DD250121A5 - PROCESS FOR PREPARING 2-OXO-1 (((SUBSTITUTED SULPHONYL) -AMINO) -CARBONYL) -AZETIDINENE - Google Patents

Abstract

The invention relates to a process for preparing 2-oxo-1- (((substituted sulfonyl) amino) carbonyl) azetidines of the general formula in which the radicals have the meaning given in the invention claim. These compounds are drugs that have antibacterial activity. Formula (T)

Description

Title of the invention:

Process for the preparation of 2-oxo-1 - [[(substituted sulfonyl) amino] carbonyl] azetidines

Field of application of the invention:

The application of the present. This invention is in the field of drugs for combating bacterial infections in mammals.

Characteristic of the known technical solutions:

Publications which underlie the present invention as prior art are currently unknown.

Aim of the invention: 30

The aim of the invention is to provide new drugs for combating bacterial infections in mammals.

-8.10.86- 378531a

Explanation of the essence of the invention:

The invention has for its object to provide new drugs for combating bacterial infections in mammals ready, which have a broad spectrum of activity.

The invention relates to a process for the preparation of compounds of general formula I.

R, -NH

NC-NH-SO ₀ -R

4- ² .

and pharmacologically acceptable salts thereof, wherein the symbols in the general formula I and in the further course of the description have the following meaning: _o

R means

¹ -ι β Ji

-A, -N NA ₂ -Ci-A ^ N

-A ₁ -N NA

OH

0-

, -NH-A ^ - ^ N-

³ I

or

OH

R .. represents an acyl radical derived from a carboxylic acid;

R ₂ and R ₃ have the same or different meaning and each represents a hydrogen atom, an alkyl group, a

-8.1186- 37853-1

Alkenyl radical, an alkynyl radical ,. a cycloalkyl group, a phenyl group, a substituted phenyl group or a 4-, 5-, 6- or 7-membered heterocycle (hereinafter R), or one of R "and R- represents a hydrogen atom and the other one Azido, halomethyl, di-

halomethyl, trihalomethyl, alkoxycarbonyl, 2-phenyläthenyl-, 2-Phenyläthinyl-, carboxyl- ₍ -CH "X - (wherein X _{1 is} an azido, amino, hydroxyl, carboxyl, alkoxycarbonyl, alkanoylamino, Phenylcarbonylamino, (substituted phenyl) -ca.rbonylamino, 10-alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) -sulfonyloxy, phenyl, substituted phenyl, cyano, 0

Il

Represents -AC-NXgX ₇ - -SX "- or an -OX" radical, where A, X ", X, and X_ have the meaning given below,

LS: '. an -SX_ or -OX "radical (where X ~ is an alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, alkanoyl, phenylalkanoyl, substituted phenylalkanoyl, phenylcarbonyl, represents substituted phenylcarbonyl or a heteroarylcarbonyl radical),

X ^χ τ

I ^ I 3

an -OCX.- or -SCX. -Rest (where one of the radicals X-, 4,4 .i

X ₅ X ₅

and X. represents a hydrogen atom and the other represents a hydrogen atom or an alkyl group, or X.sup.1 and X.

together with the carbon atom to which they are attached represent a cycloalkyl radical and X ₁ - a formyl, alkanoyl, phenylcarbonyl, substituted phenylcarbonyl, phenylalkylcarbonyl, substituted phenylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, substituted Aminocarbonyl or cyano radical), or a radical

0 -AC-NX ₅ X ₇ (where A is a -CH = CH-, - (CH ₂ ) -,

- (CH-) -O-, - (CH.) -NH- or -CH "-S-CH" group means m the 2m. 2 m I £

Has value, 0, 1 or 2, and X, and X _{7 are the} same or different and each represents a hydrogen atom, an alkyl group, a phenyl group or a substituted phenyl group

-8.10.86- 378531

1 or X _{fi represents} a hydrogen atom and X _{7 represents} an amino, substituted amino, alkanoylamino or alkoxy radical, or X, and X ₇ together with the nitrogen atom to which they are attached form a 4, 5, 6- or 7-membered

Heterocycle); 0 0

Il M

A represents a single bond, -NH-C-, -NH- or -NH-NH-C-; A represents a single bond, -NH-, · -CH ₂ -CH ₂ -NH- or

-C-NH-NH-; A .. means - (CH ₀ ) -, where ρ has the value 0 or 1,

0 0 -NH-H-NH-, -NH-C-NH-CH ₂ -, -NH-CH ₂ -, -O-CH ₂ -

fl?

_-CH2-C-NH- or -CH ₀ -C-NH-CH ₀ -; ^l

A ₄ represents -NH-, - (CH ₂ J _p -, - (CH ₂ ) _y -NH-,

0 0 CH ₀ X

Il Il, 2

-NH-C-NH-NH-, -C-NH-NH- or -N-, where X is a hydrogen atom, a carboxyl group or a carbamoyl group. indicates that ρ has the value 0 or 1 and y has the value 2, 3 or 4;

A ₅ represents a single bond, -CH ₂ -, -NH-CH ₂ -, -N = CH- or O.

Il

-C-NH- (CH ₂ ) - where q is 0 or 1; A _fi represents a single bond, -CH = CH- or - (CH ₀ ) -, wherein t is 1, 2, 3 or 4, characterized by reacting a compound of general formula VII

NH ₂ (VII)

"CH C-R-

II ³

NC-NH-SO ₀ -R

acylated with a derived from an R ₁ carboxylic acid R. acyl radical or that a -CO-NH-SO ₀ R activating group in a compound of general formula IX

-8.10.86- 37853-1

j (IX)

introduces

Τ?

1 '

C NH

The symbols used above, such as A ₁ , A ₀ , A ,, A. A _c and A represent radicals with multiple atoms. These radicals are introduced into the illustrated structural formulas in the order in which they are represented, ie from left to right. For example, if R

and A. represents -NH-C-, then the radical R is

-NH-C-N N - "^ - N- ^ OH

and not

Definitions of various terms are given below, which are used to describe the ß-lactams produced according to the invention. These definitions, unless expressly stated otherwise under certain circumstances, apply to the terms throughout the description, either individually or as part of a larger group.

The terms' alkyl 'and' alkoxy * describe both straight and branched chains, radicals having from 1 to 10 carbon atoms are preferred.

-8.10.86- 37853-1

U

The terms "cycloalkyl" and "cycloalkenyl" refer to cycloalkyl and cycloalkenyl radicals having 3, 4, 5, 6 or 7 carbon atoms.

The term 'substituted alkyl' refers to alkyl groups containing one or more (preferably 1, 2 or 3) azido, amino, halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy , Phenyloxy, substituted phenyloxy, mercapto, alkylthio, phenylthio, substituted phenylthio, alkylsulfinyl or alkylsulfonyl radicals.

The terms "alkanoyl", "alkenyl" and "alkynyl" apply to both straight-chain and branched groups, and radicals having from 2 to 10 carbon atoms are preferred.

The terms e 'halogen' and 'halo' refer to fluorine, chlorine, bromine and iodine.

The term "substituted phenyl" refers to a phenyl radical which is substituted by 1, 2 or 3 amino, halogen, hydroxyl, trifluoromethyl, C -C -alkyl, C -C -alkoxy, alkanoyloxy, and aminocarbonyl- or carboxyl radicals is substituted.

The term ¹ A-, 5-, 6- or 7-membered heterocycle "(designated" R ") refers to substituted and unsubstituted, aromatic and non-aromatic radicals containing one or more (preferably 1, 2 or 3) nitrogen radicals. Examples of substituents are oxo, halo, hydroxy, nitro, amino, cyano, trifluoromethyl, C -C -alkyl, C -C -alkoxy, alkylsulfonyl-, Phenyl, substituted phenyl, 2-furfurylideneamino, benzylideneamino, and substituted alkyl radicals wherein the alkyl group has 1 to 4 carbon atoms An example of a 4-, 5-, 6-, or 7-membered heterocycle is the heteroaryl radical . The term

ff It

Heteroaryl means 4-, 5-, 6- or 7-membered aromatic he-

- «man- 37853i

terozyklen. Examples of heteroaryl radicals are substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazolyl , Triazinyl and tetrazolyl radicals. Examples of non-aromatic heterocycles (ie, fully or partially saturated heterocyclic radicals) are substituted and unsubstituted azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidinyl, dihydrothiazolyl, and Hexahydroazepinylreste. Examples of substituted 4-, 5-, 6- or 7-membered heterocycles are 1-alkyl-3-azetidinyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-imidazolidinyl, 3-benzylideneamino 2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl (or substituted phenyl) -2-oxo-1-imidazolidinyl, 3-benzyl-2-oxo-1 imidazolidinyl, 3- (2-aminoethyl) -2-oxo-1-imidazolidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3- [_ [ alkoxycarbonyl) amino] 2-OXO-1-imidazolidinyl -, 3- \ l- {_ { alkoxycarbonyl) -amino] -ethyl-2-OXO-1-imidazolidinyl, 2-0xo-1-pyrrolidinyl ·, 2-oxo-3-oxazole · idinyl-, 4- Hydroxy-6-methyl-2-pyrimidinyl, 2-0xo-1-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydrofuranyl ·, 2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl, 4-alkyl, -2,3-dioxo-1-piperazinyl and 4-phenyl-2,3-dioxo-1-piperazinyl radicals.

The term "substituted amino" refers to a group having the general formula -NXgXg wherein X "represents a hydrogen atom, an alkyl group, a phenyl group, a substituted phenyl group, a phenylalkyl or a substituted phenylalkyl group, and X- represents an alkyl group, a phenyl group, substituted Phenyl group, phenylalkyl, substituted phenylalkyl, hydroxyl, cyano, alkoxy, phenylalkoxy, or an amino group.

The term "acyl" refers to any organic radical derived from an organic acid (i.e., a carboxylic acid) by

^ 7853i

XJ 1 & B

Distance of the hydroxyl group can be obtained. Certain acyl radicals are of course preferred, but this preference should not be construed as limiting the scope of the invention. Exemplary acyl radicals are those acyl radicals which have been used in the past for the acylation of β-lactam antibiotics including 6-aminopenicillanic acid and derivatives thereof and 7-aminocephalosporanic acid and derivatives thereof, cf. for example, "Cephalosporins and Penicillins" edited by Flynn, Academic Press (1972), DE-OS 2,716,677, BE-PS 867,994, US-PS 4,152,432, US-PS 3,971,778, US-PS 4,172,199 and GB-PS 1 348 894. The following list of various acyl radicals gives further examples of the term "acyl! ¹ , but it should not be regarded as limiting the term." Examples of acyl radicals are the following:

the: 0

Il

(a) aliphatic radicals having the general formula R.-C-,

in which R is an alkyl radical, cycloalkyl radical, alkoxy radical, alkenyl radical, cycloalkenyl radical or a cyclohexadienyl radical, or an alkyl or alkenyl radical which is substituted by one or more halogen atoms, cyano, nitro, amino, mercapto, alkylthio or cyanomethyl radicals are.

(b) Carbocyclic aromatic radicals having the general formula

253035

0 CH ₂ -OC-,

-81186- 37853-1

R

O I /

! -CH ₂ -C-

or

wherein η is 0, 1, 2 or 3, R, R and R each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a nitro, amino, cyano, trifluoromethyl group, an alkyl group of 1 to 4 And R represents an amino group, a hydroxyl group, a carboxyl salt, a protected carboxyl group, a formyloxy group, a sulfone salt, a sulfonarnino salt, an azido group, a halogen atom, a hydrazino group, an alkylhydrazino group , a phenylhydrazino group or a [] (alkylthio) thioxomethyl -] - thio radical.

Preferred carbocyclic aromatic acyl radicals are those having the formulas

HO

0 Il

CH ₂ -C-,

ο -7 ο ι: ο α

wherein R is preferably a carboxyl salt or a sulfone salt, and

is.

wherein R is preferably a carboxyl salt or a sulfone salt

(c) Heteroaromatic radicals of the general formulas OB _f - (CH ₂ J _n -C-,.

O I /

R _f -CH-C

O It

, R _{f is} -O-CH ₂ -C-,

0 0 I! Il

in which η is 0, 1, 2 or 3, R is as defined above, and -R- is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1,2, 3 or 4 (preferably 1 or 2) means nitrogen, oxygen and sulfur atoms. Examples of heterocyclic rings are thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Examples of substituents are halogen, hydroxyl, nitro, amino, protected amino, cyano, trifluoromethyl, C ^ -C. alkyl, C. -C alkoxy or

0 Il

HOOC-CH-CH - OC-NH-. I ²

-810.86- 37853i

Preferred heteroaromatic acyl radicals are the radicals of the above formulas in which R- is a 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino 1,2,4-thiadiazol-3-yl, 2-thienyl, 2-furanyl or 6-

5 aminopyridin-2-yl radical.

(d) [[J 4-Substituted-2,3-dioxo-1-piperazinyl) carbonyl] amino] arylacetyl radicals of the general formula

0 0. ,

H ii / \

10 -C-CH-NH-C-N

g ο - ο

in which R is an aromatic radical (including

carbocyclic aromatic radicals, such as those of the general

15 Formula R

^R d

and heteroaromatic groups such as are included in the definition of R), and R, an alkyl group, substitutability ^th alkyl group wherein the alkyl group is substituted with one or more halogen atoms, cyano, nitro, amino or mercapto groups, a Arylmethylenaminorest (ie, -N = CH-R,

wherein R is as defined above), an arylcarbonylamino radical (ie, 0 "5'-NH-CR _g ,

wherein R has the meaning given above) or an alkylcarbonylamino radical.

Preferred [C (4-substituted-2,3-dioxo-1-piperazinyl) carbonyl-amino-aryl-acetyl radicals are those in which R represents an ethyl, phenylmethyleneamino or 2-furylmethyleneamino group.

(e) (Substituted oximino) arylacetyl radicals of the general formula

-CC = NOR. I ^x

37853-1

«- O * W I Sa

in which R has the meaning given above and R.sup.1 is a hydrogen atom, an alkyl radical, a cycloalkyl radical, a

^CH

_X >, 2 or 3 ', -C-COOH

a 2-pyrrazolylmethyl group, a (2-oxo-3-pyrrolidinyl) -

methyl group, an alkylaminocarbonyl group, an arylaminocarbonyl group (i.e., 0

C-NH-R wherein R has the meaning given above) or a substituted alkyl radical (wherein the alkyl radical having one or more halogen atoms, cyano, nitro, amino, mercapto, alkylthio, an aromatic radical defined by R. , Carboxyl (including the salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy

(phenylmethoxy) phosphinyl, dialkoxyphosphinyl or tetrazolyl substituted).

Preferred (substituted oxyimino) arylacetyl radicals are

those in which R represents a 2-amino-4-thiazolyl group.

y Also preferred are the groups in which R. represents a methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl group.

(f) (acylamino) -arylacetyl radicals of the general formula

0 0 If II

 -C-CH-NH-C-R

 I J R

in which R has the meaning given above and R.

a rest

| C

an amino group, an alkylamino radical, a cyanoalkyl

amino group, an amido group, an alkylamido group, a cyano group

37853

Alkylamidorest or the radicals NH NH_

ti r ~ - λ ι ^Δ ii

-CH _n -NH-C- C ^X N, -CH-CH - C-NH-CH ,, 2 -j> 2 3

HO

N -CH - or

means.

