm methylene chloride, it is stirred for 30 min. at 5 C, filter and pour the filtrate dropwise over 20 min. into a 5 C cooled solution of 2.04 g of 3- £ f 4- (2-aminoethyl) -5,5-dioxo-l, 4,5,5 tetrahydro-1,2,4-triazin-3-yl3-2-thiovinyl J-2-benzhydryloxycarbonyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnido3-8-oxo-S-oxide -S-thia-1-aza-bicyclo 4 4.2, o 3 oct-2-ene, syn isomer, E form, 0.34 ecm triethylamine and 50 mg dimethylaminopyridine in 100 ecm methylene chloride. The temperature is allowed to 20 C with stirring for 1 h to rise, the mixture was concentrated to about 30 cc under 20 mmHg (2.7 kPa) at 20 ⁰ C. It is diluted with 70 cc of ethyl acetate, washed twice with 50 cc of a saturated sodium bicarbonate and three times 50 cm.sup.2 of water, dried over sodium sulfate, filtered and concentrated under 20 mmHg (2.7 kPa) at 20.degree. C. to dryness. Take up the residue in 10 ecm of tetrahydrofuran and leave at

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AP C 07 D / 221 22 1 27 1 _β ^ _ _ 57 466/11

4 C for 48 h. The mixture is filtered and concentrated under 20 mmHg (2.7 kPa) at 20 ⁰ C to dryness. The residue is triturated in 50 ecm of diethyl ether, filtered and dried. L _f 72 g of 2-benzhydryloxycarbonyl-3- { _f 4 - (2-t-butoxycarbonylglycylaminoethyl) -5,6-dioxo-1 _f 4 _f 5 _f 6-tetrahydro-l, 2,4-triazin-3-yl 3-2 are obtained -thiovinyl-7-r 2 -methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido]] - 8-oxo-5-oxide-5-thia-1-aza-bicyclo [4,2,0 " ] oct-2-ene, syn isomer, Ε-form, in the form of a brown powder,

1 infrared spectrum (KBr) ₁ characteristic bands (cm) 338O ₁ 1800, 1710, 1690, 1590, 1515, 1495, 1450, 1210, 1165, 1050, 1040, 945, 755, 700,

NMR proton spectrum

(350 MHz, DMSO d, cf in ppm, 0 in Hz) 1.35 (s, 9H, -C (CH ₃ J ₃ ); 3.33 (m, 2H,> N-CH ₂ CHgNH-); 3 , 54 (t, 0 = 5, 2H,> NCH ₂ CH ₂ NH-), 3.63 (d, 0 = 5, 2H, -COCH ₂ MH-), 3.6 and 4.3 (2d, 0 = 18, 2H, -SCH ₂ -), 3.85 (s, 3H, = NOCH ₃ ), 5.06 (d, 0 = 4, IH, H ₅ ), 5.85 (dd, 0 = 4 and 9, IH, H ₇ ), 6.78 (s, IH, H of the thiazole), 6.85 and 7.12 (2d, 0 = 16, 2H, -CH = CH-), 6.97 (s, IH, -COOCFl <); 7.18 (s, IH, · NH-thiazole); 8.0 (t, Ό = 5, IH, -COCH ₂ NfH-); 8.75 (s wide, IH, ^ NCH ₂ CH ₂ NIH-); 9.03 (d, D = 9, IH, -CONH-); 12.6 (s, IH, -NH triazine).

A solution of 1.65 g of 2-ßenzehydryloxycarbonyl-3-O4-4- (2-t-butoxycarbonylglycylamino-ethyl) ~ 5j6-dioxo-l, 4.5, 6 is treated at -10 C for 1 h 30 min tetrahydro-1,2,4-triazin-3-yl3-2-thiovinyl -7 -? / '2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido} -8-oxo-5-oxide -5-thia-laza-bicyclo / ^ 4,2, OJoct-2-ene, syn isomer, Ε-form, in

• 09/29/1980

AP C 07 D / 221 "2 2 1 2 7 1 - ^ S - 57 466/11

30 ecm of methylene chloride and 0.56 ecm of dimethylacetamide with 0.5 ecm of phosphorus trichloride. The mixture is diluted with 150 ecm of methylene chloride, washed with twice 100 ecm of a half-saturated sodium bicarbonate solution and twice 200 ecm of a half-saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated at 20 mmHg; (2.7 kPa) at 20 ⁰ C to dryness.

09/29/1980

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It is chromatographed on a column of 50 g of silica gel Merck (0 _f 06-0.2) (column diameter 2 cm, height 34 cm). It is eluted with 250 ecm of a cyclohexane / ethyl acetate mixture (50-50 vol.), 500 ecm of a 25-75 (vol.) Mixture and 1.5 1 of ethyl acetate to yield fractions of 60 ecm. Dry fractions 9-24 and recover 0.78 g of 2-benzhydryloxycarbonyl-3-t4- (2-t-butoxycarbonylglycylaminoethyl) -5,6-dioxo-l, 4,5,6-tetrahydrol, 2i4- triazin-3-yl) -2-thioquino] j '~ 7 ~ f2-methoxyimino-2 ~ (2-tritylamino-4-thiazolyl) -acetamido] -8-oxo-5-thia-1-aza-bicyo ~~ £ 4.2 .0 ^ oct-2-ene, syn isomer, Ε-form, in the form of a cream meringue,

Infrared spectrum (KBr), characteristic bands (cm) 3400, 3300, 1785, 1710, 1680, 1590, 1530, 1495, 1450, 1200, 1165, 1050, 950, 755, 700

NMR proton spectrum

(350 MHz, DMSO d _& , tf in ppm, ö in Hz) 1.38 (s, 9H, -C (CH ₃ ) ₃ ); 3.30 (m, 2H, · NCHgCHgNH-); 3.45 (d, 0 = 5, -COCH ₂ NH); 3.65 and 3.88 (2d, D = 16, 2H, -SCH ₂ -); 3.85 (t, Ό = 6, 2H,> NCI ₁ I ₂ CH ₂ MH-); 3.85 (s, 3H, = NOCH ₃ ); 5.24 (d, 0 = 4, Η _β ); 5.76 (dd, 0 = 4 and 9, H ₇ ); 6.92 and 7.00 (2d, Ό = 16, -CH = CH-); 6.93 (s, COOCH ^); 7.79 (t, Ό = 5, IH, -CH ₂ NhI CO-); 8.80 (s,>-NH_-thiazole); 9.59 (d, 0 = 9, -CONH-); 12.53 (s, -MH-triazine).