Preferred (acylamino) arylacetyl radicals of the above formula are those radicals in which R represents an amino or amido group. Likewise preferred are the radicals in which R represents a phenyl or 2-thienyl group.

(g) [[[3-Substituted-2-oxo-1-imidazolidinyl-1-carbonyl} -amino} -aryl-acetyl radicals of the general formula

Il

0 0 C -

Il H ^ - \

-C-CH-NH-CN NR _n j II ^k R CH_-CH ₉

G

R is as defined above, and R is hydrogen, alkylsulfonyl, arylmethyleneamine (i.e., -N = CH-R, where R is the same as defined above).

g g.

35), 0

-C-R (where R is a hydrogen atom, an m m

-QinRR-37853Ί

Alkyl radical or a halogen-substituted alkyl radical), an aromatic radical as defined above by R, an alkyl radical or a substituted alkyl radical, where the alkyl radical is substituted by one or more halogen atoms, cyano, nitro, amino or mercapto groups "means ,

Preferred ε [[3-substituted-2-oxo-1-imidazolidinyl] carbonyl-amino} -aryl-acetyl radicals of the above formula are those radicals in which R represents a phenyl or 2-thienyl group. Likewise preferred are those radicals in which R, a water

Substance atom, a methylsulfonyl, phenylmethyleneamino or 2-Furylmethylenaminogruppe means.

The compounds prepared according to the invention form basic salts with various inorganic and organic bases, which are also within the scope of the invention. Such salts are ammonium salts, alkali metal salts, alkaline earth metal salts, organic base salts such as dicyclohexyl

) amine, benzathine, N-methyl-D-glucamine or hydrabamine. The pharmacologically acceptable salts are preferred, although the other salts are also valuable, e.g. for the isolation or cleaning of the product.

Some of the compounds prepared according to the invention can be crystallized from water-containing solvents or recrystallized. In these cases, water of hydration can be formed. The invention includes stoichiometric hydrates as well as compounds containing variable amounts of water, which may be obtained by methods such as e.g. Lyophilization occurs.

The β-lactams of the general formula I contain at least one chiral center, the carbon atom in the 3-position of the β-lactam nucleus, to which the acylamino substituent (R ₁ -NH) is attached. The invention is directed to the β-lactams,

η ι: Ο Λ

wherein the stereochemistry at the chiral center at the 3-position of the β-lactam nucleus is the same as the configuration at the 6-position carbon of the naturally occurring penicillins (e.g., penicillin G) and the configuration at the carbon atom in Fig. 7 Position of the naturally occurring cephamycins (for example cephamycin C). Also included within the scope of the invention are racemic mixtures containing the β-lactams described above.

·

The .beta.-lactams of the general formula I and their pharmacologically acceptable salts have activity against gram-positive and gram-negative organisms. The inventively produced. Compounds may be used as agents for combating bacterial infections, including urinary and respiratory infections, in mammals such as domestic animals (e.g., dogs, cats, cows, or horses) and humans.

^For combating bacterial infections in mammals, a compound prepared according to the invention may be administered to a mammal in need of treatment in an amount of about 1.4 mg / kg / day to about 350 mg / kg / day, preferably about 14 mg / kg / day to about. , 100 mg / kg / day. All types of administration which have hitherto been used for the administration of penicillin and cephalosporins at the site of infection can also be used for the β-lactams prepared according to the invention. Such methods are oral, intravenous, intramuscular and suppository administration.

The .beta.-lactams of the general formula I can be prepared from an amino-2-azetidinone protected in position 3 of the general formula

Formula II. Τ>

2 R ₄ -NH I _(II)

Ns C-R "

NH

-mnaR- 378B31

  -16-

getting produced. In the general formula II and in the further course of the description, the symbol ⁿ R 'denotes an amino-protecting group. These groups are well known in the field of β-lactam chemistry and it is not critical which group is chosen. Examples are the benzyloxycarbonyl group, trityl group and tert-butoxycarbonyl group. The reaction of a β-lactam of the general formula II with an isocyanate of the general formula III

O = C = N-SO ₂ -Y, (III)

in which Y is a leaving group such as chlorine ', the corresponding compound of general formula IV

? (IV)

R ₄ -NH

, Jz NC-NH-SO ₂ -Y.

The reaction is preferably carried out in an inert organic solvent such as ethyl acetate, tetrahydrofuran, dimethoxyethane, dichloromethane, acetonitrile or mixtures of these solvents. The replacement of the leaving group

Y through the desired group R can be determined using a. suitable nucleophile of the general formula V

RH (V)

be achieved, optionally in the presence of a base such as triethylamine, wherein the corresponding compound having the general formula VI

R ₄ -NH-

(VI)

N-C-NH-SO-RIi 2

is obtained.

In another embodiment, the substitution of the leaving group by reacting a compound of general formula IV with a protected form of a compound of

37853Ί

general formula V. After the replacement reaction, the protective groups can be removed by known methods, so that a compound of general formula VI is obtained.

Protected forms of a compound of general formula V and all reactants described herein containing a 3-hydroxy-4-pyridone group are the compounds in which the hydroxyl group is protected, the compounds in which the hydroxyl group and the ring nitrogen are protected, and compounds in which both pyridone oxygen atoms are protected. Exemplary protecting groups are silyl, such as trimethylsilyl, benzyl and acyl, such as acetyl. When silyl is used, subsequent deprotection may be by hydrolysis or fluoride-mediated cleavage. When benzyl is used, subsequent deprotection of the protecting group may be by hydrogenolysis. When acyl is used, subsequent removal of the protecting group may be by hydrolysis.

, The removal of a protecting group from a compound of general formula VI using conventional methods yields the corresponding important intermediate compound of general formula VII

^R 2

b NH-

.CH CR ₃

.NC-NH-SO ₂ -R

or a salt thereof. The deprotection method, of course, depends on the particular protecting group R. For example, when R. is a tert-butoxycarbonyl protecting group, removal of the protecting group may be accomplished by treatment of a compound of general formula VI with an acid such as formic acid or trifluoroacetic acid. For example, when R. is a benzyloxycarbonyl protecting group, removal of the protecting group by catalytic

O "7 O V- Q λ

Hydrogenation of a compound of general formula VI carried out. In another embodiment, the R.sup.-protecting group can be carried out simultaneously with the other pyridone protecting groups immediately after the replacement reaction described above.

Conventional acylation methods can be used to convert an intermediate of general formula VII to the corresponding product of general formula I. examples

Examples of suitable processes are the reaction of a compound of the general formula VII with a carboxylic acid R ₁ -OH or the corresponding carboxylic acid halide or the carboxylic anhydride. The reaction with a carboxylic acid is readily carried out in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming an active ester in situ, such as N-hydroxybenzotriazole. If the acyl radical R _{1 contains a} reactive functional group, such as amino or carboxyl groups, it may be necessary first to protect these functional groups and then first to carry out the acylation reaction in order finally to remove the protecting group from the product obtained.

Another embodiment for preparing the compounds of general formula I consists in the acylation according to the above-described acylation of a 3-amino-2-azetidinone of the general formula VIII

Fri.

I (VIII)

: -r "λ I

to an intermediate of general formula IX

R

IX) R-NU ι

-R1086- 378531

In the 1-position of a compound of general formula IX can be prepared using the methods described above

0 a -C-NH-SO ^ -R activation group are introduced to obtain the corresponding products of general formula I. If the acyl side chain R _{1 contains} reactive functional groups, such as amino groups, it may be necessary to first protect these functional groups, then carry out the addition of the activation group in the 1-position, and finally the protective product obtained from the product obtained to remove.

Another synthesis for the preparation of compounds of general formula I involves the use of a 3-azido-2-15; azetidinone of general formula X.

ι ² (X)

^N 3. j

L ^ n ----- ^ _- , ΓΛ.Λ

In the 1-position of the compound of general formula X, using the methods described above

a -C-NH-SO.-R activating group are introduced to the corresponding compound of general formula XI

H

 N_ I (XI)

^ CH CR-

II ³ SO ₄ C ₂ NC-NH-SO ₂ -R

(J 0

to obtain. Reduction of an intermediate of general formula XI gives the corresponding intermediate of general formula VII.

-810.86- 37853-1

'(ViD

_H tR ₃

-NC-NH-SO ₀ -R. ti 2

The reduction may be by catalytic hydrogenation, for example with palladium on charcoal or platinum oxide _; or by reducing agents, such as zinc or triphenylphosphine. As described above, from these important intermediates (compounds of general formula VII), using common acylation processes, the products of general formula I can be obtained.

In another embodiment, a 3-azido-2-azetidinone of the general formula X can be converted to the corresponding 3-amino-2-azetidinone of the general formula VIII

? 2

NH ₂ I (VIII)

^ CH CR ₃

NH '

be reduced. The reduction by catalytic hydrogenation, for example mj-t palladium-on-charcoal or platinum oxide, may be carried out with reducing agents such as zinc or triphenylphosphine A 3-amino-2-azetidinone of general formula VIII may be prepared as described above ( ie first acylation and then treatment as described above to introduce an O

11

C-NH-SO 2 -R-activating group in the 1-position) to the products of general formula I.

In a further synthesis for the preparation of the compounds of the general formula I in which R ₂ and R ₄ each represent hydrogen atoms, a 6-acylaminopenicillanic acid is used

-810.86- 37853-i

-21-of the general formula XII

(XII)

CH-COOH

or a salt thereof as a starting material. By adaptation of methods described in the literature obtained from the corresponding 6-Acylaminopenicillansäure the general formula XII, the 3-acylamino-2-azetidinone, see. Chem. Soc. Special Publication No. 28, (1977), p. 288, The Chemistry of Penicillins, Princeton University Press, p. 257, and Synthesis, 494 (1977).

As described in the literature, 6-acylaminopenicillanic acid or a salt thereof can be desulfurized by reduction with Raney nickel to give a compound of general formula XIII.

(XIII) 'CH ch

T ι ²

-N-CH-CH (CH ₃ ) ₂ COOH

The reaction can be carried out in water under reflux conditions.

Replacement of the carboxyl group of a compound of general formula XIII by an acetate group and subsequent hydrolysis gives the corresponding 3-acylamino-2-azetidinone of general formula XIV.

(XIV)

The treatment of a compound of general formula XIII

-3.10.86- 378531

with copper (II) acetate and lead tetraacetate in an organic solvent such as acetonitrile, the carboxyl group is replaced by an acetate group. The hydrolysis of the compound obtained can be carried out with potassium carbonate in the presence of sodium borohydride.

In the 1-position of a compound of the general formula XIV 0

11

a -C-NH-SO 2 -R activating group can be introduced according to the processes described above, thus obtaining products of general formula I in which R and R each represent a hydrogen atom.

Another embodiment of each of the above-described synthetic routes for preparing a compound of the general formula I in which R_ and R- are each hydrogen atoms consists in the desulfurization of 6-aminopenicillanic acid, the acylation of the resulting compound to give a compound of the general formula XIII and of further Umset-2Q tion according to the methods described above to a 3-acylamino-2-azetidinone of the general formula XIV and then a product of general formula I.

The azetidinones of the general formula I can also be prepared from amino acids of the general formula XV

OH "2

NH, «- · vXV)

^ CH C-R ₃

/ -On 30

getting produced. The amino group is first protected with a protecting group R ₄ such as tert-butoxycarbonyl. The carboxyl group of the protected amino acid is then reacted with an amine of general formula XVI ZO-NH ₂ (XVI)

-810-86- 378531

ZDU J

reacted in the presence of a carbodiimide, wherein Z represents an alkyl group, a benzyl group or a triphenylmethyl group, so that one obtains a compound of general formula XVII.

υπ

P -JMTT I P

(XVII) -0-Z

The hydroxyl group of a compound of general formula XVII is converted to a leaving group ("OL") with a reagent such as methanesulfonyl chloride or pyridine-S0 ₃ complex.

The fully protected compound of general formula XVIII

OIL

(XVIII)

is cyclized by treatment with a base such as potassium carbonate. The reaction is preferably carried out in an organic solvent or a mixture of an organic solvent and water under reflux conditions to give a compound of general formula XIX.

(XIX) -N-O-Z

In another embodiment, the cyclization of a compound of the general formula XVII can be carried out without first converting the hydroxyl group into a leaving group. Treatment of a compound of general formula .35 XVII with triphenylphosphine and diethyl azodicarboxylate gives a compound of general formula XIX.

-8.10.86- 37853Ί

£. * J W ϊ & ti

Exemplary methods for the conversion of a compound of general formula XVIII to a compound of general formula XIX are described in J. Amer. Ch-em. Soc. , 102 (1980), 7026, and in J. Org. Chem., 47 (1,982), - 51,60.

Both of the above-described methods of ring-closing a compound of the general formula XVII lead to inversion of the stereochemistry on the carbon bearing the radicals R ₂ and R ₃ when R ₂ and R _{3 are} not the same.

Removal of the protecting group from the 1-position of an azetidinone of general formula XIX can be accomplished by reduction with sodium when Z is an alkyl radical to give an intermediate of general formula II wherein at least one of R ₇ and R 1 Hydrogen atom is. When Z is a benzyl group, catalytic hydrogenation, for example with palladium on charcoal, leads first to the corresponding N-hydroxy compound, which upon treatment with titanium trichloride gives an intermediate product of general formula II. When Z is a triphenylmethyl group, treatment with formic acid or 70 percent acetic acid / water results in the corresponding N-hydroxy compound.

In the 1-position of a compound of general formula II / 25 can according to the methods described above a

C-NH-SCU-R activating group. From the obtained compound, the protective groups can be removed _; and it can be acylated.

The nucleophiles of the general formula V in which R is the radical

* 2 6 ι. means'. _.: .. "<\ ^H

and A ₁ and A ₂ each represent a single bond

-310.86- 378531

Z5U

-25-

by reacting a silylated derivative of 2-imidazolidinone or the anion of 2-imidazolidirione formed with a strong non-nucleophilic base with an activated, suitably protected derivative of an acid of general formula XX

(Xx:

are prepared, after removing the protective group, the corresponding compound of general formula XXI

, ff ίίϊΓ ~ ^0Η <* ">

receives. The reaction can be carried out in an inert organic solvent such as dimethylformamide, acetonitrile, dichloromethane or tetrahydrofuran. The acid of general formula XX can be activated with dicyclohexylcarbodiimide or a combination of dicyclohexylcarbodiimide and hydroxybenzotriazole. An activated and protected in a suitable manner derivative of a compound of general) formula XX can also be the corresponding acid chloride, which was prepared with reagents such as phosphorus pentachloride, thionyl chloride, oxalyl chloride or triphenylphosphine-carbon tetrachloride, or a mixed anhydride with reagents such as Diphenylphosphorylchlorxd, pivaloyl chloride or isobutyl chloroformate.

The compound of general formula XX in which A, an

can be prepared according to the methods described in the literature, cf. Helv. Chem. Acta, 43 (1960), p. 469 and J. Med. Chem., 17 (1974), p. 1.

The compound of general formula XX, in the A-. -CH = CH-

-310.86- 378531

ZDU

by oxidation of the suitably protected compound of formula XXII

(XXII) CH ₂ -OH

to the corresponding suitably protected aldehyde

of the formula XXIII O

HO U 0 (XXIII)

:H

¹ N

and by reacting the aldehyde with a carboxyl-protected derivative of formula XXIV

(XXIV)

and removal of the protecting group, wherein the compound XXV o

HO Il "(XXV)

CH = CH-C-OH

Il II *** '

H receives. The compounds of the general formula XX in which Kr is - (CH ₀ ), -, where t has the value 2, 3 or 4,

D i. X.

, can be prepared by conjugation of a suitably protected compound of. Formula XXIII with a Wittig reagent of the general formula XXVI

0 (XXVI)

_L C-OH

whose carboxyl group is suitably protected by subsequent hydrogenation of the obtained exocyclic

-810.86- 378531

.-27-

Be prepared double bond and by removing the protective groups, wherein a compound of general formula XXVII

(Xxvii:

in which t has the value 2, 3 or 4, receives.

The compounds of general formula XX in which A _{g is} - (CH-) and t is 1 can be prepared by reacting a suitably protected compound of general formula XXVIII

(XXVIII)

in the L, a leaving group, such as chloride; Bromide, methanesulfonyloxy or toluenesulfonyloxy, with cyanide and subsequent hydrolysis and deprotection to give the compound of general formula XXVII in which t is 1. A compound of general formula XXVIII may be prepared from a compound of formula XXII which is suitably protected by conventional methods such as reaction with thionyl chloride or with methanesulfonyl chloride / triethylamine.

The nucleophiles of the general formula V in which R is the radical

A _{1 represents} a single bond and A is -NH-,

37853-1

can be prepared by reacting an activated and optionally protected derivative of a compound of general formula XX with 1-amino-2-imidazolidinone, wherein after removal of the protective group, the compound of general formula XXIX

(XXIX)

receives.

The nucleophiles of the general formula V in which R is the radical

- ^A - | - ^N ^ ^ .NA, -CA, - ^ N ^

O H

If A _{1 is} a single bond and Ä is -CH ₇ -CHp-NH-, can be prepared by reacting an activated and optionally protected derivative of a compound of general formula XX with 1- (2-aminoethyl) -2-imidazolidinone, wherein one after removal of the protective group. a compound of general formula XXX

(XXX)

ι-ι κ ii ir ^

ö receives.

The nucleophiles of the general formula V in which R is the radical - 0

, 0

Γ I

-A, -. 1

A _{1 represents} a single bond and A is -C-NH-NH-, may be prepared by reacting the compound of formula XXXI

-810.86- 37853Ί

-29-

O O

-O-C-NH-NH-C-Cl

(XXXI)

with a silylated form of the 2-imidazolidinone, the 2-imidazolidinone anion formed with a strong non-nucleophilic base or with 2-imidazolidinone in the presence of an organic base; wherein the compound of formula XXXII

receives.

The catalytic hydrogenation of the compound of formula XXXII gives the compound of formula XXXIII

H ₂ N-NH-CN

(XXXIII)

which may be coupled with an activated and optionally protected derivative of a compound of general formula XX, wherein after removal of the protecting groups a compound of general formula XXXIV

1 ° ° fill ^oil

HN. .N-C-NH-NH-C-A, ^ - ^ N ^ -

^(Xxxiv)

"ö. I

receives.

In another embodiment, the compound of formula XXXIII may be prepared by reacting 1-chlorocarbonyl-2-imidazolidinone with tert-butoxycarbonyl-protected hydrazine to give the compound of formula XX.XV

(XXXV)

HN ^ T-C-NH-NH-C-O-C (CH-).

χ ... ^{3 3}

250

and subsequent deprotection of the compound of formula XXXV.

The nucleophiles of the general formula V in which R is the radical

-A ₁ -N .NA ₀ -CA ₂

ä H

means A is -NH-C- and A _{0 represents} a single bond can be prepared by reacting a compound of general formula XXXVI

0 _r Q ff Ir-OH (XXXVi:

.Cl-CN _v .x! 5 d H

which is suitably protected, are prepared with hexamethyldisilazane to give, after hydrolysis and deprotection, a compound of general formula XXXVII

, _> \ ", (XXXVII)

receives.

The suitably protected compounds of general formula XXXVI can be prepared by reacting with phosgene a silylated form of a compound of general formula XXI which is optionally protected.

Alternatively, a compound of the general formula XXXVII may be prepared by reacting a protected form of a compound of the general formula XXI with chlorosulfonyl isocyanate, followed by hydrolysis of the resulting intermediate and deprotection.

-8.10.86- 378531

The nucleophiles of the general formula V in which R is the radical

"1 ^J \ z ^N ~ ^A 2 ~ ^C 'b ι ö H

Il

A is -NH-C- and A "is -NH-, may be prepared by reacting a silylated form of the compound of general formula XXXVIII

I 1 (XXXVIII)

HNii-NH prot,

d '=

in which the symbol Prot can be an amino-protecting group, such as tert-butoxycarbonyl or benzyloxycarbonyl, with "5-phosgene, whereby a compound of the general formula XXXIX

π j I (XXXIX)

Cl-C-N ^^. N-NH-Prot,

which can be reacted with hexamethylsilazane, wherein after removal of the protective group, the compound of formula XL ₀

U L I

NH ₉ -CN .N-NH ₉ (XL)

_; ² V

receives.

The reaction of the compound of the formula XL with an optionally protected, activated form of a compound of the general formula XX gives, after removal of the protective group, a compound of the general formula XLI

(XLI) 0, 1 0

H In another embodiment, a compound of formula XL may be prepared by reacting the compound of formula XLII

378531

250

f / λ (XLII

HN .N-N = CH

δ be prepared with chlorosulfonyl isocyanate, which, after hydrolysis, the compound of formula XLIII

ϊ ι-ι j ^ ^(XLIII)

receives

 10

Treatment of this compound with aqueous acid gives a salt of the compound of formula XL.

The nucleophiles of the general formula V in which R is the radical J

₁ -N 0

H means O

A. is -NH-C- and A _{2 is} -CH ₂ -CH ₂ -NH- can be prepared by deprotecting 1 - (aminocarbonyl) -3- {j 2 -I {- (tert -butoxy) carbonyl ] -aminoQ-ethyl ^ -2-imidazolidinone and coupling of the resulting compound with an activated form of a compound of general formula XX ₇ which is optionally protected, to obtain, after removal of the protective group, a compound of general formula XLIV

? \ I 1 Ο Λ- OH (XLIV)

HNCN .N-CH-CH -NH-CA ^ "^ N ^ ^Δ > f ^{2 2 6} I '.

The nucleophiles of the general formula V in which R is the radical

I 1 9 Λ-0Η

N -H

378531

- ³³ :

when A is -NH-C- and A is -C-NH-NH- can be obtained by reacting a silylated form of a compound of general formula XXXIV, which is optionally protected, with phosgene and then hexamethyldisilazane to give, after hydrolysis and deprotection of a compound of general formula XLV

O il, N-C-

sustaining.

O O

.N-C-NH-NH-C-A

(XLV)

25 30 35

In another embodiment, a compound of general formula XLV may be prepared by reacting a protected form of a compound of general formula XXXlV with chlorosulfonyl isocyanate and then hydrolysing the resulting intermediate and deprotecting it In another embodiment, a compound of formula XXXII may be treated with chlorosulfonyl isocyanate followed by hydrolysis of the resulting intermediate to give the compound of formula XLVI

receives.

Removal of the protecting group from the compound of formula XLVI by hydrogenolysis gives the compound of formula XLVII

(XLVII)

Il,..., ^. J-C-NH-NH-,

δ which can be coupled with an activated and optionally protected derivative of a compound of the general formula XX to obtain a compound of the general formula XLV after removal of the protective group.

-8.10.S6- 37853-t

The nucleophiles of the general formula V in which R is the radical

A _{1 represents} -NH- and A "represents a single bond can be prepared by coupling a compound of general formula XXXVIII to an activated form of a compound of general formula XX, which is optionally protected, and then deprotecting, wherein a compound of general formula XLVIII

J. , (XLVIII)

Q Γ7 ~ ^0Η

receives.

The nucleophiles of the general formula V in which R is the radical

20

"OH

-A-N JI-A, -C-A, -Y "- 2 6

A is -NH- and A "is -NH- may be prepared by coupling a mono-protected (preferably tert-butoxycarbonyl or benzyloxycarbonyl) derivative of 1,3-diamino-2-imidazolidinone with an activated form of a compound of the present invention general formula XX, which is optionally protected, and subsequent removal of the protective groups are prepared, wherein the compound of general formula XLIX

I 1 It [ίΐΓ ° ^Η (XLIX)

2 ~ ^ s _n X "~ & I

receives.

-810.86- 378531

In another embodiment, a compound of general formula XLIX can be formed by nitrosation of a protected form of a compound of general formula XXIX and subsequent reduction of the nitroso group and deprotection.

The nucleophiles of the general formula V in which R is the radical

i i? X

-A ₁ -N NA ₂ -CAgN

ö H

when A _{1 is} -NH- and A _{2 is} -CH ₂ -CH ₂ -NH- can be prepared by nitrosation of a compound of general formula XXX, which is suitably protected, to give a suitably protected compound the general formula L

-CH ₂ -NH-C-Ag

(D

0H

ö H

and, when this compound is reduced and the protecting groups removed, a compound of general formula LI

p-, 0 jfVoH (LI)

H_n-N. .N-CH ₀ -CH ₀ -NH-CA, - "^ N ^

ä η

receives

 The nucleophiles of the general formula V in which R is the radical

O

A _{1 is} -NH- and A _{3 is} -C-NH-NH-

-8.10.86- 37853-1

by nitrosation, reduction and deprotection of a protected derivative of a compound of general formula XXXIV. The "compound obtained has the general formula LII

(LII) -

^ -C-NH-NH-C-A,

on .

In another embodiment, a compound of general formula LII may be formed by reacting a compound of general formula XXXVIII with phosgene to give a compound of general formula LIII

1 1 π ^(LIII)

Prot-NH-NN-C-Cl

0, which, when reacted with a monoprotected hydrazine in the presence of a base, the compound of general formula LIV

¹ I Il 1 r tu 1

Prot-NH-N. .NC-NH-NH- ^ProtIlVl 5

results (the two protection groups must be different).

Selective removal of the hydrazide protecting group yields a compound of general formula LV

(LV)

-NH-N. ^ N-C-NH-NH

Prot-NH-N. ^ N-C-NH-NH V ^

The coupling of a compound of the general formula LV with an activated, optionally protected form of a compound of the general formula XX and the subsequent removal of the protective groups gives a compound of the general 35th

my formula LII.

37853-i

35

The nucleophiles of the general formula V in which R is the radical

Il

means A _{1 is} -NH-NH-C- and A _? is a single bond can be prepared by reacting a compound of general formula XXXVI (preferably a protected derivative thereof) with hydrazine (preferably in single-slit form) in the presence of a base or with a silylated form of hydrazine or monoprotected hydrazine, a protected derivative of the compound of general formula LVI

15

N-NH-CN _x ^ NC-; O

(LVI) Il I 111 J. ^{1 1} I

H,

from which by conventional methods the protective groups can be removed.

In another embodiment, a compound. of the formula XXXV (either a silylated derivative thereof or an anion formed therefrom by reaction with a strong base) is reacted with an activated form of a compound of the general formula XX which is suitably protected and subsequently the protecting groups are removed, to obtain a compound of general formula LVI.

30

The nucleophiles of the general formula V in which R is the radical

-810.86- 378531

a Sm a

-38-

A _{1 is} -NH-NH-C- and A _{2 is} -NH-, may be prepared by selectively removing the nonhydrazide protecting groups of a compound of general formula LIV and then coupling with an activated ^ optionally protected compound of general formula XX and the following Removal of the protective group are formed, to give a compound of general formula LVII

H ₂ N-KH-CN,

, N-NH-C-Ag

receives.

(LVII;

The nucleophiles of the general formula V in which R is the radical

A _{1 is} -NH-NH-C- and A _{2 is} -CH ₂ -CH ₂ -NH- may be prepared by sequentially reacting a compound of general formula XXX or a protected derivative thereof with phosgene and subsequently with hydrazine or a monoprotected derivative thereof in the presence of a silylating agent, such as methyl-N- (trimethylsilyl) -trifluorazetamide, to give, after deprotection, a compound of general formula LVIII

O. O

H_n-NH-CN. .N-CH ₀ -CH ₀ -NH-CA,

(LVIII)

receives.

In another embodiment, an aminogen-protected derivative of 1- (2-aminoethyl) -2-imidazolidinone, the

if it is silylated, reacted with phosgene and then with, a monoprotected derivative of hydrazine in the presence of a base or silylation agent, such as N-methyl-N- (trimethylsilyl) trifluoroacetamide or bis (trimethylsilyl) -acetamide to give a protected derivative the compound of the formula LIX

(LIX)

be implemented. The radicals used to protect the terminal amino groups in a compound of formula LIX should be chosen so that the protecting group on the aminoethyl group can be selectively removed. The compounds obtained after removal of the protecting group may be coupled with an activated form of an acid of the general formula, XX or a protected derivative thereof, to give, after deprotection, a compound of the general formula LVIII.

The nucleophiles of the general. Formula V, where R is the rest

-A-. -N-) ¹ Y ^ Vh

O O

/ A is -NH-NH-C- and A _{2 is} -C-NH-NH-, can be prepared by reacting the compound of formula XXXII, optionally in the form of the silylated derivative, with phosgene, wherein a protected derivative of the Compound of formula LX

O Q (LX)

H ₂ N-NH-CN ^ Ji-C-Cl Y

obtained with a protected derivative of hydrazine

can be coupled, wherein a protected derivative with the formula LXI ·

-8.10.86- 37853Ί

O (LXI)

H ₀ N-NH-CN .NC-NH-NH ₀

receives. °

The radicals used to protect the terminal amino groups in a compound of general formula LXI should be selected so that one of the protecting groups can be selectively removed. The compound obtained after removal of the protecting group can be protected with an optionally protected Coupled form of an acid of the general formula XX, wherein after removal of the protective group is a compound of general formula LXII

O ₁ 0 0 ^ j-OH

^ ^ NC-NH-NH-CA, - "- ^ N ^ Ö · H

(LXII)

H-N-NH-C-N.

receives.

The nucleophiles of the general formula V in which R is the radical

-A ₁ -N

0 ^:

may, according to the method described above for the preparation of the nucleophiles of the general'formula V, in the R may be the rest

30 -A ₁

means, but with the appropriate 2,3-piperazinedione reactants replacing the 2-imidazolidinone reactants

 The nucleophiles of the general formula V in which R is the radical

-αuiftR-378531

1-ZV ⁰¹¹

A _{1 is} a single bond and A _{5 represents} a single bond. may be prepared using a suitably protected derivative of compound LXIII

(LXIII) HO-

¹ ^ N ^ - C-OH

H are produced. A compound of formula LXIV

(LXIV) 15

can be prepared by conversion of a protected form of the compound of formula LXV

(LXV) HO-

-N-I

to a protected form of the compound of formula LXIV according to the method of K. Heyns et al., Chem. Ber., 87 (1954), p. 1440, followed by removal of the protecting group to give the compound of formula LXIV receives per se.