A solution of 0.73 g of 2-benzhydryloxycarbonyl-3-O-4-ol (2-t-butoxycarbonylglycylamino-ethyl) -5,6-dioxo-l, 4,5,6-one is treated at 50 C for 30 min. tetrahydro-1,2,4-triazin-3-yl} -2-thiovinylj-7- | f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-8-oxo-5-thia-l- aza-bicyclo

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£ 4,2.Oj oct-2-ene, syn-isomer, Ε-form, in a mixture of 15 ecm of formic acid and 15 ecm of water. It is concentrated under 0.05 mm Hg (0.007 kPa) at 50 ⁰ C to dryness, the residue is taken up three times with 150 cc 'ethanol, whereby (2.7 kPa) is evaporated off each time under 20 mmHg at 20 ⁰ C. The solid is then taken up in 25 ml of ethanol

29, .9.1980

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of 45 C _1, stirred for 30 min, allowed to cool and filtered. After drying, one obtains 0.39 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido] -2-carboxy-3,6-dioxo-4-β (2 -glycylaminoethyl) -l, 4,5,6-tetrahydro-l, 2 _# 4-triazin-3-ylJ-2-thiovinylJ-8-oxo-5-thia-1-aza-bicyclo φ-, 2.0) oct-2-ene, syn isomer, Ε-form, as formate in the form of a yellow powder,

-1 Infrared Spectrum (KBr), characteristic bands (cm) 3700-2200 _f 1765, 1705, 1675, 1610, 1585, 1530, 1035,

NMR ~ proton spectrum

(350 MHz, DMSO dg, </ "in ppm, O in Hz) 3.2-6.6 (m, 8H, -SCH ₂ -, ^ -NCH ₂ CH ₂ N ^ and -COCHgN CT); 3, 85 (s, = N0CH _3); 5.12 (d, 0 = 4, H _5); 5.67 (dd, 3 = 4 and 9, H _7); 6.35 (d, O = 16 - CI ^ = CHS-), 6.73 (s, H of the thiazole), 7.15 (s wide, -NH ₂ ), 8.2 (s, H of the formate), 8.6 (m, -CH ₂ NhICO-); 9.54 (d, O = 9, -NHCO-).

The 3-f4- (2-aminoethyl) -5,6-dioxo-l, 4,5,6-tetrahydrol, 2,4-triazin-3-ylJ-2-thiovinyl) -2-benzhydryloxycarbonyl ~ 7- £ 2-methoxyimino-2- (2-1-rylamino-4-thiazolyl) -acetamide idol-8-oxo-S-oxide-S-thia-1-aza-bicyclo f4.2.0j oct-2-ene, syn isomer, Ε-shape, can be made in the following way:

To a solution of 40 ⁰ C of 3.36 g of 2-benzhydryloxycarbonyl-3 / C 4 (2-t-butoxycarbonylaminoethyl) -5 _f 6-dioxo-l, 4,5,6-tetrahydro-l, 2,4 -t riazin-3-yl3-2-thiovinyl-3-7-i'-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido-1-S-oxo-5-oxide-5-thia-1-aza bicyclo /^4.2.0^ oct-2-en, syn-isomer, Ε-form (prepared as described in Example 28) in

29.9.1980 AP C 07 D / 221 271 "2 2 1 2 7 1 - W -., 57 466 / lJL

45 ecm acetonitrile is added dropwise over 10 min. A solution of 1.14 g of p-toluenesulfonic acid hydrate in 15 ecm acetonitrile. The mixture is stirred for 2 h at 40 C and allowed to cool. Place 100 ecm of a half-saturated sodium bicarbonate solution, stir vigorously for 1 h and filter. After drying, 2.73 g of 3-£ 4 4-((2-aminoethyl) -5,6- are obtained.

29.9.1980 AP C 07 D / 221 2 2 12 7 1 - 500 - 57 466/11

2-thiovinyl J-2-benzhydryloxycarbonyl-7-O-2-methoxyimino-2- (2-tritylamino-4-thiazolyl) acetamido-O-oxo-5-oxide-5-thia-1-aza-bicyclo f4.2 , 0j oct-2-ene, syn isomer, E ~ form, in the form of a brown powder,

~ 1 Infrared Spectrum (KBr) ₁ characteristic bands (cm) 3260-2300, 1800, 1715, 1685, 1595, 1520, 1500, 1450, 1215, 1180, 1040, 945, 755, 700.

NMR proton spectrum

(350 MHz, DMSO d _B, CTin ppm, D in Hz) 3.08 (m, 2H ^ ₁ N-CH ₂ CFl ₂ -NH _2); 3.63 and 4.30 (2d, D = 18, 2H, -SCH ₂ -); 3.85 (s, 3H, = NOCH ₃ ); 4.09 (t, 0 = 6, 2H, ^> NCH ₂ CH ₂ NH ₂ ); 5.07 (d, 0 = 4, H ₅ ); 5.87 (dd, O = 4 and 9, H ₇ ); 6.80 (s, H of thiazole); 6.95 (s, -COOCHO; 7.07 and 7.13 (2d, D = 16, -CH = CH-); 9.0 (d, O = 9, -NHCO-); 12.62 (s broad, -NH-triazine).

Example 64

To a solution of 2 g of 3-jr4- (2-aminoethyl) -5,5-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl3-2-thiovinyl J-2 benzhydryloxycarbonyl-7-C2-methoxyimino-2- (2-t-ritylamino-4-thiazolyl) -acetamido J-8-0X0-5-thia-1-aza-bicyclo / "4,2.Oj oct-2-ene, syn isomer , Ε-shape, in 60 cc tetrahydrofuran is added at 20 C with stirring, a solution of 0.5 g of potassium bicarbonate in 1.5 cc of water and 0.16 cc Methylchlorf ormiat. it is stirred for 1 h 30 min. at 20 ⁰ C and After 1 h 30 min, dilute with 100 ecm of tetrahydrofuran, dry over sodium sulfate, filter and concentrate to dryness under 20 mmHg (2.7 kPa) at 30 ° C. Fix the product to 5 g Silica gel Merck (0.06-0.2) and chromatographed on a column of 25 g silica gel Merck (0.06-0.2) (column diameter 1.5 cm, height 15 cm), eluting with 500 ecm one

29.9.1980 AP C 07 D / 221 2 2 12 7 1 - 50/1 _ 57 466/11

Cyclohexane-ethyl acetate mixture (40-60 vol.), 500 ecm of a 20-80 (VoI.) ~ Mixture and 500 ecm of ethyl acetate, to obtain fractions of 25 ecm. Concentrating the fractions 19-32 at 20 ⁰ C under 20 mmHg (2.7 l <Pa) and obtains 0.7 g of 2-ßenzhydryloxycarbonyl ~ 3- £ k5,6-dioxo ~ 4- (2-methoxycarbon'ylaminoethyl) -l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl3-2-thiovinyl5-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamidoJ-S-oxo -S-thia-1-aza-bicyclo f4.2.03, oct-2-ene, syn isomer, Ε-form, in the form of a yellow powder.