A compound of formula LXV may be prepared from a suitably protected form of a compound of formula LXIII by conversion to an ester such as ethyl or methyl ester, reaction with hydrazine and removal of the protecting groups. In another embodiment, a suitably protected, activated form of connection of the For-

-8.186- 378531

mel LXIII are reacted with a monoprotected hydrazine to give a compound of formula LXV after removal of the protective groups.

The reaction of the compound of formula L'XIV or a suitably protected derivative thereof with 2- (chloroethyl) isocyanate, cjegebenenf alls in the presence of a base such as triethylamine or a silylating agent gives, after removal of the protective group, the compound of formula LXVI.

0 ff "^ OH (LXVI

Il Cl-CH ₂ -CH ₂ -NH-C-NH

Treatment of the compound of the formula LXVI or a suitably protected derivative thereof with a base gives, after removal of the protective groups, the compound of the formula LXVII,

(LXVII;

The nucleophiles of the general formula V in which R is the radical

Jut *

A. is a single bond and A _{5 is} -CH ₂ -, can be prepared by reacting the compound of formula LXVIII

(LXVIII)

or a derivative thereof in which the pyridone group is

-RK) RIi-37853i

suitably protected and the primary amino group is not protected, be prepared with 2- (chloroethyl) isocyanate, which, after removal of the protective groups, the compound of formula LXIX

CI-CH ₀ -CH ₀ -NH-C-Nh-CH ^

2 2 ² I

receives.

Treatment of the compound of formula LXIX or a suitably protected derivative thereof with a base yields "the compound of formula LXX.

15 ', ^ \ - OH ^(LXX)

HN. .N-CH ₀

Ύ ² ί

, A compound of formula LXVIII can be prepared from a suitably protected compound of general formula XXVIII by treatment with azide, reduction of the azide and deprotection.

The nucleophiles of the general formula V in which R is the radical

25. ·

means a single bond and is A. A is -N = CH- or -NH-CH represents _0, may be prepared by condensation of 1-Atnino-2-imidazolidinone with the aldehyde of formula XXIII, which is optionally protected, wherein, after removal of the protective group, the compound of the formula LXXI / V- ^ h (LXXI)

HN N-N = CH ^ ΝαH

-8.10.86- 37853Ί

-44-getting.

Reduction of the compound of formula LXXI, optionally protected, by catalytic hydrogenation with sodium cyanoborohydride affords the compound of formula LXXII.

(LXXII)

10

The nucleophiles of the general formula V in which R is the radical

-OH

Il

A. is a single bond and A _{5 is} -C-NH- (CH ₂ ), can be prepared by reacting 1-chloro-carbonyl-2-imidazolidinone with a compound of general formula LXXIII

j? (LXXIII)

iV ^0H

H ₂ N- (CH ₂ ) -

or a suitably protected derivative thereof in the presence of a base or with a silylated derivative of a compound of the general formula LXXIII, the deprotection of the compound of the general formula LXXIV

30

receives.

The nucleophiles of the general formula V in which R is the radical

378531

-45-

-OH

I 've

-A ₁ -N _n JI-A ₅ -

0

Il

and A. is -NHC-, may be prepared by reacting a suitably protected derivative of a compound of formulas LXVII, LXX, LXXI, LXXII or LXXIV with phosgene to give a protected derivative of general formula LXXV

J? (LXXV)

JUT ⁰ «

Ύ "" H

which can be reacted with hexamethylsilazane to give, after removal of the protective groups and hydrolysis, a compound of the general formula LXXVI

0 rr 7, UH (LXXVI)

ö H

receives.

In another embodiment, nucleophiles of general formula V in which R is the radical

It

and A. is -NHC-, prepared by reacting a suitably protected derivative of a compound of formulas LXVII, LXX, LXXI, LXXII or LXXIV with chlorosulfonyl isocyanate to give, after hydrolysis and deprotection, a compound of general formula (II)

378531

-46 Formula LXXVI receives.

The nucleophiles of the general formula V in which R is the radical

and A _{1 is} -NH-, may be prepared by nitrosation of a suitably protected derivative of a compound of formulas LXVII, LXX, LXXI, LXXII or LXXIV with, for example, nitrous acid, reduction of the resulting compound with, for example, zinc under acidic conditions, and removal the protecting groups are prepared, wherein a compound of general formula LXXVII

! LXXVII)

receives. In another embodiment, the connections may be

Il

fertilizing the general formula LXXVII, in which A is ₅ -C-NH- (CH ₂ ), by reacting a compound of the general; Formula XXXIX be prepared with an optionally protected form of a compound of general formula LXIV or LXVIII in the presence of a base or a Silylxerungsmittels, wherein after removal of the protective groups, the compound of general formula LXXVIII

_ _N Jf (LXXVIII)

o rrV-oh

NC-NH- (CH ₂ ) - ^ - "" ^ N Ö H

receives

 35

In another embodiment, the compounds

-810.86- '378631

_47-

of the general formulas LXXVII, in which A _{1 represents} --N = CH- or -NH-CH ₇ -, by reacting monoprotected 1,3-diamino-2-imidazolidinone with a compound of formula XXIII or a protected derivative thereof and subsequent removal of the protecting groups to the derivative of general formula LXXVII wherein A is --NH = CH-. Reduction of this derivative gives the compound of the general formula LXXVII in which A ₁ . -NH-CH ₇ -ist

 10

The nucleophiles of the general formula V in which R is the radical

and A _{1 is} -NH-NH-C-, may be prepared by reacting a suitably protected compound of the general formula LXXV with a monoprotected hydrazine in the presence of a base or silylating agent.

After deprotection the products have the general formula LXXIX - -

if I 1 fill ° ^H (LXXIX

HNNHCIL ^ ^

L _x .

The nucleophiles of the general formula V in which R is the radical 30

A _{1 is} a single bond and A _n . is a single bond or -CH ₇ - can be prepared by reacting a compound of formula LXIV or LXVIII or a

-8.10.86- 378b3

suitably protected derivative thereof with aziridine or an activated aziridine using acyl or sulfonyl radicals for activation, after deprotection the compound of formula LXXX

(LXXX) OH

H receives.

A compound of formula LXXX or a suitably protected derivative thereof may be prepared by reaction with a dialkyl oxalate and optionally removal of the protecting groups to the desired piperazinedione having the formula LXXXI

ι ι ι jr-i, LXXXI)

being transformed.

The nucleophiles of the general formula V in which R is the radical

A _{1 is} a single bond and A is -N = CH- or -NHCH "-, can be prepared according to the above-for the preparation of the nucleophiles of the general formula V in which R

30

the rest

"OH

^ -A ^ - ^ N ^ ö

A _{1 is} a single bond and A _{1 represents} -N = CH- or -NHCH--, processes are described,

"Hnftfi

but 1.-amino-2,3-piperazinedione replaces the 1-amino-2-imidazolidinone. The compounds obtained have the formulas LXXXII and LXXXIII.

(LXXXII)

ίο

HN N-NH-CH J.

QP = -

(LXXXIII)

15

The nucleophiles of the general formula V in which R is the radical

20 25 30 35

means A. is a single bond and. A ₅ -C -NH- (CH ₂ ) may be prepared by reacting an optionally protected derivative of the compound of formula LXXXIV

(LXXXIV)

N-C-Cl

with a compound of the formula LXXIII or a suitably protected derivative thereof in the presence of a base or a silylating agent. From the obtained intermediate, the protective groups can be removed, to give a compound of general formula LXXXV

(LXXXV)

378b3

receives.

The nucleophiles of the general formula V in which R is the radical

~ 0 Ή

and A is -NH- can be prepared by nitrosation of a protected derivative of a compound of the general formulas LXXXI, LXXXII, LXXXIII or LXXXV with, for example, nitrous acid, reduction of the resulting compound, for example with zinc under acidic conditions, and removal of the protecting groups in which a compound of the general formula LXXXVI

(LXXXVI)

receives

 20

Alternatively, the compounds of general formula LXXXVI, wherein A _{5 is} -N = CH- or -NH-CH--, can be prepared by reacting monoprotected 1,4-diamino-2,3-piperazinedione with a compound of Formula XXIII or a protected derivative thereof and by removing the protective groups from the product to obtain a compound of the general formula LXXXVI in which A is -NH-CH-, which are then reduced to a compound of the general formula LXXXVI can, in which a -NH-CH-- means. In another embodiment, the reduction of -N = CH- may precede the removal of the protecting groups.

The nucleophiles of the general formula V in which R is the radical 35

-A -NN-A ^ - ^ N

378531

ο - ⁵¹ -

It

and A _{1 represents} -NH-NH-C-, can be prepared by reacting a suitably protected derivative of a compound of formula LXXXI, LXXXII, LXXXIII or LXXXV with phosgene, wherein the compound of general formula LXXXVII

(LXXXVII)

οίο, which can be reacted with hexamethyldisilazane, which, after removal of the protective groups and hydrolysis, the compound of general formula LXXXVIII

(LXXXVIII)

H ₂ NCN

receives.

In another embodiment, the nucleophiles of general formula V in which R is the radical

0

* f I

and A _{1 is} -NHC-, are prepared by reacting a suitably protected derivative of a compound of formula LXXXI, LXXXII, LXXXIII or LXXXV with chlorosulfonyl isocyanate to give, after hydrolysis and deprotection, a compound of general formula LXXXVIII.

The nucleophiles of the general formula V in which R is the radical

0 35

• Ν '

-8.10.86- 378b3i

  -52-

means and A-. - (CH ") - have been described above, cf. the formulas LXIV and LXVIII.

The nucleophiles of the general formula V in which R is the radical

O O

and A _{3 is} -NH-C-NH- or -NH-C-NH-CH ₂ - may be prepared by reacting a compound of formula XXXI with an optionally protected compound of formula LXIV or LXVIII in the presence of a base or a silylating agent and the subsequent removal of protective groups are made.

In another embodiment, the nucleophiles of general formula V in which R is the radical

20

and A _{3 represents} -NH-C-NH- or -NH-C-NH-CH ₂ -, from a suitably protected form of a compound of formula LXIV or LXVIII by reaction with phosgene and subsequent treatment with a monoprotected derivative of hydrazine in the presence of a base or silylating agent and removal of the protecting groups.

The nucleophiles of the general formula V in which R is the radical

35

378531

&. WW

and A _{3 represents} -GH ₂ -C-NH- or -CH ₂ -CO-NH-CH ₂ - may be obtained by coupling an activated N-protected glycine derivative with a compound of the formula LXIV or .LXVIII, which is optionally protected , and subsequent removal of the protecting groups.

The nucleophiles of the general formula V in which R is the radical

-NH-A

and A-, -NH-CH--, may be prepared by reacting an optionally protected derivative of the aldehyde of formula XXIII with hydrazine or "monoprotected hydrazine, followed by reduction of the carbon-nitrogen double bond and subsequent deprotection.

In another embodiment, a monoprotected hydrazine at the free amino group may be monoalkylated with a compound of general formula XXVIII which is suitably protected followed by removal of the protecting groups to give a nucleophile of general formula V in which R the rest ' -

-NH-A ₃

and A _{3 represents} -NH-CH ₂ -.

The nucleophiles of the general formula V in which R is the radical

-7 π ι: ο Α

means and A-. -O-CH ₉ - can be prepared by reacting a suitably protected derivative of the compound of formula XXII with N-hydroxyphthalimide under Mitsunobu conditions (presence of triphenylphosphine and diathylazodicarboxylate) to give a protected derivative of compound LXXXIX

Q Q

(LXXXIX)

from which the protecting groups can be removed, the compound XC

(XC)

HO

CH ₂ -O-NH ₂

receives.

Alternatively, the compound of formula XC may be prepared by reacting a compound of formula XXVIII, suitably protected, with N-hydroxyphthalimide in the presence of a base.

The nucleophiles of the general formula V in which R is the radical

0 P rfS-OH

-NH-A ₄ -CA ₁ - -N

  H

and A represents -NH- can be prepared by reacting a monoprotected hydrazine with an activated, optionally protected derivative of an acid of general formula XX, wherein after removal of the protective groups, a compound of general formula XCI

-8.10.86- 37853-1

XCI)

receives.

In another embodiment, the compounds of general formula XCI can be prepared by reacting a carboxylic acid ester of a suitably protected derivative of a, p, compound of general formula XX with hydrazine and subsequent deprotection.

The nucleophiles of the general formula V in which R is the radical

-NH-A. -C-A; - "^ 4 6

and A. represents - (CH ₉ ) -, where ρ is 0, can be prepared by reacting ammonia or hexamethyldisilizane with an activated, optionally protected derivative of an acid of the general. Formula XX, wherein after removal of the protective groups, a compound of general formula XCII

V ^ucii)

, NH ₀ -CA.N

H receives.

The nucleophiles of the general formula V in which R is the radical 9

and A. is - (CH ₉ ) -, where ρ is 1, may be prepared by treating a suitably protected, activated derivative of a compound of general formula XX

-310-86- 37853-i

i & ι

-56-

be prepared with diazomethane and then with hydrochloric acid, wherein a protected derivative of a compound of general formula XCIII

S (XCIII)

gets, in'the L, means chlorine. A compound of general formula XCIII, wherein L represents chlorine, can then be treated with \ Q an iodide or bromide salt such as sodium iodide or lithium bromide to give a protected derivative of a compound of general formula XCIII in which L, bromo or iodine is, gets. Replacement of the leaving group L, wherein L, chlorine, bromine or iodine, with azide and the subsequent closing and removal of the protecting group results in a compound of general formula XCIV

OH ^{XCIV)

20 - ^H

The nucleophiles of the general formula V in which R is the radical

and A 'is - (CH-) -NH-, may be prepared by reacting an optionally monoprotected compound of general formula XCV

NH ₂ - (CH ₂ ) -NH ₂ (XCV)

with an activated, optionally protected derivative of an acid of the general formula XX, wherein after removal of the protective groups a compound of the general formula XCVI

Cj C

j - (CH ₂ ) _y -NH-CA

-8.10.86- 378531

XCVI:

-57-getting. ·.

The nucleophiles of the general formula V in which R is the radical

0 -NH-A. -C-A

0 ·

Il

and A. is -NH-C-NH-NH-, can by reacting a compound of general formula XCI, which is suitably protected, with a compound of general formula XCVII

0 prot-NH-NH-C-CL (XCVII)

in the presence of a silylating agent and subsequent deprotection.

The nucleophiles of the general formula V in which R is the radical

11

means and A. is -C-NH-NH-, can by reaction O

ti

of -NH ₂ -CNH-NH- in the presence of a base or of a silylating agent with an activated, optionally protected derivative of the general formula XX, whereby after removal of the protective groups a compound of the general formula XCVIII

(XCVIII)

receives. 35

The nucleophiles of the general formula V in which R is the radical

-fliHRfi- 37853-Ϊ

O rfSrOH

-NH-A. -C-A, 4 6

CH "X

and A. is -N-, can be prepared by reacting an optionally protected hydrazine derivative of the general formula XCIX

NH ₂ -NH-CH ₂ -X (XCIX)

^with an activated, optionally protected derivative of an acid of the general formula XX, where, after removal of the protective groups, a compound of the general formula C is obtained

15

NH ₂ -N-Cj

receives.

Alternatively, the compounds of general formula C in which X represents a hydrogen atom may be prepared by reacting methylhydrazine with a carboxylic acid. ester derivative of the acid of general formula XX or a suitably protected derivative thereof.

25

The compounds of general formula I in which R is the radical

O

means are preferred. Most preferred are the compounds of general formula I in which R is the radical

35

_ ο v \ Q ß - 3 7 9, Ϊ-, 3 ·!

represents. Likewise preferred are the compounds of general

my formula I, in which R. the rest -.C ^ = N-O-R. means

and R 2 is amino-4-thiazolyi and R 1 is a methyl group, ethyl group, carboxymethyl group, 1-carboxy-1-methyl-

ethyl group, 1-carboxy-1-ethyl group or the radical -C-COOH, where s has the value 1, 2 or 3. The use of these preferred R ₁ -acyl radicals results in a product which is present as a syn or anti isomer or as a mixture of the isomers. The syn isomer is more effective than the anti isomer.

The examples illustrate the invention. EXAMPLES

example 1

Di-sodium salt of [3S (Z)] - 2- [QQi - (2-amino-4-thiazolyl) -2-LC ¹ - [[CC ³ -C [( ¹ , 4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidyl] amino] oxy] -2-methyl propionic acid

A) 2- (hydroxymethyl) -5- (phenylmethoxy) -4H-pyrene-4-one

69 g ((3 moles) of sodium are dissolved in 5 ml of methanol, and then (with 425.3 g of 3 mol) of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one. The mixture is stirred at 30 ⁰ C is stirred until a clear solution is obtained The mixture is then treated with 595 g (3.5 mol) of benzylbromide and stirred at reflux for 1 hour The very dark, warm solution is poured into 15 ml of ice-water The product crystallizes out immediately ,

The collected crystals are washed first with 8 liters of water and then twice with 2.5 liters of ether. The product

-810.86- 37853 ·!

] is allowed to stand overnight and finally dried at 50 ⁰ C for 16 hours. The yield is 646 g (92.6 %).

B) 4-oxo-5- (phenylmethoxy) -4H-pyran-2-carboxylic acid

232 g (1 mol) of 2- (hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one are charged to a 10 liter stirred flask containing 6.6 liters of acetone and 400 ml of water. The clear solution is cooled in an ice bath to ⁰ +5 C. While the temperature is maintained at +5 to +10 ⁰ C, the solution is added dropwise over 1 hour with 640 ml of Jones reagent (202 g CrO. ,, 600 ml of water, 174 ml H ₂ SO.). It is stirred for 2 hours without cooling. The reaction mixture is filtered through a • glass frit and the dark green residue with 500 ml

- | _5 acetone washed. The filtrate is evaporated until all acetone is removed. The aqueous, partially crystalline product is treated with 1.2 liters of methanol and the mixture is then heated to its boiling point. The resulting dark green clear solution is placed in an ice bath and the product is allowed to crystallize out. The crystalline product is filtered off and washed with 500 ml of a cold solvent mixture of 250 ml of methanol and 250 ml of water and finally dried. The yield is 195 g (79 %) . From the mother liquor, an additional 5 % of the product can be isolated.

C) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid

300 g (1.22 mol) of 4-oxo-5- (phenylmethoxy) -4H-pyran-2-carbongo acid are placed in a flask and carefully added with stirring 5 liters of 33 % Na.OH. The reaction mixture is then stirred under reflux. After 3 hours, another liter of 33 % NH.OH is slowly added. It is stirred for a further 2 hours under reflux. The reaction solution is then evaporated until the product crystallizes out. The product is returned to the reaction flask.

and added with water until a clear solution is obtained (about 5 liters, pH 6.38). This solution is stirred vigorously while concentrated hydrochloric acid is added dropwise until a pH of 3 is reached. The precipitated white product is filtered off, washed thoroughly with water and dried. The yield is 273 g (1.12 mol, 91.8 %).

D) 1,4-dihydro-4-oxo-N- (2-oxo-1-imidazolidinyl) -5-phenyl-IQ methoxy) -2-pyridinecarboxamide

12.26 g (0.05 mol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid and 5.56 g (0.055 mol) of 1-amino-2-imidazolidinone are dissolved in 120 ml of dimethylformamide suspended. The suspension is mixed with 0.3 g of dimethylaminopyridine and 0.4 g of N-hydroxybenzotriazole. After stirring for 30 minutes at room temperature, the mixture is added dropwise with a solution of 11.35 g (0.055 mol) of dicyclohexylcarbodiimide in 50 ml of dimethylformamide and the mixture is then stirred overnight at room temperature. The precipitated precipitate of dicyclohexylurea is filtered off and the filtrate is evaporated under reduced pressure. The .sirupöse residue crystallized when treated with aqueous sodium hydrogen carbonate solution from being obtained a yield of 11.7 g of the title compound, mp 158-160 ⁰ C. Additional 0.8 g of the product having a melting point 162-164 ° C crystallize from the aqueous filtrate.

E) 1, ^ Dihydro-S-hydroxy-oxo-N- (2-oxo-1-imidazolidinyl) -2-pyridinecarboxamide

A suspension of 12 g (0.0365 mol) of 1, 4-dihydro-4-oxo-N- (2-OXO-1-imidazolidinyl) -5- (phenylmethoxy) -2-pyridinecarboxamide in 150 ml of acetonitrile is charged with 36, 1 ml (0.146 mol) of bis (trimethylsilyl) acetamide is added to give a slightly turbid solution. After filtering, 6 g of 10%

-810.86- 37853i

Added palladium-on-charcoal and passed hydrogen through the stirred reaction mixture. After 60 minutes of hydrogenation, the catalyst is filtered off and the solution is mixed with 15 ml of methanol and 2 ml of acetic acid. It is further stirred overnight, whereby the title compound in a yield of 6.6 g and a F. crystallized from 270 to 275 ° C.

F) (3S) - [Ί - [[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl-amino-2-oxo-1-imidazolidinyl] - sulfonyl] amino]. carbonyl] -2-oxo-3-azetidinyl] -carbamic acid phenyl ester

A suspension of 13.8 g of (S) -2- [_ [_ { phenylmethoxy) carbonyl "] aminoj-2-azetidinone in 500 ml of ethyl acetate is treated with 5.63 ml (0.0626 mol) of chlorosulfonyl isocyanate is stirred for 1 hour at room temperature, whereby a solution of (S) -1 - {'[_ (chlorosulfonyl) amino] carbonyl] -3- [[(phenylmethoxy) carbonyl] amino]] -2- azetidinone is formed. The solution is cooled to 0 ° C and slowly added at this temperature with a solution of silylated 1,4-dihydro-5-hydroxy-4-oxo-N- (2-OXO-1-imidazolidinyl) -2-pyridinecarboxamide. This was prepared by adding 46.4 ml (0.25 mol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide to a suspension of 14.9 g (0.0626 mol) of 1,4-dihydro-5-hydroxy- 4-oxo-N- (2-oxo-1-imidazolidinyl) -2-pyridinecarboxamide in 500 ml of ethyl acetate and stirring for 30 minutes. Subsequently, the mixture is mixed with 150 ml of dichloromethane and stirred overnight at room temperature. The clear solution is mixed with 26.2 ml (0.188 mol) of triethylamine and then with 300 g of ice and 200 ml of water. The pH is 6.5.

After stirring for 1 1/2 hours, the two phases are separated and the aqueous phase washed with three times 200 ml portions of ethyl acetate. After removal of the remaining ethyl acetate under reduced pressure, the pH of the aqueous phase is adjusted to 2 by slow addition of 2N hydrochloric acid (47 ml) with cooling. The crystals are filtered off, suspended in 200 ml of ethyl acetate

-310.86- 378531

-63-

and stirred for 1 hour. Then the crystals are filtered off, washed twice with 30 ml of ethyl acetate and twice with 50 ml of petroleum ether and dried under reduced pressure. There are obtained 28.6 g of the title compound with a mp of 190 to 200 ⁰ C (dec.).

G) (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl]] -amino '] -2-oxo i -imidazolidinyl]] sulfonyl] -2-oxo-1-azetidinecarboxamine trifluoroacetate salt (1: 2)

A mixture of 15 ml of trifluoroacetic acid and 3.5 ml of thioanisole is treated at room temperature with 4 g (0.00713 mol) of (3S) -Ql - CCCII ^ - [D ¹ - 4-dihydro-5-hydroxy-4-oxo-2 -pyridinyl) -carbo-

] _5 nyl] -amino-2-oxo-1-imidazolidinylj-sulfonyl] amino]] carbonyl] -2-oxo-3-azetidinylJ-carbaminic acid phenylmethyl ester and cooled to 1O ⁰ C. The clear solution is stirred at 10 ⁰ C overnight. After evaporation under reduced pressure at room temperature, the syrupy residue is treated with ether to give the title compound as a yellowish solid. The yield is practically quantitative

H) Q3S (Z) 3 - [[. 1- (2-Amino-4-thiazolyl) -2 - [[i - [[[[3- [I] (1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl]] sulfonyl]] amino] carbonyl] -2-OXO-3-azetidinyl] amino]] -2- oxo-ethyl-bis [] -amino]] oxy] -2-methylpropionic acid diphenyl! methyl ester

A solution of 3.08 g (0.007 mol) of (Z) -2-amino-iy - [[2- (diphenylmethoxy) -1, 1-dimethyl-2-oxoethoxy]] -imino "] -4-thiazole acetic acid in 70 ml dimethylformamide is treated with 2.9 ml (0.021 mol) of triethylamine are added and, after cooling to -30 ⁰ C under nitrogen with 1.55 ml (0.07 mol) of diphenyl chlorophosphate. The mixture is stirred for 1 hour at -30 ^0C. Then 1.95 ml (0.014 mol) of triethylamine are added and then 0.007 mol of (3S) -3-amino-N- [ß- [[(1,4-dihydro-5-

-810.86- 37853-1

hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide trifluoroacetate (1: 2) salt. The reaction mixture is stirred for 2 hours at -10 ⁰ C and 1 hour at 0 ⁰ C. Then the solvent is removed under reduced pressure. Treatment of the residue with water and ethyl acetate gives an insoluble product which solidifies upon treatment with ether. The yield of the crude compound is 8.0 g.

I) Di-sodium salt of [3S (Z)] -2 - [[[Ί- (2-Amino-4-thiazolyl) - ² ~ [Γ ¹ - Γ CΓ ^[3 ~ [D ^1/4 dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -aminoj-2-οxo-1-imidazolidinyl] -sulfonylj-aminojcarbonylJ-2-oxo-3-azetidinyl] amino] -2-oxo-ethylidene] - aminoj-oxyj-2-methylpropanoic acid

8 g of crude [3S (Z) J -2- [[[1- (2-amino-4-thiazolyl) -2- [[i - [[[[3- [Q 1, 4-dihydro-5-hydroxy 4-oxo-2'-pyridinyl) carbonyl] amino] 2-OXO-1-imidazolidinyl] sulfonyl] amino] carbonylj-2-OXO-3-azetidinyl] amino] -2-oxoethylidene] amino oxy] -2-methyl

20; propionsäurediphenylmethylester are dissolved in 15 ml of anisole suspendiert- After cooling to -10 ⁰ C, the suspension is added dropwise 80 ml of trifluoroacetic acid and then the mixture was stirred for 1 hour at -10 ^0C. Upon addition of ether at 0 °, the trifluoroacetate salt of the free acid of the product precipitates (4.1 g of the crude compound). The crude compound is suspended in water and the pH is adjusted to 5.5 by addition of sodium bicarbonate solution. The resulting solution is freeze-dried. The crude sodium salt is then purified by chromatography on HP-20 (a macroreticular styrene-divinylbenzene copolymer resin, Mitsubishi Chemical Industries, Ltd.). The product is eluted with water, giving 0.52 g of the product.

NMR (DMSOd ₆ ): δ = 1.35 (s, 3H); 1.40 (s, 3H), 3.37 (dd, IH); 3.47 (t, 2H); 3.81 (t, 2H + dd, IH); 5.05 (m, IH); 6.75 (s, IH); 7.27 (s, IH); 7.72 (s, 1H); 11.52 (broad s, 1H).

-818.86- 378t3i

] _. , Example 2

Di-Sodium salt of [2S (Z)] -2- [[(j - (2-amino-4-thiazolyl) -2 - [[1 - [[[^ 2 - [(1, 4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino} sulfonyl} amino} carbonyl} -2-oxo-3-azetidinyl] arnino} -2-oxoethylidene} amino] oxyJ-2-methylpropionic acid

A) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid 2- (1,1-dimethylethoxy) carbonyl] hydrazide

61.3 g (0.25 mol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid are suspended in 500 ml of dimethylformamide at room temperature and then with 39.65 g (0.3 mol ) N- (tert-butoxycarbonyl) hydrazine, 1.5 g of dimethylaminopyridine and 2.0 g of N-hydroxybenzotriazole. The mixture is stirred for 30 minutes at room temperature. Then, the mixture is added dropwise with stirring within 30 minutes with 57.7 g (0.28 mol) dissolved in 100 ml of dimethylformamide D-icyclohexylcarbodiimid and stirred overnight at room temperature. The precipitated dicyclohexylurea is filtered off and the filtrate is evaporated under reduced pressure. The syrupy residue crystallizes after treatment with dilute sodium bicarbonate solution. The dried crude product is recrystallized from 2 liters of ethyl acetate. The yield of the title compound is 69.5 g, mp 173-175 ⁰ C.

· Another 3.2 g.mit F. of 160 to 165 ° C are obtained after evaporation of the mother liquor.

B) 1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid hydrazide

370 ml of trifluoroacetic acid at 0 ⁰ C and 69 g (0.191 mol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinearbonsäure-2- \ X 1, 1-dimethyläthoxy) carbonyl} -hydrazide added. The mixture is stirred for 1 hour at room temperature and then evaporated. The syrupy residue is treated with ether.

There are obtained 68.2 g of the crude 1,4-dihydro-4-oxp-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide trifluoroacetate (1: 2) salt as a solid.

-ftmftR-378531

The precipitate crystallizes after 1 hour of stirring. The yield of the title compound is 6.6 g.

After evaporation of the ethyl acetate phase and treatment with petroleum ether to obtain a further 1.4 g of the title compound.

D) (3S) -3-amino-N- [2- (1,4-dihydro-5-hydroxy-4-oxo-2-pyri *)

dinyl) carbonyl "} hydra" ino] sulfonyl] -2-o xo-1-azetidinecarboxamide trifluoroacetate (1: 2) salt

A stirred mixture of 22 ml of trifluoroacetic acid and 5.3 ml of thioanisole is treated at room temperature with 6.6 g (0.0133 mol) of (3S) -jj - [. [[[[[. [1, 4-dihydro-4-oxo -5- (phenylmethoxy) -2-pyridinium

] _5 ⁿ yl] carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester was added and the mixture was stirred overnight at room temperature. The trifluoroacetic acid is removed under reduced pressure and the syrupy residue is treated with ether. The title compound is obtained in a guantitative yield.