•• I Infrared Spectrum (KBr), characteristic bands (cm) 3400, 3300, 1790, 1720, 1690, 1590, 1525, 1495, 1450, 1040, 755, 740, 700

A mixture of 0.7 g of 2-benzhydryloxycarbonyl-3-f5,5-dioxo-4- (2-methoxycarbonylaminoethyl) -1,4,5,6-tetrahydro-1,2-diene is treated at 50 ° C. for 40 minutes , 4-triazin-3-ylJ-2-thiovinyl-7- / 2-methoxyimino-2- (27-tritylamino-4-thiazolyl) acetamidoj-S-oxo-S-thia-1-aza-bicyclo / C4.2.0 j oct-2-ene, syn-isomer, E-form, 10 ecm formic acid and 5 ecm water. The mixture is filtered and concentrated at 30 C under 0.05 mm Hg (0.007 kPa) to dryness, taken up with four times 50 cc of ethanol to obtain concentrated each time to dryness (below 20 mm Hg; 2.7 kPa) at 20 ⁰ C and subsequently triturated again in 30 ecm of ethanol, filtered, washed with twice 20 ecm of diethyl ether and dried. 0.35 g of 7-f2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-J-2-carboxy-3-one-half- _{liter of} 6-dioxo-4- (2-methoxycarbonylaminoethyl) -1 L, 4 _{L is obtained} 5,6-tetrahydro-1,2,4-triazin-3-yl3-2-thiovinylj-8-oxo-5-thia-1-aza-bicyclo 4.24,2.dJ oct-2-ene, syn isomer, Ε Shape, in the form of a yellow powder.

Infrared spectrum (KBr), characteristic bands (cm) 3340, 3210, 3100, 2200, 1770, 1710, 1685, 1625, 1590, 1530, 1035, 945

, - 29.9.1980

AP C 07 D / 221 271 221271 - .502 / .. ₅₇ 466 / n

NMR proton spectrum

(350 MHz ₁ DMSO _dβ , (/ * in ppm, 3 in Hz) 3.55 (s, 3H, -COOCH ₃ ), 3.62 and 3.79 (2d, 0 = 18, 2H, -SCH ₂ -), 3.85 - 3.93 (mt, 5H, N0CH = ₃ and rs N CH ₂ -);. 5.19 (d, 0 = 4, IH, H in 6); 5.75 (dd, 3 = 4 and 9, IH, H in 7), 6.74 (s, IH, H of the thiazole), 9.58 (d, 0 = 9, IH, -CONH-), 12.53 (s wide, IH, = N NH CO- or = NN = C-)

OH

The 3-C4- (2-amino-ethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-

^ 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido3,8-oxo-5-thia-1-aza-bicyclo / 4,2,2-octo-2-ene, syn isomer, Ε-form , can be made in the following way:

A solution of 25 g of 2-benzhydryloxycarbonyl-3-t ^ 4- (2-t-butoxycarbonylaminoethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1 is treated at 40 ^° C. for 1 h, 2, A- triazin-3-yl] .- 2-thiovinyl? -7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido3-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, syn isomer, Ε Form, (obtained as described in Example 28 above) in 170 ecm of acetonitrile with a solution of 8.4 g of p-toluenesulfonic acid in 100 ecm of acetonitrile. The resulting gummy precipitate is separated by decantation from the supernatant liquid and treated with vigorous stirring with 800 eq of a saturated sodium bicarbonate solution. It is filtered, washed twice with 50 ecm of water and dried in air. 15.3 g of 3 - ^ * 4- (2-aminoethyl) -5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazine-3-yl-J-2-thiovinyl-J-2 are obtained -benzhydryloxycarbonyl-7-] j2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-J-8-oxo-5-thia-1-aza-bicyclo-1,2,2,30-oct-2-ene, syn- Isomer, Ε-form, in the form of a yellow powder,

29.9.1980 AP C 07 D / 221 2 2 12 7 1 - 502? Ι - 57 466/11

Infrared spectrum (KBr), characteristic bands (cm) 3400, 3150-2200, 1785, 1715, 1690, 1585, 1520, 1495, 1445, 1205, 1180, 1160, 1030, 940, 750, 700

, 09/29/1980

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2 2 1 2 7 1 .- 50 * _ _{57 466/11}

Example 65

At 4 ⁰ C is treated a solution of 2 g of 3- ^ f4 (2-aminoethyl) -5,6-dioxo-l, _4,5-f 6-tetΓahydΓO l _{f 2/4-tΓiazin-3-yl3-} 2-thiovinyl-3-2-ben2-hydryloxycaphenyl-7 - / * 2-methoxy-amino-2- (2-tritylamino-4-thiazolyl) -acetamide oj-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2 -en, syn-isomer, E-form _f in 25 ecm of tetrahydrofuran with 0.35 ecm of methyl isocyanate. The mixture is stirred for 2 h at 5 C and 2 h at 20 ⁰ C. It is concentrated under 20 mmHg (2.7 kPa) at 20 ⁰ C to dryness, taken up again in 20 ecm of diethyl ether and filtered. This gives 1.4 g of yellow powder, which is fixed to 10 g of silica gel Merck (0.05-0.2) and chromatographed on a column of 20 g of silica gel Merck (0.06-0.2) (column diameter 1.5 cm, height 15 cm).

It is eluted with 200 ecm of a mixture of cyclohexane-ethyl acetate, 20-80 vol.) And 500 ecm of ethyl acetate, whereby fractions of 25 ecm wins. 2 ₅ under 20 mmHg (2.7 kPa) at 20 ° C to dryness - the fractions are evaporated 15th 0.5 g of 2α-benzhydryloxycarbonyl-3 - // T5,6-dioxo-4-f2- (3-methylureido) -ethyl-1,4,5,5-tetrahydro-1,2,4-triazine is obtained. 3-ylJ} -2-thiovinyl-7-f2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-1-oxo-S-triaza-1-aza-bicyclo-4,2, O. oct. 2-ene, syn isomer, Ε-form, in the form of a yellow powder.

- 1 infrared spectrum (KBr), characteristic bands (cm) 3400, 1785, 1710, 1685, 1585, 1535, 1495, 1445, 1030, 940, 760, 700

29.9.1980 AP C 07 D / 221 2 2 12 7 1 - 503 " ₅₇ 466 / n

A mixture of 0.5 g of 2-benzhydryloxycarbonyl-3-jf /! / F 5,6-dioxo-4-2- (3-methyl-ureido) -ethyl3-l is treated at 50 ^° C. for 40 minutes. 4,5,6-tetrahydro-l, 2,4-triazin-3-ylj, 3,2-thiovinyl-3,7-r2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetamido-1-e-oxo-S; thia-l-aza-bicyclo C4.2.0J 0ct-2-ene _f syn isomer, e-form _f 8 cc of formic acid and 4 cc of water, is filtered, concentrated under mrnHg 0.05 (0.007 kPa) at 30 ⁰ C. to dryness, takes with you

29.9.1980 AP C 07 D / 221 12 7 1 - 50b "57 466/11

four times 50 ecm of ethanol, each time under 20 mmHg (2.7 kPa) at 20 ⁰ C concentrated to dryness and then triturated in 40 ecm of ethanol, filtered, washed with twice 10 ecm of diethyl ether and dried.

This gives 0.3 g of 7- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido3-2-carboxy-3- {rC5,6-dioxo-4-f2- (3-methylureido) -ethyl] -l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl-J-2-thio-vinyl-8-oxo-5-thia-1-aza-bicyclo C4.2.0 J oct-2 en, syn isomer, Ε form, in the form of a yellow powder.

1 infrared spectrum (KBr), characteristic bands (cm) 3320, 3200, 1775, 1710, 1680, 1635, 1585, 1535, 1040,

NMR pVotonenSpektrum

(350 MHz, DMSO _dβ , <Γ in ppm, 0 in Hz) 3.30 (m, 5H, -CH ₂ NH- and ^ s-NC] ^ ₃ ); 3.60 and 3.78 (2d, 0 = 18, 2H, -SCH ₂ -); 3.85 (s wide, 5H, = N0ChI ₃ and> NCH ₂ -); 5.18 (d, 0 = 4, IH, H ₆ ); 5.74 (dd, 0 = 4 and 9, IH, H ₇ ); 6.09 (t, 0 = 6, IH, -NH-CH ₂ -); 6.74 (s, IH, H of the thiazole); 6.82 and 7.12 (2d, D = 16, 2H ₁ -CH = CH-); 9.58 (d, 0 = 9, IH, -CONH-); 12.52 (s, IH, -NH- of the triazine).

Example 66

The mixture is stirred at 50 ⁰ C for 30 min., A solution of 1.19 g of 7- / "2- (2-Am in 0-4 thiazolyl) -2-methoxy (in inoacetamidoj -2-carboxy-3-f 5 , 6-dioxo-4-formylmethyl-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl) -2-thiovinyl J-8-oxo-5-thia-1-aza-bicyclo 4.2.0j oct-2-ene, syn isomer, Ε-shape, and 0.247 g of cysteamine hydrochloride in 30 cc of pyridine. It is concentrated under 0.05 mm Hg (0.007 kPa) at 30 ⁰ C to dryness, taken up in 20 cc of ethanol to , filtered, washed twice with 20 ecm of ethanol and twice 20 ecm of diethyl

29.9.1980 AP C 07 D / 221 "221271 - 50ΐ . 57 466/11

ether. 1.3 g of the pyridine salt of 7 ~ 2 (2-amino-4-thiazolyl) -2-methoxyimino-acetamide idoJ-2-carboxy-3/8-dioxo-l, 4 are obtained , 5,6-tetrahydro-4- (2-1hiazolidinylmethyl) -1,2,4-triazin-3-yl-1-yl-2-thioviny1-8-oxo-5-thia-1-azabicyclo ε 4.2.Oj. oct -2-ene, syn isomer, Ε-form, in the form of a yellow powder,

-1 Infrared Spectrum (KBr), characteristic bands (cm) 3400, 3280, 3200, 2000, 1775, 1710, 1680, 1610, 1380, 1035, 750, 685. ,

NMR proton spectrum

(350 MHz, CF ₃ COOD, ppm S in, O in Hz) 4.32 (s, 3H, -OCH _3); 5.40 (d, D = 4, IH, H in Figure 6); 6.04 (d, D- 4, H in 7); 7.25 and 7.78 (2d, 3 = 16, 2H, -CH = CH-); 7.50 (s, IH, H of the thiazole).

Example 67

One erivärmt at 50 ⁰ C for 20 minutes, a mixture of 1.78 g of 7-f2- (2-Amino-4-thiazolyl) -2-carboxy-3- £ methoxyiminoacetamido3-2-(5,6-dioxo-4 -formylmethy1-1,4,5,6-tetrahydrol, 2,4-triazin-3-yl) -2-thiovinyl3-8-oxo-5-thia-1-azar-bicyclo /! 4.2, O. oct. 2-ene, syn-isomer, E-form, 50 ecm of pyridine and 0.42 g of hydroxylamine hydrochloride. Concentrate under 0.05 mmHg (0.007 kPa) at 30 ⁰ C to dryness, the residue is taken up in 20 ecm of ethanol, filtered, washed with twice 20 ecm of ether and dried. The resulting residue (1 * 3 g) is heated in 20 ecm of water to 60 C, one removes a small insoluble fraction by filtration, allowed to cool, the pH by addition of 3 ecm of acetic acid to 3 and heated to 70 ⁰ C for dissolution. The mixture is filtered, allowed to rise to 20 ⁰ C and then brought to 4 ° C during 2 h After filtration and drying, 0.8 g of 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino- acetamido'l-

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2-ca rboxy-3- ^ 5, ö-dioxo ^ - (2-hydroxy in ethyl) -1,4,5,6-tetrahydro-1,2,4-triazin-3-yl] -2-thiovinyI ^ -8-oxo-5-thial ~ aza-bicyclo £ 4.2.Oj oct-2-ene, mixture of isomers syn, syn, E and syn, anti, E, in the form of a cream-colored powder.

- 1 infrared spectrum (KBr), characteristic bands (cm) 3700 - 3200, 1770, 1710, 1680, 1585, 1530, 1040, 940

NMR proton spectrum

(350 MHz, CF ₃ COOD, (T in ppm, O in Hz) 3.89 (s, 2H, -SCH ₂ -); 4.30 (s, 3H, -OCH); 5.39 (d, 0 = 4, IH, H in 6), 6.04 (d, 0 = 4, IH, H in 7), 7.28 and 7.77 (2d, O = 16, 2H, -CH = CHS-); 7.50 (s, IH, H of the thiazole).

Example 68

A mixture of 2.9 g of 2-Benzhydryloxycarbony1-3- £ Γ4- (2,2-dimethoxyethyl) -5,6-dioxo-1,4,5,6-tetrahydro-1,2 is heated under reflux for 24 h, 4-triazin-3-yl] -2-thiovinyl-7 - / * 2-methoxyimino-2- (2-tritylamino-4-thiazolyl) -acetarnido] -8-oxo-5-thia-1-aza-bicyclo [4] , 2.0j oct-2-ene, syn-isomer, e-form, 50 ecm tetrahydrofuran and 0.49 g methoxyam-ηη hydrochloride. Concentrate under 20 mmHg (2.7 kPa) at 30 ⁰ C to dryness, triturate in 20 ecm of water, filtered, washed with twice 10 ecm of ethanol and dried. 0.92 g of 2-ßenzhydryloxycarbonyl-3-5 f5,6-dioxo-4- (2-methoxyiminoethyl) -1, 4,5,6-tetrahydro-1, 2,4-triazin-3-yl3-2 are obtained -thiovinyl-7-p-2-methoxyimino-2 ~ (2-tritylamino-4-thiazolyl) acetamido ^ -S-oxo-S-thia-1-aza-bicyclo; 4,2.03oct-2-ene, mixture of Isomers syn, E, syn and anti, E, syn.