E) [3S (Z)] - 2 - [[[i- (2-amino-4-thiazolyl) -2 - [[i - [[[[2 - [(1, 4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl] hydrazino = - sulfonyl] amino "] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2- Methylpropionäurediphenyl- methyl ester

A solution of 5.84 g (0.0133 mol) of (Z) -2-amino-cp - [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] -imino] -4-thiazole-acetic acid in 135 ml of dimethylformamide is mixed with 5.6 ml of triethylamine and after cooling to -30 ⁰ C with 3.57 g (0.0133 mol) of diphenylchlorophosphate. The mixture is stirred for 1 hour at -30 ° C, treated with 3.72 ml of triethylamine and then with 0.0133 mol of (3S) -3-amino-N - [[2-Q1,4-dihydro-5-hydroxy 4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] 2-oxo-1-azetidinecarboxamide trifluoroacetate (1: 2) salt.

-810.86- 37853-i

2b U I'll

] The crude 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide trifluoroacetate (1: 2) salt is dissolved in 52 ml of acetonitrile and stirred with cooling for 1 hour. The crystals are filtered off and resuspended in 600 ml of acetone tril. The suspension is mixed with 135 ml of bis (trimethylsilyl) -acetamide and then with 28 g of 10% palladium on charcoal. Subsequently, hydrogen is passed through the stirred solution. The hydrogenation is complete after 90 minutes. After filtration, 70 ml of methanol IQ and 2 ml of acetic acid are added. It is stirred overnight, the crystals formed are filtered off. This gives 19.4 g of the title compound having a mp of 290 to 340 ⁰ C (Zers.).

C) (3S) - [i -L [[[[[1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] hydrazino] sulfonyl] amino] carbonyl " ) -2-oxo-3-azetidinyl | -carbamic acid phenylmethyl ester

A suspension of 5.19 g (0.0236 mol) of (S) -3 - [[(phenylmethoxy) carbonyl] amino] -2-azetidinone in 160 ml of ethyl acetate is stirred at room temperature with 2.05 g (0 , 0236 mol) of chlorosulfonyl isocyanate. The mixture is stirred at room temperature for 1 hour to give a solution of (S) -1 - [ chloro-onyl) -amino *] -carbonyl] -3- [[(phenylmethoxy) -carbonyl] -amino] -2- azetidinone is formed. The solution is cooled to 0 ⁰ C and treated with 80 ml of dichloromethane, 9.9 ml (0.0707 mol) of triethylamine and a solution of silylated 1,4-dihydro-5-hydroxy-4-oxo-2-pyridincarbonsäurehydrazid added. The latter was obtained from a suspension of 3.99 g (0.0236 mol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid hydrazide in 50 ml of ethyl acetate and 8.75 ml of N-methyl-N- (trimethylsilyl) trifluoroacetamide (0.0472 mol). The mixture is stirred at room temperature overnight and then ice-water is added and stirring is continued for a further 30 minutes. The aqueous phase is covered with ethyl acetate and acidified to a pH of 2.5.

-S10.86- 37853-1

The mixture is stirred for 2 hours at -10 ⁰ C and 1 hour at 0 ⁰ C. The solvent is removed under reduced pressure and the syrupy residue with 150 ml of ethyl acetate and 70 ml ice water by adding 2N hydrochloric acid to a pH from 1.5 to 2, treated. The insoluble portion is removed and digested with ether, whereby 5.3 g of the crude product are obtained.

F) Di-sodium salt of [_3S (Z)] -2- [[qi - (2-amino-4-thiazolyl) 2- [Ql - [[[[[2 - [(1, 4-dihydro-5-hydroxy -4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoathyliden] amino] oxy] -2- methylpropionic

5.3 g (0.0069 mol) [3 S (Z)] -2- [[Ql - (2-amino-4-thiazolyl) -2- [Ql - [[[[2- (1; 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxo-ethylidene] -amino ] -oxy] -2-methylpropionic acid are suspended in 10.6 ml of anisole. The suspension is cooled to -10 ⁰ C and treated while stirring with 53 ml of trifluoroacetic acid. The mixture is stirred at this temperature for 1 hour and then treated at -10 ⁰ C with 200 ml of ether to precipitate the trifluoroacetate salt of the free acid of the title compound. The yield is 7.3 g.

. ·

The crude product is dissolved in a mixture of 100 ml of water and 50 ml of acetone. The pH is adjusted to 5 to 5.5 and the acetone is removed under reduced pressure. The remaining aqueous solution is lyophilized. There are obtained 8.1 g of the crude product, which is purified by chromatography on HP-20, eluting with water. The chromatography gives 1.05 g of the product.

NMR (DMSOd ₅ ): δ = 1.40 (s, 3H); 1.42 (s, 3H); 3.25 (dd, IH); 3.70 (dd, IH); 5.10 (m, IH); 6.75 (s, IH); 7.40 (s, IH); 7.80 (s, IH); 11.32 (broad s, IH).

-8.10.86- 378531

1 'Example 3

The di-sodium salt of [ßS (Z) J -2- [[[- - (2-amino-4-thiazolyl) -2-LE ^ "CLC [3 - [[. (1, 4-dihydro-5-hydroxy 4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidizolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] -amino] -oxy] - 2-acetic acid

A) | ~ 3S (Z)] - 2 - [[[i- (2-Amino-4-thiazolyl) -2 - [[i - [[[3 - [[(1 , A-

dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl-amino] -2- IQ oxo-1-imidizolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino ] -2-oxoethylidyl] amino '] oxy] -2-acetic acid diphenylmethyl ester

A solution of 2.06 g (0.005 mol) of (Z) -2-amino-OT - [[2- (di-] 5-phenylmethoxy) -2-oxoethoxy] -imino] -4-thiazoleacetic acid in 100 ml of dimethylformamide is added Added 2.1 ml (0.015 mol) of triethylamine. The mixture is cooled to -30 ⁰ C and treated with stirring with 1.1 ml (0.005 mol) of diphenylchlorophosphate. After stirring for 1 hour at -30 ⁰ C additional 1.4 mL (0.1 mol) of triethylamine at -30 ° C are added and then 2.7 g of (3S) -3-amino-N - [[3- [ [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide-trifluoroacetate ( 1: 2) salt.

'".

The reaction mixture is stirred for 2 hours at -10 ⁰ C and 1 hour at 0 ⁰ C. The solvent is evaporated under reduced pressure. The oily residue is suspended in water and the pH of the suspension is adjusted to 2 by the addition of 2N hydrochloric acid. The suspension is stirred for 30 minutes at room temperature, filtered off, the solid is resuspended in water and filtered again. After drying under reduced pressure over phosphorus pentoxide, 5.0 g of the crude product are obtained. The material is used in the next step without further purification.

-810.86- 378531

B) Di-sodium salt of [3S (Z)] -2- [[[i - (2-amino-4-thiazolyl) -2-CD - [[CD-CD ¹ > 4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl) carbonyl]} - amincQ-2-oxo-1-imidizolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] oxy] -2-acetic acid

5.0 g crude [3 S (Z ) ~ \ -2- [[[- - (2-amino-4-thiazolyl) -2- [[- - - [[[[3- [£ (1, 4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl '] amino] 2-OXO-1-imidizolidinyl] sulfonyl] amino carbonyl] -2-OXO-3-azetidinyl] - amino "] -2-oxoäthyliden] amino] oxy] -2-essigsäurediphenylmethylester are suspended at -10 ⁰ C in a mixture of 10 ml of anisole and 50 ml of trifluoroacetic acid. The reaction mixture is stirred for 1 hour at -10 ⁰ C and subsequently 100 ml of ether are added cautiously to precipitate the crude trifluoroacetate salt of the title compound, the yield is 3.7 g, the crude compound is dissolved in a mixture of 30 ml of water and 60 ml of acetone, and the pH of the mixture is reduced by adding The acetone is evaporated off and the aqueous phase is lyophilised to give 3.9 g of the crude product The crude product is purified by chromatography on HP-20 The product is eluted with water there will be factions n of 10 ml each. The fractions containing the product are lyophilized. It will be one

25- yield of 0.6 g of the material, which is a-n HP-20 rechromatographiert. There are obtained 0.25 g of fine product.

^ Example 4

[3S (Z) J -2- [[[i- (2-amino-4-thiazolyl) -2- [[i - [[[[[[(1,4-dihydro-5-hydroxy-4-oxo) 2-pyridinyl) -methyl] -amino-sulfonyl] -aminoj-carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2-methylpropionic acid

A) 2- (Hydroxymethyl-5- (phenylmethoxy) -4- (1H) -pyridinone

-810.86- 37853: 1

A mixture of 9.65 g (41.59 mmol) of 2- (hydroxymethyl) -5- (phenylmethoxy) -4 H -pyran-4-one, 95 mL of concentrated ammonia and 20 mL of ethanol is heated at-reflux overnight. Then an additional 75 ml of ammonium hydroxide are added and the mixture is refluxed for 2 hours and then cooled. The resulting brown solid is filtered off and washed with water until the washings become neutral. are. The crude product is suspended in methanol, filtered, washed with ethanol and hexane and dried under reduced pressure. The yield of the title compound is 7.1 g.

B) 2- (chloromethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone monohydrochloride

A suspension of 3 g (12.99 mmol) of 2- (hydroxymethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone in 15 ml of chloroform is cooled to 0 ° under argon and acidified with 6.1 ml (83 ml, 83%). 62 mmol) thionyl chloride. Within a few minutes, a homogeneous solution is obtained. After stirring for an additional 5 minutes, a cream solid precipitates. The cooling bath is removed and the mixture heated at reflux for 45 minutes. The mixture is cooled to 0 ° and the white precipitate is filtered off, washed with chloroform and hexane and dried under reduced pressure. The yield of the title compound is 3.65 g.

C) 2- (azidomethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone

A mixture of 3.50 g (12.54 mmol) of 2- (chloromethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone monohydrochloride, 4.08 g (62.7 mmol) of sodium azide and 2.19 ml ( 12.54 mmol) of diisopropylethylamine in 70 ml of dimethylformamide is stirred under argon for 3 1/2 days at room temperature. The mixture is additionally treated with 4.08 g of sodium azide and then heated to 45 to 50 ⁰ C for 2 hours. After cooling, the reaction mixture is poured into 500 ml of water, leaving an insoluble white solid.

-310.86- 37853Ί

fabric is formed. The pH of the supernatant is lowered from 8.5 to 7.5 with dilute hydrochloric acid and the white solid is then filtered. After washing with. Water, acetone and hexane, the solid is dried under reduced pressure. The yield of the title compound is 2.81 g.

D) 2- (Aminomethyl) -4- (phenylmethoxy) -4- (1H) -pyridinone

A mixture of 2.03 g (7.93 mmol) of 2- (azidomethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone and 200 mg of platinum oxide in 100 ml of dimethylformamide is added under a nitrogen atmosphere for 6 hours at room temperature The catalyst is filtered off and the solution is concentrated under reduced pressure to give 1.5 g (82 % yield) of the title compound as a gray powder.

E) (3S) - [J - QCCCCC ^1, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] methyl] amino] sulfonyl] amino] carbonyl] -2-oxo- 3-azetidinylX-carbamic acid phenylmethyl

A stirred suspension of 2.330 g (10.13 mmol) of 2- (aminomethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone in 60 ml of ethyl acetate is charged with 3.76 ml (20.26 mmol) of N-methyl -N- (trimethylsilyl) trifluoroacetamide. The resulting solution is stirred for 30 minutes at room temperature and then cooled to 0 ^° C. In parallel, a stirred suspension of 2.288 g (10.13 mmol) of (S) -3-CB phenylmethoxy) carbonyl] amino] -2-azetidinone in 60 ml of ethyl acetate with 882 μ liter (10.13 mmol) of chlorosulfonyl isocyanate added. The resulting solution is stirred for 30 minutes at room temperature, cooled to 0 ° and finally with 4.23 ml (30.30 mmol) of triethylamine and then with the solution of the above-described silylated 2- (aminomethyl) -5- (phenylmethoxy) -4 - (1H) -pyridinone added. The mixture is stirred for 2 days at room temperature.

~ · - rs i

Concentrate the concentrate under reduced pressure, dissolve the residue in CH, CN-water (40:60) and reduce the pH to 2.9, separating off a thick oil. After cooling to 5 ° C, the oil solidifies. The solid is separated, washed four times with water and dried under reduced pressure. There are obtained 3.4 g of crude product. The crude product is dissolved in a min of dimethylformamide and applied to a column (1 liter) of HP-20 resin. The column is eluted stepwise with an acetone-water gradient. The desired substance is eluted at about 65 % acetone. The appropriate fractions are collected and lyophilized. There are obtained 2.69 g of the title compound.

F) [3S. (Z)] J-2 - [[[i- (2-Amino-4-thiazolyl) -2 - [[i - [[[[[[(1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl) -methyl]] -amino-sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidyl] amino] oxy] -2-methylpropionic acid diphenylmethyl ester (as a mixture of monopotassium and monotriethylammonium salt)

A mixture of 912 mg (1.64 mmol) of (3S) -Qi - [[[[[Ql, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -methyl] -amino] sulfonyl ] -aminoj-carbonyl] -2-oxo-3-azetidinyl] -carbamic acid phenylmethyl ester, 625 mg (3.28 mmol) of p-toluenesulfonic acid monohydrate and 190 mg of 10% palladium on charcoal in 16 ml of dimethylformamide is placed in a hydrogen atmosphere stirred until 3.28 mmol (73 ml) of hydrogen are consumed (about 3 hours).

A stirred solution of 846 mg (1.804 mmol) of (Z) -2-amino- [[2- (diphenylmethoxy) -1, 1-dimethyl-2-oxoethoxy] -imino] -4-thiazole acetic acid in 16 ml of dimethylformamide is added -20 ⁰ C with 374 uLiter (1.804 mmol) of diphenyl chlorophosphate and then with 450 uLiter (3.28 mmol) of triethylamine.

The solution is stirred for 1 hour at -20 ⁰ C and then the above-described mixture of hydrogenated (3S) - Q - [[[[CD> f '

] _ Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] methyl] -amino] sulfonyl] -amino "] -carbonyl] -2-oxo-3-azetidinyl] -carbamic acid ephenylmethyl ester resulting mixture is 1 - stirred for an hour at -20 ⁰ C and then at 5 ° C overnight, the catalyst is filtered off, the volatiles removed under reduced pressure and the residual oil taken up in a small volume of acetone / water (75 to 25, pH. 5.2) and added dropwise to a stirred suspension of 20 ml Dowex 50x2-400 (K ⁺ ) (styrene-divinylbenzene copolymer gel with -SO ₃ -! _ Q groups) in acetone / water (35: 65) The mixture is filtered for 40 minutes and the filtrate is lyophilized to give 2.1 g of a solid The solid is dissolved in a small amount of acetonitrile / water (40 to 60, pH 5.6) and applied to a column (800 ml). of HP-20] _g resin The column is eluted stepwise with an acetonitrile / water gradient The desired compound is b about 30 % acetonitrile is eluted. The appropriate fractions are collected and lyophilized. There are obtained 254 mg of the non-pure title compound.