- 1

Infrared spectrum (KBr), characteristic bands (cm) 3700 - 2500, 1785, 1715, 1685, 1585, 1550, 1495, 1450

09/29/1980

AP C 07 D / 221 2 2 1 2 7 1 _r 509 - 57 465/11

1050, 950, 745 and 700

NMR proton spectrum

(350 MHz, DMSO dg, <Tin ppm, 3 in Hz) 3.35 (s, 3H, -CH = NO-CH ₃ ); 3.70 and 3.90 (2d, D = 18, 2H, -SCH ₂ -); 3.95 (s, 3H, = NOCH ₃ ); 5.30 (d, D = 4, IH, H in Figure 6); 5.88 (dd, 0 = 4 and 9, IH, H in 7); 6.95 and 7.05 (2d, Ό = 16, 2H, -CH = CH-); 9.84 (d, 0 = 9, IH, -CONH-); 12.70 (s, IH, = N NH CO- or = NN = C-)

OH

The mixture is stirred at 50 C for 30 min. A solution of 0.85 g of 2-benzhydryloxycarbonyl-3-r5,6-dioxo-4- (2-methoxyiminoethyl) -1, 4,5,6-tetrahydro-l, 2nd , 4-triazin-3-yl) -2-thiovinyl-7: 2-methoxyimino-2- (2-ethyl-4-thiazolyl) -acetamido-S-oxo-S-thia-1-aza-bicyclo.RTM .Oj oct-2-ene, syn mixture of isomers, e, syn and anti, e, syn, ECM 20 in formic acid and 15 cc of water. It is concentrated unter.0,05 mmHg (0.007 kPa) at 45 ⁰ C to dryness , the residue treated with 40 cc of ethanol is taken up, evaporated under 20 mmHg (2.7 kPa) at 20 C for Trockne.und repeating this operation twice. It is triturated the resulting yellow solid in 20 cc of ethanol at 50 ⁰ C, allowed to cool and The mixture is filtered, yielding 0.44 g of 7-C2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamidoj-2-carboxy-3-5,5,6-dioxo-4- (2-methoxyiminoethyl) -1,4 , 5,6-tetrahydro-1,2,4-triazin-3-yl-Q-2-thiovinyl-3-8-oxo-5-thia-1-aza-bicyclo [4.2.0] oct-2-ene, mixture of isomers syn , syn, E and syn, anti, E, in the form of a yellow powder.

1 infrared spectrum (KBr), characteristic bands (cm) 3700-2000, 1775, 1710, 1690, 1630, 1585, 1550, 1050,

29.9.198ο

AP C 07 D / 221

22 127 1 - 5 * ο _{57 465/11}

NMR proton spectrum

(350 MHz, DMSO _dβ , </ "in ppm, J in Hz) 5.24 (d, 3 = 4, IH, H in 6), 5.80 (dd, 3 = 4 and 9, IH,

H in 7); 6.95 and 7.10 (2d, 3 = 16, 2H, -CH = CH-); 9.77

(d, 3 = 9, IH, -CONH-).

29.9.1980 -

cAA_AP C 07 E / 221

22 1 27 1 " ⁵ ^ 57 466/11

The invention also relates to pharmaceutical compositions containing active product of at least one compound of general formula I in the pure state (in the free form or in the form of a salt) or in the form of a composition, together with one or more pharmaceutically acceptable additives. The medicines can be used orally, parenterally or rectally.

As solid compositions for oral administration, tablets, pills, powders or granules may be used. In these compositions, the active product of the invention is mixed with one or more inert diluents or additives, such as sucrose, lactose or starch. These compositions may also contain other substances than the diluents, for example a lubricant, such as magnesium stearate.

As liquid compositions for oral administration it is possible to use pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents, such as water or paraffin oil. These compositions may also contain substances other than the diluents, for example humectants, sweeteners or flavoring agents Medium.

The compositions for parenteral administration may be sterile aqueous or nonaqueous solutions, suspensions or emulsions. As the solvent or vehicle, there may be used propylene glycol, a polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, for example, ethyl oleate. These compositions may also contain additives, in particular humectants or wetting agents, emulsifiers or

29.9.1980 AP C 07 D / 221 2 2 1 2 7 1 _ 5Λλ ~ 57 466/11

Dispersant. The sterilization can be done in several ways, for example by means of a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or

29.9.1980 AP C 07 D / 221 22 127 1 -S12> - 57 466/11

by heating. They may also be prepared in the form of solid sterile compositions which are dissolved at the time of use in sterile water or any other injectable sterile medium.

The compositions for rectal administration are suppositories which may contain excipients other than the active product, such as cocoa butter or suppository wax.

In human therapy, the pharmaceutical compositions of the invention are particularly valuable in the treatment of infections of bacterial origin.

In a general way, the physician will determine the dosage or posology that he most suitably holds, as a function of age, weight, degree of information, and other factors inherent in the patient being treated. In general, the dosages are 1-10 g per day of the active compound by oral, intramuscular or intravenous route in the adult.

The following example is illustrative of a composition of the invention without any limitation.

29.9.1980 AP C 07 D / 221 271 22 127 1.-SIH- .57466 / 11

An injectable solution of the following composition is prepared:.

Sodium salt of 7- / 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -2-CaTbOXy-S- C ( 5,6-dioxo-4-formylmethyl-1,4,5,6-tetrahydro) l, 2,4-t-riazin-3-yl) -2-thiovinyl] -8-oxo-5-thialazza-bicyclo [4.2-O] oct-2-ene (syn isomer, E-form) aldehyde hydrate 267 mg

Sodium chloride 1.5 mg

injectable solvent 2 ecm

This solution contains 250 mg of active product, calculated as the acid-free aldehyde.

Claims (2)

29.9.1980 AP C 07 D / 221 2 2 1271 - 5 / l5 ~ 57 466/11 claim for invention 1. methyl, L-2-amino-2-carboxyethyl or phenyl, 2. 2-pyridyl, optionally N-oxidized, 3. 2-pyrimidinyl or 3-pyridazinyl substituted in the 6-position by a methyl or acetamido radical, and optionally N-oxidized, 4. 5,6-0,10X0-1,4,5, δ-tetrahydro-1,2,4-triazin-3-yl, substituted in the 4-position a) an alkyl radical having 1-3 carbon atoms, an alkyl radical having 1 or 2 carbon atoms, substituted by an alkyloxy, alkylthio, phenyl, formyl, carbamoyl, alkylcorbamoyl, dialkylcarbamoyl, alkyloxycarbonyl or 2-thiazolidinyl radical, b) an allyl radical or 2,3-dihydroxypropyl radical, c) an alkyl radical having 2 or 3 carbon atoms, substituted by hydroxy, carbamoyloxy, acyloxy (unsubstituted or substituted by amino), 09/29/1980 AP C 07 D / 221 271 2 12 7 1 - ^ ^S - ⁵⁷ .466 / 11 Amino, alkylsulfonylamino. Acylamino (unsubstituted or substituted \ by amino), alkyloxycarbonylamino, ureido, alkylureido or d) a radical of general formula II, wherein Alk is alkylene having 1 or 2 carbon atoms, X * and Y ¹ * represent oxygen atoms, R * ⁴ alkyl radicals and R ^{0 represents} a hydrogen atom, 29.9.1980 AP C 07 D / 221 22 1 27 t-b-Zfl- 57 466/11 e) an alkyl radical having 1-3 carbon atoms, substituted by an alkyloxyimino or hydroxyimino radical, 4 ', l, 3,4 ~ triazole ~ 5 ~ yl or 2-alkyloxycarbonyl-l, 3,4-triazol-5-yl, which are substituted in the 1-position by a radical of general formula II, as defined above or by a formylalkyl or 2,3-dihydroxypropyl radical; , , 5. l, 4-dialkyl-5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl; 1-alkyl-5,6-dioxo-1,4,5,6-tetrahydro-1,2,4-triazin-3-yl or 2-alkyl-5,6-dioxo-l, 2,5,6- tetrahydro-l, 2,4-triazin-3-yl, 6. 1-alkyl-o-alkyloxycarbonyl-1-triazole-5-yl, 7. a) l, 3,4-thiadiazol-5-yl, unsubstituted or substituted by an alkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or acylaminoalkyl radical, b) l, 2,4-th-iadiazol-5-yl, substituted by an alkyl radical, 8. a) l, 3,4-oxadiazolyl-5-yl, substituted by alkyl or phenyl, b) 4-alkyl-2-oxazolyl, 9. 5-tetrazolyl, substituted in the 1-position by a) an alkyl radical, unsubstituted or substituted by formyl, b) an alkyl radical having 2 or 3 carbon atoms, 29.9.1980 AP C 07 D / 221 2 1 2 7 1 - ^ O - 57 466/11 substituted by hydroxy, amino, alkylamino, dialkylamino, acylamino, or c) a radical of general formula II as defined above; 09/29/1980 AP C 07 D / 221 271 1. 'alkyl, L-2-amino-2-carboxyethyl, phenyl, 2. 2-pyridyl, 3-pyridyl or 4-pyridyl and their N-oxides, 3. 2-pyrimidinyl, 3-pyridazinyl, substituted in the 6-position (by an alkyl, methoxy, amino or acylamino radical) 29.9.1980 AP C 07 D / 221 2 1271 * ⁵ ^ - 57 465/11 rest) and optionally N-oxidized or tetrazoles »-Γ4 ^ 5-b3-pyridazin ~ 6-yl, 4, 5,6-D 10x0-1,4,5,6 ^ etrahydro-1,2,4-triazin-3-yl, substituted in the 4-position; l, 3,4-triazol-5-yl or 2-alkoxycarbonyl-l, 3 _/ 4-triazol-5-yl _/ which are substituted in! -Location a) is an alkyl radical, unsubstituted or substituted by an alkyloxy, alkylthio, phenyl, formyl, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, acyl, alkyloxycarbonyl or 2-thiazolidinyl radical, b) by an allyl , 2,3-dihydroxypropyl, l _t 3-dihydroxy-2-propyl, 2-formyl-2-hydroxyethyl- _t 3-formyloxy-2-hydroxypropyl, 2,3-bis-formyloxypropyl or 1,3-bis-formyloxy-2-propyl radical, c) by an alkyl radical having 2-4 carbon atoms substituted by a hydroxy, carbamoyloxy, acyloxy (whose acyl part may be substituted by an amino, alkylamino or dialkylamino radical), alkylsulfinyl, alkylsulfonyl, amino, alkylamino , Dialkylamino, suifamino, alkylsulfonylamino, suifamoylamino, acylamino (whose acyl part is optionally substituted by hydroxy, amino, alkylamino or dialkylamino), alkyloxycarbonylamino, ureido, alkylureido, dialkylureido, d) by a radical having one of the general formulas: 29.9.1980 AP C 07 D / 221 127 1 - ^5/1 >"57 455/11 - Alk - C II R ^ß or -ChU-CHOH-CH III wherein Alk is an alkyl radical having 1-4 carbon atoms, X "* ¹ and Υ · * · are the same and are oxygen or sulfur atoms and R * ^{4 is} an alkyl radical or X ** and Y * ^{4 are the} same or different and represent oxygen or sulfur atoms and the radicals R ⁰ * together represent an alkylene radical having 2 or 3 carbon atoms and R ° represents a hydrogen atom or an alkyl radical having 1-3 carbon atoms, e) by an alkyl radical having 1-5 carbon atoms, substituted by an alkyloxyimino or hydroxyimino radical,. ₄ 5. l, 4-dialkyl-5,6-dioxo-l, 4,5,6-tet rahydr-o-l, 2,4-t-riazin-3-yl; l-alkyl-5,6-dioxo-l, 4,5,6-tetrahydro ~ l, 2,4-triazin-3-yl; 2-alkyl-5,6-dioxo-1, 2,5,5-tetrahydro-I ₁ 2,4-triazin-3-yl; 6 · l, 3,4-triazol-5-yl; 1,2,3-triazol-S-yl or 1-alkyl-1,2,4-triazol-5-yl, unsubstituted or substituted in the 3-position by allyloxycarbonyl, 7, a) l, 3,4-thiadiazol-5-yl, unsubstituted or substituted by an alkyl, trifluoromethyl, alkyloxy, alkylthio, hydroxyalkylthio radical whose alkyl part contains 2 to 4 carbon atoms, alkylsulfonyl, hydroxy , Hydroxyalkyl, carboxy, carboxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, acylamino or acylaminoalkyl radical, .29.9.1980 AP C 07 D / 221 271 2 1271 - ^ ⁹ - 57 466/11 b) l, 2,4-thiadiazol-5-yl, substituted by an alkyl or alkyloxy radical, 8. a) l, 3,4-oxydiazol-5-yl, unsubstituted or substituted by an alkyl, trifluoromethyl, phenyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or acylaminoalkyl radical, b) 2-oxazolyl or 4-alkyl-2-oxazolyl, 9, 5-tetrazolyl, unsubstituted or substituted in the 1-position a) an alkyl radical, unsubstituted or substituted by alkyloxy, sulfo, carboxy, formyl or sulfamoyl, b) an alkyl radical having 2-4 carbon atoms substituted by hydroxy, amino, alkylamino, dialkylamino. Acylamino, carboxyalkylamino, sulfamoylamino, sulfamino, ureido, alkylureido or dialkylureido, c) an alkyl radical having 1-5 carbon atoms, substituted by hydroxyimino or alkyloxyimino, d) a phenyl, 2,3-dihydroxypropyl, 1,3-dihydroxy-2-propyl, 2-formyl-2-hydroxyethyl, 3-formyloxy-2-hydroxypropyl, 2,3-bis-formyloxy- propyl or 1,3-bis-formyloxy-2-propyl radical, or e) a radical of general formula II, wherein R is a hydrogen atom, or a radical of general formula III; 29.9.1980 AP C 07 D / 221 271 2 21 27 1 - 5 * ° -. 57 465/11 the symbol R represents a hydrogen atom or an alkyl, vinyl or cyanomethyl radical, and the symbol R 'is a hydrogen atom or a readily enzymatically eliminable radical of the general formula 09/29/1980 AP C 07 D / 221 271 22 1 27 1 ../5*1 .. 57 456/11 - CH - OCOR ¹ " R " in which R "denotes a hydrogen radical or an alkyl radical and R" ^{1 represents} an alkyl radical or the cyclohexyl radical, wherein the abovementioned alkyl or acyl moieties and moieties (unless specifically indicated) are straight or branched and contain 1-4 carbon atoms, in their syn or anti forms and the E or Z forms and their mixtures and their addition salts with acids, their metal salts and their addition salts with nitrogenous bases, characterized in that a) in the event that the radical R contains no substituent of the general formula -Alk-CH (OH) OR **, one acid of the general formula C - COOH Il wherein R is as defined above, and the amine function has been previously protected (and the oxime, if R ^{0 is} hydrogen) or a reactive derivative of this acid with a 7-amino-cephalosporin of the general formula 29.9.1980 AP C 07 D / 221 2 1271 - .51% - 57 466/11 - CH = CH - SR COOR where R is as defined above, R is a hydrogen atom, a radical of the general formula - CH OCOR ¹ "