G) [3S (Z)] - 2 - [[(j- (2-amino-4-thiazolyl) -2 - [[iQ [[[[(1,4-dihydro-5-hydroxy-4-oxo) 2-pyridinyl) -methyl] -amino] -sulfo, nylj-amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] -amino] -oxy] -2-methylpropionic acid

A stirred suspension of 131 mg of the mixture of mono-

potassium and monotriethylammonium salt of the above non-pure [3S (Z)] -2- [_ [_ [) - (2-amino-4-thiazolyl) -2- [1 - [[[[[[1, 4- dihydro 5-hydroxy-4-oxo-2-pyridinyl) -methyl] -amino] -sulfonyl] amino] on carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidyl] amino] -oxy ] -2-Methylpropionsäure-diphenylmethylesters' in 3 ml of dichloromethane and 0.3 ml of anisole is added dropwise at 0 ⁰ C with 4.7 ml of trifluoroacetic acid. After stirring at 5 ^° C. for 45 minutes, 2 ml of toluene are added and the volatile substances are removed under reduced pressure. The residual oil is washed three times with 4 ml of hexane and washed with

-imflififi- 37853Ί

250

The solid is washed once with ether (10 ml) and dried under reduced pressure The above reaction and work-up are washed with 166 mg [3S (Z)] - 2 - [[[i - (2-Amino-4-thiazolyl) -2 - [[i UCC [D ¹ , '1-dihydro-S-hydroxy-1-oxo-1-pyridinyl) -methyl] -amino] sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy-2-methylpropylmic acid e-diphenylmethyl-1-ester (mixture of monopotassium and monotriethylamine salt) wherein an acetonitrile / water is used and treated on a column (200 ml) of HP-.20 resin chromatogra ⁱ initialed, Der: are combined in 2 ml CH-CN-water (60, pH 2, 5, ^40!). The desired material is eluted at a CH ₃ CN to water ratio of 20:80 and the appropriate fractions are pooled and lyophilized to give 103 mg of [3 (Z)] - 2 - [[[i- (2-amino-4- thiazolyl) -2 - [[i - [[[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl] -amine o] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy-2-methylpropionic acid ^. as a white solid.

Example 5

Di-sodium salt of [~ 3S (Z)] -2- [[[1- (2-amino-4-thiazolyl) -2-L [1 - [[CU ² - C [2- D ¹ , 4-dihydro 5-hydroxy-4-oxo-2-pyridinyl) -carbonyIj-hydrazino] -carbonyl] -hydrazino-1-sulfonyl] -amino] -carbonyl-2-oxo-3-azetidinyl-J-amine [2-oxoethylidene] -amino] oxy] -2-methyipropionsäure

A) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid 2- [Q 4 -methoxyphenyl) methoxy] carbonyl] hydrazide

A stirred suspension of 4.90 g (0.020 mole) of 1,4-dihydro-4-OXO-5- (phenylmethoxy) -2-pyridinecarboxylic acid, 4.50 g (0.022 mole) of 4-methoxybenzylcarbazate, 0.12 g (1 , 0 mmol) 4-dimethylaminopyridine and 0.155 g (1.0 mmol) of 1-hydroxybenzotriazole hydrate in 25 ml of anhydrous dimethylformamide is treated at room temperature with a solution of 4.45 g (0.022 mol) of dicyclohexylcarbodiimide in 25 ml of anhydrous dimethylformamide.

"Ε ·

and stirred overnight. The precipitate is filtered off and the filtrate is evaporated under reduced pressure. The residue solidifies when stirred with ether and aqueous sodium bicarbonate solution. The solid is collected, washed with water and finally dried under reduced pressure. The crude compound (8.14 g) is extracted in a Soxhlet apparatus with 800 ml of CH 2 Cl 2, 7 hours. 5.70 g (67 %) of pure 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid 2 - [[(4-methoxyphenyl) methoxy] cocarbonyl hydrazide crystallize directly from the cold CHCl ₃ ~ extract. An additional 1.5 g (18 %) of the neat title compound can be obtained by evaporation of the CHC1_ solution under reduced pressure. F. 174.5 to 178 ° C.

B) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide trifluoroacetate (1: 2) salt

An ice-cold suspension of 3.71 g (8.76 mmol) of 1,4-dihydro-4-OXO-5- (phenylmethoxy) -1-pyridinecarboxylic acid 2- [[] (4-methoxyphenyl) methoxy] Carbonyl ^ hydrazide in 15 ml of anhydrous dichloromethane is added to a solution of -10 ⁰ C of 3.81 ml (35.04 mmol) of anisole in 38 ml of trifluoroacetic acid. After 20 minutes of stirring at 0 ⁰ C, the solution is evaporated under reduced pressure. The title compound is obtained as a solid. This is stirred with a few ml of anhydrous ether, collected by suction and dried under reduced pressure. The yield is 3.25 g (99 %), mp 173-175 ° C (Zers-)

 30

C) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide

A suspension of 3.19 g (8.55 mmol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide trifluoroacetate (1: 2) salt in 35 ml of anhydrous acetonitrile is added with 3.84 ml

2SO

(19.64 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide and stirring continued for 30 minutes at room temperature. After evaporation under reduced pressure, the residue is taken up in ether and treated dropwise with 1 ml of methanol. The precipitate is collected by suction, washed with ether and petroleum ether and dried under reduced pressure. There are obtained 2.05 g (92 %) of the title compound with a mp of 204 to 208 ⁰ C (dec.).

D) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid 2-yl [[2- (phenylmethoxy) carbonyl]} hydrazino] carbonyl]] hydrazide

With cooling, a suspension of 5.19 g (0.02 mole) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide in 20 ml of anhydrous acetonitrile with 11.69 ml (0.060 mole) of N Methyl-N-trimethylsilyl trifluoroacetamide added and stirred for 30 minutes at room temperature. The clear solution is evaporated under reduced pressure and the residue redissolved in 30 ml of anhydrous dichloromethane. This solution is added dropwise to a stirred solution of 4.57 g

(0.020 mol) of PhCH ₂ OCNHNHCOCl (J. Gante, Chem. Ber. 97 (1964), 2551) in 60 ml of dichloromethane at 0 to 5 ° C. After 2 1/2 hours of stirring at this temperature, the solution is evaporated under reduced pressure and the solid foam dissolved in 20 ml of methanol. Evaporation under reduced pressure gives the title compound as a solid foam, which becomes crystalline upon stirring with anhydrous ether. The yield is 8.87 g (98 %), mp> 120 ° C (dec.).

E) 1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid 2- (hydrazinocarbonyl) hydrazide dihydrochloride

A solution of 4.02 g (8.9 mmol) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridines ar bonsäure- 2 - \ £ JJ2- (phenylmethoxy) carbonylj-hydrazinqj-carbonylj-hydrazide in 50 ml of methanol,

- ft in ft R -

which contains 2.94 ml (35/6 mmol) of concentrated hydrochloric acid, is hydrogenated in the presence of 0.4 g of palladium (10 %) on carbon for 10 minutes. The catalyst is filtered off and the solvent is distilled off under reduced pressure. The title compound remains as a solid (2.58 g),

which is stirred with a few ml of anhydrous ether, collected by suction and dried under reduced pressure. The yield is 2.47 g (92 %), mp 235-236 ° C (Zers ..)

 10

F) (3S) - [1 - [[[[2 - [[2-Q (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] hydrazino-carbonyl "] - hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -carbamic acid phenylmethyl ester

A suspension of 1.5 g (5.0 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-.2-pyridinecarboxylic acid-2 (hydrazinocarbonyl) -hydrazide dihydrochloride in 20 ml of anhydrous acetonitrile is mixed with 4.86 ml ( 25.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide. After stirring at room temperature for 45 minutes, the clear solution is evaporated under reduced pressure and the residue is dissolved in 20 ml of anhydrous ethyl acetate (solution A). -

A suspension of 1.10 g (5.0 mmol) of (S) -3 - [[(phenylmethoxy) carbonyl] amino] -2-azetidinone in 40 ml of anhydrous acetic acid ethyl ester is added with 0.45 ml (5.0 mmol ·) "chlorosulfonyl isocyanate was added with stirring. The mixture is stirred for 1 hour at room temperature and then cooled to 0 ⁰ C. After addition of 10 ml of anhydrous dichloromethane and 2.09 ml (15.0 mmol) of triethylamine solution A at 0 ⁰ C After stirring overnight at 0 ^° C., the reaction mixture is poured into ice-water and the organic layer is separated off After acidifying the aqueous phase to pH 2 by adding 1N hydrochloric acid, the title compound is obtained as a sticky precipitate. which by

-810.86- 378531

is collected, washed with water and dried under reduced pressure. The yield is 1.76 g (64 %) .

G) (3S) -3-Amino-N - [- [2 - [[2-Q (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] carbonyl] -hydrazine] sulfonyl] -2-OXO-1-azetidinecarboxamide trifluoroacetate (1: 2) salt

A mixture of 5.13 ml trifluoroacetic acid and 1.21 ml of thioanisole is at '0 ⁰ C with 1.73 g (3.1 mmol) of (3S) - (j - [£ [[2- _[L 2 - [( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -carbamic acid phenylmethyl ester After stirring overnight at room temperature, the solution is evaporated under reduced pressure and the residue is stirred with anhydrous dichloromethane The precipitate is collected by suction, washed with dichloromethane and dried under reduced pressure. Yield of the title compound is 1.78 g. 88 %).

H) [3S (Z)] - 2-Q [l] i- (2-Amino-4-thiazolyl) -2 - [[i - [[Qr_2 - [. [2 - [(1 , < dihydro-5 -hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino J-2-oxoethylidyl] amino ] -oxy] -2-methyl-propionic acid diphenylmethyl ester

At -30 ⁰ C a solution of 1.10 g (2.5 mMol4- (Z) -2-amino- (X- [_ {j 2-diphenylmethoxy) -1, 1-dimethyl-2-oxoäthoxy] is - imino] 4-thiazoleacetic acid in 22 ml of anhydrous dimethylformamide with 1.05 ml (7.5 mmol) of triethylamine and 0.53 ml (2.5 mmol) of diphenylchlorophosphate are added after stirring for 1 hour at -30 ° C 1.05 ml (7.5 mmol) of triethylamine, followed by 1.62 g (2.5 mmol) of (3S) -3-amino-N- [2- [2- [ 1,4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] carbonyl] hydrazino] sulfonyl] -2-oxo-1-azetidinecarboxamide

-Q in OC

trifluoroacetate (1: 2) salt. The mixture is stirred for 2 hours at -10 ⁰ C and 1 hour at 0 ⁰ C. The solvent is removed under reduced pressure, and the residue taken up in a few ml of ethyl acetate and ice-water. The pH of the mixture is adjusted to 2 ^J with dilute hydrochloric acid. The insoluble matters are collected by suction and stirred with a few ml of ethyl acetate until they become crystalline. The yield after drying under reduced pressure is 1.72 g (82 %) of the title compound.

I) Di-sodium salt of [3 S (Z ) -2- [[ε- (2-amino-4-thiazolyl) -2-LD-L [[[2- LL ² L ⁽¹ ) 4-] dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] [hydrazines] carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl 2-amino] -2-oxoethylidene ] amino] oxy] -2-methyl propionic acid

A suspension of 1.68 g (2.0 mmol) crude "[jS (Z) J-2 - [[[1- (2-amino-4-thiazolyl) -2 - [_ [1 - [. [2 - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2- Oxo-3-azetidinyl] amino] -2-oxoäthyliden3-amino] -oxy ^ -2-methylpropionsäurediphenylmethylester in 3 ml of anhydrous dichloromethane is added with 2.0 ml of anisole and then with 20 ml of trifluoroacetic acid at -10 ⁰ C nach -minütigem stirring at 0 ⁰ C, the solvent is under reduced pressure at 0 to 5 ⁰ C removed. the residue is taken up in ice water and ether, and the pH by addition of 1% dilute sodium hydroxide solution adjusted to 6.0. the organic Phase and the insoluble material (0.38 g) are separated and the aqueous phase

3Q freeze-dried (2.65 g). The residue from the lyophilization is purified on XAD-2 resin (macroreticular styrene-divinylbenzene copolymer) eluting with water. After lyophilization, 0.25 g (17 %) of the title compound are obtained as a colorless powder having a melting point> 213 ° C. (dec.).

-31086- 378531

1, . , Example .. 6

Di-sodium salt of Q3S- {3C ( iZ), 4ß]] -2- [[Ql - (2-amino-4-thiazolyl) -2-Q] - [[[[2- Q 1, 4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] amino] carbonyl] -4-methyl-2-

5. oxo-3-azetidinyl] _-amino] -2-oxoethylidene] _-amino] -oxy] -2-methyl-

thy propionic acid!

A) (3S-trans) -Q1- £ [[[2 - [[i, 4-dihydro-4-oxo-5-hydroxy-2-pyridinyl] carbonyl] hydrazino] sulfonyl] amino carbonyl] -4-. rnethyl-2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester

A suspension of 2.34 g (3S-trans) - (4-methyl-2-oxo-3-azetidinyl) -carbaminsäurephenylmethylester in 50 ml of anhydrous ethyl acetate is treated with 1.41 g Chlorsulfonylsiocyanat. After 1 hour of stirring at room temperature, a clear solution is formed (solution A).

A suspension of 1.70 g of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid hydrazide in 50 ml of anhydrous ethyl acetate is treated with 6 g of N-methyl-N- (trimethylsilyl) trifluoroacetamide. After 1 hour of stirring at 50 ⁰ C, a * clear solution is obtained (solution B).

After cooling to -10 ⁰ C, solution A is treated with solution B and the mixture is stirred overnight at room temperature. After cooling to -15 ⁰ C, 3 g of triethylamine are added and then 150 ml of ice water. After 1 hour of stirring at ^{0 0} C, the organic phase is washed with 50 ml of water. The pH of the combined water phases is adjusted to 2 with 1N HCl and they are extracted three times with 100 ml of ethyl acetate. The combined organic phases are dried and the solvent evaporated. There are obtained 3.64 g of the title compound.

B) (3S-trans) -3-amino-N - [[2- (4,2-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] -4-methyl -2-oxo-

2bu

-82-1-azetidinecarboxamide trifluoroacetate (1: 2) salt

3.5 g of (3S-trans) - [i- [ε [2-ol, 4-dihydro-4-oxo-5-hydroxy-2-hyridinyl} carbonyl} hydrazino] sulfonyl-amino ] -carbonyl] -4-methyl-2-oxo-3-azetidinyl ^] -carbaminsäurephenylmethylester in 20 ml of thioanisole are added at room temperature with 50 ml of trifluoroacetic acid and the reaction mixture then stirred for 13 hours. After addition of 100 ml of ether, 3.2 g of a crude precipitate are obtained. This precipitate is then stirred for 1 hour in 50 ml of isopropanol-methylene chloride (1: 1). There are obtained 2.21 g of the title compound.