ι
R " as defined above, or an easily eliminable protecting group, and η has the meaning of O or 1, and then, if η = 1, reducing the resulting oxide and splitting the protective groups and then optionally the product obtained in an addition salt with an acid, in converts a metal salt or an addition salt with a nitrogen-containing base; or b) in the event that the radical R contains no substituent of the general formula -Alk-CH (OH) OR ** ·, one thiol (free or in the state of the alkali or alkaline earth metal salt) having the general formula R - SH (wherein the substituent R, as defined above, is protected in the acetal state, defined by 09/29/1980 AP C 07 D / 221 2 2 1 2 7 1 "5 ^ 3. ₅₇ 466/11 general formulas -Alk-CR ¹ ^ (X * R *) (Y ^ R * *) and -CH ₂ CHOH-CH (X ** R ^ (Y * R ^) in which R represents a formyl or acylalkyl radical) with a cephalosporin derivative (or optionally with an isomeric mixture) of the general formula 09/29/1980 AP C 07 D / 221 271 2 2 12 7 1 -Ö-ty- 57 466/11 " R ₂ - NU J,> »- CH = CH - R COOR in which R ⁰ , R ₁ and η are as defined above, wherein, if η = O, this derivative is in the 2- or 3-Bicyclooctenform, and if η = 1, this derivative is in the 2-bicyclooctene form, wherein the substituent on the carbon atom in the 3-position of the bicyclooctene has the E or Z stereoisomerism, R _{2 represents} a hydrogen atom or a protective group for the amino group, and R, a remainder of the general formulas or -0-CO R " in which R 'is a straight or branched alkyl radical having 1-4 carbon atoms, trifluoromethyl, trichloromethyl radical or a phenyl radical unsubstituted or substituted by a halogen atom or by an alkyl radical or the nitro group, and R "is as defined R or an acylmethyl , 2-acylethyl, 2-acylpropyl, acyloxycarbonylmethyl, 09/29/1980 AP C 07 D / 221 22 127 1 CDC ^{Z Δ} ' * ' ' - O <tO - 57 466/11 Represents 2-alkyloxycarbonylethyl or 2-alkyloxycarbonylpropyl radical, 29.9.1980 AP C 07 D / 221 271 22 127 1.SW. 57 466/11 and, if η = 1, reducing the resulting oxide, if any, to deprotecting and optionally converting the resulting product into an addition salt with an acid, a metal salt or an addition salt with a nitrogenous base; or c) in the event that the radical R does not contain a substituent of the general formula -Alk-CH (OH) OR ⁰ *, a thiol ester of the general formula R ₂ -NH ~ C - CO - S - R II wherein R, R "and R are as defined above, wherein, if R is a hydrogen atom, the oxime may be protected if R has an amino, alkylamino, formyl or acylalkyl substituent, this is protected, and if R has a hydroxy or carboxy substituent, this is present in free form or protected}, with a 7-amino-cephalosporin of the general formula 0 = 1 N ν, TT CH = CH-R ₃ COOR ₁ wherein R ₁ , R, and η are as defined above, and which has the same stereoisomerism as that 29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 - ⁵ ^ - ⁵⁷ 466/11 defined above product if η = 1 reduces the oxide obtained if there is reason to eliminate the 'protecting groups and optionally converting the obtained product into an addition salt with an acid, a metal salt or an addition salt with a _{nitrogen-f-containing} base; or d) in the event that the radical R contains no substituent of the general formula -Alk-CH (OH) OR *, a thiourea of the general formula R ₂ NH CS NH ₂ used, wherein R _{2 is} a hydrogen atom or a protective group, with a compound of the general formula tf) " Hal CH ₀ CO C CONH ² Il wherein R, R, η and R are as defined above and Hai represents a chlorine or bromine atom, and then, if η = 1 reduces the oxide obtained, if necessary, cleaves the protecting groups and optionally the product obtained in an addition 6 salt with an acid, a metal salt or an addition salt with a nitrogenous base converts; or 29.9.1980 AP C 07 D / 221 271 2 2 1 2 7 1 - SM _ sy 466/11 e) in the event that the radical R is a 5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl radical substituted in the 4-position, a 1,3 , 4-triazol-5-yl or 2-alkyloxycarbonyl-l, 3,4-triazol-5-yl-rest, which are substituted in the 1-position by an alkyl radical having 2-4 carbon atoms, which itself by a Carbamoyloxy or acyloxy group (whose acyl part is optionally substituted by an amino, alkylamino, or dialkylamino) is substituted, it is a compound of the general formula -CH = CH-S- (Q) ^ OH COOR (wherein R, R ₁ and η are as defined above, R '~ is a protecting group and - (R) -Alk ¹ OH is a 5,6-dioxo-4-hydroxyalkyl-l, 4,5,6-tetrahydro-1 2,4-triazin-3-yl- _f l -hydroxyalkyl-l, 3,4-triazol-5-yl or 2-alkyloxycarbonyl-l-hydroxyalkyl-1-hydroxybenzyl-5-yl radical), by any known method of obtaining a carbamate or an ester from an alcohol without altering the remainder of the molecule, optionally, reducing the resulting oxide, deprotecting, and optionally recovering the resulting product into an addition salt with an acid, a metal salt or converting an addition salt with a nitrogenous base; or 29.9.1980 AP C 07 D / 221 271 22 1 27 1. S * ° l _ 57 466/11 f) in the event that the radical R is a 5,6-dioxo-l, 4,5,6-tetrahydro-l, 2,4-triazin-3-yl radical substituted in the 4-position, a l _f 3i4-triazol-5-yl or 2-alkyloxycarbonyl-l, 3,4 ~ triazol-5-yl radical which are substituted in the 1-position by an alkyl radical having 2-4 carbon atoms, which itself is replaced by a sulfamino , Alkylsulfonylamino, sulfamoylamino, acylamino 2 2 1 2 7 1 - 09/29/1980 AP C 07 D / 221 57 465/11 (the acyl moiety of which is optionally substituted by hydroxy, amino, alkylamino or dialkylamino), alkyloxycarbonyl-amino, ureido, alkylureido or dialkylureido, or represents a 1,3,4-thiadiazol-5-yl residue represented by an acylamino - or acylaminoalkyl radical, or represents a l, 3,4 ~ 0xadiazol ~ 5-yl ~ rest, which is substituted by an acylaminoalkyl radical, or, represents a 5-Tet'razolylrest., Which in the! -position by an alkyl radical substituted with 2-4 carbon atoms which is substituted by an acylamino, suifamoylamino, suifamino, uireido, alkylureido or dialkylureido group, a compound of the general formula R ' ₂ NH. CH = CH-S- NH, wherein R, R and η are as defined above, R 'is a protective group and - ^ 2s -NHp is ^a 5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazine-3 yl-rest substituted at the 4-position, a 1,3,4-triazol-5-yl or 2-alkyloxycarbonyl-l, 3,4-triazol-5-yl radical substituted in the 1-position are substituted by an aminoalkyl radical (having 2-4 carbon atoms), or a 1, 3,4-thiadiazol-5-yl radical substituted by an amino or aminoalkyl radical, or a 5-tetrazolyl radical substituted at the 1-position by a 29.9.1980 AP C 07 D / 221 2 12 7 1 " 554 - 57 466/11 Aminoalkyl radical (having 2-4 carbon atoms), by any known method of forming an amide, sulfamide, carbamate or urea function, without attacking the remainder of the molecule, and then, if η = 1, reducing the resulting oxide, cleaves the protecting groups and then optionally converts the product obtained into an addition salt with an acid, a metal salt or an addition salt with a nitrogenous base; or 29.9.1980 AP C 07 D / 221 271 2 2 12 7 1 ... 532 - 57 466/11 g) in the event that the R radical R is a 5,6-dioxo-l, 4,5,6-tetrahydro-1,2,4-triazin-3-yl radical substituted in the 4-position, a " !, S ^ -triazol-S-yl or 2-Alkyloxycarbonyl ~ l, 3,4-triazol-5-yl-rest, which are substituted in the 1-position, by a 2-Thiazolidinylalkylrest, by an -A- CH (OH) OR * radical or by a hydroxyiminoalkyl radical or alkyloxyiminoalkyl radical whose iminoalkyl part contains 1-5 carbon atoms, or a 5-tetrazolyl radical substituted in the 1-position by a hydroxyiminoalkyl radical or an alkyloxyiminoalkyl rust whose iminoalkyl part contains 1-5 carbon atoms, is an addition reaction of cysteamine, an alcohol, hydroxylamine or an alkyloxyamine with a compound of general formula R ₂ NH - CH = CH-S- Ik ¹ CHO wherein R, R ₁ and R _{p are} as defined above, and -JRJ-Alk ¹ -CHO is a 5,6-dioxo-4-formylalkyl-1,4,5,6-tetrahydro-1,2,4-t riazin-3-yl, 1-formylalkyl-1,3,4-triazol-5-yl, 2-alkyloxycarbonyl-1-formylalkyl-1,3,4-triazol-5-yl or 1-formylalkyl-5 tetrazolyl radical, carried out by any known method for preparing such addition derivatives of carbonylated functions, then removed the protective groups and optionally the product obtained in an addition salt with an acid, a metal 29.9.1980 AP C 07 E / 221 2 1 2 7 1 - ⁵ ^ -. 57 466/11 salt or an addition salt with a nitrogenous base converts; or 09/29/1980 AP C 07 D / 221 271 2 2 12 7 1 "^^ ^{'57 45} S / ¹¹ h) in the event that the radical R ^{1 is} a radical of the general formula -CH- OCO R " ¹
ι R " as defined above, characterized by esterifying a compound of formula I in which R ^{1 is} a hydrogen atom by any known method of preparing an ester starting from an acid without attacking the remainder of the molecule then optionally converting the product obtained into an addition salt with an acid, 2 * Process according to item la), characterized in that one acid dor general formula in which R is as defined in point 1 and whose amine function was previously protected by a t-butoxycarbonyl, 2,2'-trichloroethoxycarbonyl, trichloroacetyl, chloroacetyl, trityl, dibenzyl, benzyl, benzyloxycarbonyl , p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, formyl or trifluoroacetyl group. 09/29/1980 AP C 07 D / 221 271 2 2 12 7 1 - ⁵ ^ ⁵⁷ 466/11 3 »process according to point la), characterized in that one acid of the general formula -C- COOH
Il wherein R is a trityl or tetrahydropyranyl or 2-methoxy-2-propyl group as a protecting group for the oxime function. 4e method according to item la), characterized in that one uses a 7-amino-cephalosporin, wherein the easily eliminable radical represented by R. is selected from methoxymethyl, t-butyl, benzhydryl, p-nitrobenzyl and p-Methoxybenzylresten. 5. The method according to item la), characterized by reacting a reactive derivative of the acid of the general formula N'-C-COOH Il wherein R is as defined in item 1 selected from the anhydride, a mixed anhydride, a reactive ester and a halide of this acid. 29.9.1980 AP C 07 D / 221 2 2 1 2 7 1 - 536. 57 466/11 6. The method according to item Ib) _1, characterized in that one carries out the reaction in the presence of a pyridine or a tertiary organic base. 7 »method according to item Ic), characterized in that. a thiolester is used, wherein optionally the radical R is protected by an amino-protecting group as defined in point 2 or in the form of the acetal by a radical of all
or -CH ₂ CHOH-CH (X a radical of the general formula -Alk-CR ^ß (X 8, method according to point Id), characterized in that one converts a thiourea, in whose formula the radical R _? is selected from the t-butoxycarbonyl, 2,2,2-Trichlorethoxyca.rbonyl, trityl, dibenzyl-r, benzyl, benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, formyl or Trifluorocetylreeten. 9. Method according to item Ie), characterized in that a cephalosporin is used in whose formula R ' _{2 is} selected from the amino-protecting groups indicated in point 2, 10 »method according to point If), characterized in that one uses a cephalosporin, in whose formula R'ρ is defined as in point Ie). 11. A method according to item If), characterized in that one protects for the preparation of a compound defined in point If), in which R- a hydroxyl or amino substituent protects these functions in the reagents used. 09/29/1980 AP C 07 D / 221 22 1 27 1 »53T-. _{57 4δ5 / 11} 12, method according to point Ig), characterized in that one uses a cephalosporin, in whose formula Rp is a protective group selected from the amino-protecting groups, listed in point 2. 13. The method according to item 1, characterized in that the radical R in the general formula I is selected from the following Eedeutungen: 1, Process for the preparation of 3-thiovinyl-cephalosporins of the general formula I. N 1 -C-CONH-, f / I / Il -CH = CH-SR COOR ' in / in the symbol R is selected from the following meanings: 2 2 12 7 1 - ^5tH ~ · ^{57 4} 66 / ii the symbol R denotes a hydrogen atom, a methyl radical, vinyl radical or cyanomethyl radical and the symbol R ^{1 represents} a hydrogen atom, wherein the alkyl or acyl radicals or moieties mentioned above (unless specifically indicated) contain 1 or 2 carbon atoms, in the syn or anti forms and the E or Z forms and their mixtures, as well as their addition salts with acids, their metal salts and their addition salts with nitrogen-containing bases,