C) [3S- [3Of (Z), 4βJ] -2 - [[l- (2-amino-4-thiazolyl) -2- [lj - [[[[2 - [(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonyl ^ - ^ hydrazine] -sulf ony \] -aminoj-carbonyl "] -4-methyl-2-oxo-3-azetidinyll-amino] -2-oxoäthyliden] -amino] -oxy} -2-methylpropionic acid diphenylmethyl ester

A solution of 1.8 g of (Z) -2-amino-iV- [Q (diphenylmethoxy) -1, 1-dimethyl-2-oxoethoxy-1-imino] -4-thiazoleacetic acid and 1.2 g of triethylamine in 30 ml of dimethylformamide at -30 ⁰ C mixed with 2.1 g of diphenyl chlorophosphate. After stirring for 45 minutes at -30 ⁰ C 1.95 g (3S-trans) -3-amino-N - [[2-Q 1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) Carbonyl ^ hydrazino "] sulfonyl]] -4-methyl-2-oxo-1-azetidincarboxamid trif luoracetat- (1: 2) salt in 10 ml of dimethylformamide was added and then 0.8 g of triethylamine After 2 hours stirring at -10 ⁰ C and stirring for 1 hour at 0 ⁰ C, the dimethylformamide is UNR. ter removed under reduced pressure. the residue is treated with "

250 ml of methyl acetate and 400 ml of ice water. The pH of the water phase is adjusted to 1.5 with 2N HCl and this is extracted twice with 200 ml portions of ethyl acetate. The organic phase is dried over sodium sulfate and evaporated. There are obtained 1.3 g of the crude title compound.

η: " η J

D) Di-sodium salt of [3S- [βo {{ Z), 4β] "J-2- [_ [[j - (2-amino-4-

thiazolyl) -2- [y] - [ε [2- [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino-1-sulfonyl-amino] carbonyl] 4-methyl 2-oxo-3-azetidinyl] amino-2-oxoethylidene] -amino] oxy] -2-methylpropionic acid

A solution of 1.2 g of [3S- [30f (Z), 4β]] -2- [[[i - (2-amino-4-thiazolyl) -2- [Ji-- Q [[I ~ J2- [1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl] carbonyl "] hydrazino] sulfonyl] amino] carbonyl] -4-methyl-2-oxo-3-azetidinyl] - amino] -2-oxoethylidyl] -aminoj-oxy] 2-methylpropionic acid diphenylmethyl ester in a mixture of 10 ml of methylene chloride and 15 ml of anisole is added 30 ml of trifluoroacetic acid at -5 ° C. After stirring for 30 minutes, 100 ml of ether are added This precipitate is suspended in 20 ml of water and the pH is adjusted to 6.5 with sodium bicarbonate The clear solution is then chromatographed on XÄD-2, eluting with water 0.28 g of the pure title compound are obtained.

Example 7

Di-sodium salt of [3S (Z) "] -1 - [_ [Jj - (2-amino-4-thiazolyl) -2- [_ [_} - HlTC" * "[[(1,4-dihydroxy) 5-hydroxy-4-oxo-2-pyridyl-carbonyl "] - amino] -2-OXO-1-imidazolidinyl"] -sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl "] -amino ] -2-oxoethylidene] -amino] -oxy] cyclopentanecarboxylic acid

A) ljS (Z)] - 1 - [[Qi- (2-amino-4-thiazolyl) -2-LD - [[[[ ^3- LB ¹ , 4-dihydro-5-hydroxy-4-oxo-2 -pyridinyl) carbonyl] amino "] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene"] amino] - oxy] cyclopentanecarboxylic acid diphenylmethyl ester

A suspension of 3.9 g (8.3 mmol) of (Z) -2- (diphenylmethoxy) carbonyl] cyclopentyl-oxy] [- imino] -4-thiazole acetic acid in 100 ml of anhydrous acetonitrile is added

O -! O Γ "

Added 3.5 ml (25 mmol) of triethylamine, whereby a clear solution is obtained. After cooling to -30 ⁰ C 1.8 ml (8.3 mmol) of diphenyl chlorophosphate are added and the mixture for 1 hour at -30 ⁰ C. (solution A).

At the same time, 4.5 g (8.3 mmol) of (3S) -3-amino-N-

[[J3- (4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide - trifluoroacetate (1: 2) salt is suspended in 100 ml of anhydrous LQ 1 ethyl acetate, followed by addition of 7.2 ml of bis (trimethylsilyl) acetamide at room temperature, giving a clear solution after 5 minutes After stirring for 1 hour, the solution is cooled to 0 ^° C. (solution B).

Solution A is added dropwise at -30 ⁰ C within 10 minutes while stirring with solution B. The mixture is stirred for 1 hour at -10 ⁰ C and 1.5 hours at 0 ⁰ C. The volatiles are evaporated and the residue with water

2Q digested. The residue solidifies and the solids are collected and resuspended in water at a pH of about 2 again. After stirring for 30 minutes, the solid is collected and dried. It will be 12.0 g of crude. Title compound obtained.

B) Di-sodium salt of [3S (Z)] -1 - Q [[1- (2-amino-4-thiazolyl) -

2-LD - [LED- [Q ¹ , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] _-amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino-carbonyl ] -2-oxo-3-azetidinyl-3-amino-2-oxoethylidene] j OQ amino], - oxy] cyclopentanecarboxylic acid

12 g of crude [3S (Z)] -1 - [[Ql - (2-amino-4-thiazolyl) -2- [Ql - [[QQ3-LD - CLLC ³ - \ SS ¹ .4-dxhydro-5 -hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] -sulfonylj-amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene ] -amino] -oxy] -cyclopentanecarboxylic acid diphenylmethyl ester are dissolved in 20 ml

/ -> ο ι

• i anisole and admixed to -10 ⁰ C and 100 mL of trifluoroacetic acid upon cooling. The mixture is stirred for 1 hour at -10 ⁰ C and then treated at -10 ⁰ C with 300 ml of ether, wherein a precipitate precipitates. After 1 hour of

The precipitate is filtered off. It will receive 5.7g. This compound is dissolved in a mixture of 30 ml of water and 60 ml of acetone, and the pH of the solution is adjusted to 5.5 by addition of 0.1N NaOH at 0 ° under stirring, the acetone being evaporated under reduced pressure and the aqueous solution is freeze-dried to give 5.7 g of a solid residue, which residue is chromatographed on HP-20, eluting with water to give 1.69 g (27 %) of the pure title compound.

¹ H-NMR (DMSO-d ₆ + CF ₃ COOH): δ = 1.67 (s, 4H); 2.07 (2, 4H); 3.65 (t, 2H); 3.75 (dd, IH); 3.97 (dd, IH); 4.07 (t, 2H); 5.07 (dd, IH); 7.00 (s, IH); 7.67 (s, IH); 8.07 (s, IH); ppm.

Example 8

Di-sodium salt of [3S (Z) J-2- [ε (j - (2-amino-4-thiazolyl) -2-LE ¹ - [LEL ³ -D ¹ '4 -dihydro-5-hydroxy-4 -0x0-2-pyridinyl) -methyl] 2-OXO-1 -imidazolidinyl] -sulfonyl]] -amino]] -carbonyl3-2-oxo-3-azetidinyl-3-amino] [- 2-oxoethylidene] -amino] -oxy ] -2-methylpropionic acid

A) 2- (azidomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone

3Q A suspension of 2, .Og (6 mmol) of 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone in 20 ml of acetonitrile is charged with 3.9 g (60 mmol ) Sodium azide and 0.1 g of {J8] -Crown-6. The mixture is refluxed for 4 hours. The salts are filtered off by suction and the filtrate is evaporated under reduced pressure. The residue is purified by column chromatography on silica gel with ethyl acetate /

-mnftfi- 37853Ί

Methanol 8: 2 purified. 1.86 g of the title compound with a melting point of 120 ^° C. are obtained.

B) 2- (Aminomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone

1.0 g (2.89 mmol) of 2- (azidomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone are dissolved in 50 ml of methanol and admixed with 0.10 g of platinum oxide , Hydrogen is then passed through the mixture for 30 minutes, and then the catalyst is filtered off by filtration through Hyflo. The filtrate is evaporated under reduced pressure and the oily residue is digested with ether. There are obtained 0.89 g of the crystalline title compound with a mp of 207 ⁰ C.

O 2 -LCCCi 2 -chloroethyl) -amino-carbonyl] -amino] -methyl] -5- (phenylmethoxy) -2- (phenylmethyl) -4- (1H) -pyridinone

A suspension of 48.0 g (0.15 mol) of 2- (aminomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone in 1.5 liters of ethyl acetate is mixed with 12.8 ml Added (0.15 mol) of 2-chloroethyl isocyanate. The mixture is stirred overnight at room temperature and the product is filtered off by suction. It is washed with ethyl acetate and then dried under reduced pressure. There are obtained 59.6 g of the title compound with a F. of 130 ⁰ C.

D) 2-Q 2 -0-oxo-1-imidazoylidinyl) -methyl] -5- (phenylmethoxy) -1 (phenylmethyl) -4- (1H) -pyridinone

A mixture of 60.8 g (0.13 mol) of 2-CCLC ^ 2-Crilor-α-thyl) -amino-carbonyl] amino-methyl-5- (phenylmethoxy) -2- (phenylmethyl) -4- ( 1 H) -pyridinone and 1.3 liters of ethanol is added dropwise with a solution of 7.29 g (0.13 mol) of potassium hydroxide 'in 500 ml of ethanol. The reaction mixture is heated at reflux for 3 hours and then the solvent

evaporated under reduced pressure. The residue is purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (7; 3) as eluent. There are obtained 23.1 g of the product, which is further purified by recrystallization from acetonitrile. There are obtained 17.0 g of the title compound with a mp of 190 ⁰ C (Zers *.).

E) 5-Hydroxy-2- [(2-oxo-1-imidazolidinyl) -methyl] -4- (1H) -pyridinone-p-toluenesulfonic acid salt

A solution of 4.98 g '(12.8 mmol) of 2-Q (2-oxo-1-imidazolidinyl) methyl-5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone in 90 ml Dimethylformamide is added with 4.86 g (25.6 mmol) of p-toluenesulfonic acid monohydrate and 1.0 g of palladium on charcoal. Hydrogen is then passed through the mixture for 30 minutes. The catalyst is filtered off by suction and the filtrate is evaporated under reduced pressure. The residue is digested with dichloromethane and ether. The product is filtered off by suction. There are obtained 4.12 g of the title compound with a mp of 195 ° C.

F) 5-hydroxy-2 - [(2-oxo-1-imidazolidinyl) -methyl] -4- (1H) -. pyridinone

4.0 g (10.5 mmol) of 5-hydroxy-2- [(2-oxo-1-imidazolidinyl) -methyl] -4- (1H) -pyridinone-p-toluenesulfonic acid salt are dissolved in 50 ml of water and the pH Value of the solution is adjusted to 6.5 by addition of 2N sodium hydroxide solution. The precipitate is filtered off with suction, washed with water and dried under reduced pressure. There are obtained 1.5 g of T, telverbindung with a F. of 280 ⁰ C (dec.).

-810.86- 378531

1. G) (S) - [1 - [[[[3 - ^ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl-methyl-2-oxo-1-imidazolidinyl] sulfonyl ] -aminqj-carbonyl] 2-oxo-3-azetidinylJ-carbamic acid phenylmethyl ester

1.10 g (5 mmol) of (S) -3- [_ ( phenylmethoxy) carbonyl] amino-2-azetidinone are dissolved in 20 ml of anhydrous methyl acetate and mixed with 0.44 ml (5 mmol) of chlorosulfonyl isocyanate , The mixture is stirred for 1 hour at room temperature (solution A).

A suspension of 1.04 g (5 mmol) of 5-hydroxy-2-Q2-oxo-1-imidazolidinyl) -methyl} -4- (1H) -pyridinone in 10 ml of anhydrous ethyl acetate is charged with 3.70 ml (20 mmol ) N-methyl-N- (trimethylsilyl) trifluoroacetamide and the mixture heated to 60 ⁰ C. The resulting clear solution is evaporated under reduced pressure at 60 ⁰ C and the residue dissolved in 1Ό ml of anhydrous ethyl acetate (solution B).

Solution A is treated with solution B and the reaction mixture is stirred at room temperature overnight. The solvent is evaporated under reduced pressure and the residue is digested with ether. There are obtained 2.91 g of the title compound having a melting point of 180 ⁰ C (dec.).

H) (S) -3-amino-N-1-yl - [_ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl] -2-oxo-1-imidazolidinyl} sulfonyl] -2-oxo-1-azetidinecarboxamide, trifluoroacetate salt

A mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid is mixed with 0.5 g (0.93 mmol) of (S) - [j-Q [_Q [3-Q 1, 4-dihydro-5-hydroxy-4-. oxo-2-pyridinyl) -methyl]] -2-oxo-1-imidazolidinyl "] sulfonyl] -amino} -carbonyl]} -2-oxo-3-azetidinyl] -carbamic acid phenylmethyl ester The solution is stirred at room temperature overnight and then evaporated under reduced pressure, the residue is triturated with ether, filtered off with suction and dried under reduced pressure.

37853 "

-89-

There are obtained 0.40 g of the title compound with a mp of 155 ° C.

I) [3S (Z)] - 2 - [[[; i- (2-amido-4-thiazolyl) -2 - [. [I - [[[[3-qi, 4-dihydro-5-hydroxy 4-oxo-2-pyridinyl) -methylJ-2-oxo-i-imidazolidinyl ^ J-sulfonyl] -amino]] -carbonyl] -2-oxo-3-azetidinyl} -aminoJ-2-oxoethylidyl] -amino ] -oxy] -2-methylpropionic acid diphenylmethyl ester

A suspension of 0.41 g (0.93 mmol) of (Z) -2-amino-OT- [2- [2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] -imino] -4-thiazole acetic acid in 20 ml of anhydrous acetonitrile are mixed with 0.39 ml (2.8 mmol) of triethylamine. The mixture is cooled to -30 ⁰ C and treated dropwise with 0.19 "ml (0.93 mmol) of diphenyl chlorophosphate was added. The reaction mixture is 1 hour stirred at -30 ⁰ C (solution A).

0.48 g (0.93 mmol) of (S) -3-amino-N- [1- ( 1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl] -2- oxo-1-imidazolidinyl] sulfonyl] -2-OXO-1-azetidinecarboxamide trifluoroacetate salt are suspended in 20 ml of anhydrous acetonitrile and 0.78 ml (3.2 m-MoI) of bis-trimethylsilylacetamide are added. The suspension is stirred for 30 minutes at room temperature and then added to the solution A.

·

The reaction mixture is stirred for 1 hour at -10 ⁰ C and then for 1.5 hours at 0 ⁰ C. The resulting clear solution is evaporated under reduced pressure. The oily residue is mixed with 50 ml of water. The pH of the mixture is adjusted to 2 by the addition of 2N hydrochloric acid and the disodium salt of [3S (Z) "] -2- [_ [(j - (2-amino-4-thiazolyl) -2 - [_ [ j -QCCE ^3- D ¹ , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl J-2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] 2-oxo-3 azetidinyl] -aminoj-2-oxoethylidene] -amino] oxy-3-methylpropionic acid is crystallized out, the product is filtered off with suction, washed with water and concentrated under reduced pressure.

-51386- 37853-1

] dried derdem pressure. There are obtained 0.7 g of the title compound.

J) Di-sodium salt of Q3S (Z)] -2-Q [Ql - (2-amirio-4-thiazolyl) -2-QQ1 - [[[[[3- [(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) -methyl] -2-OXO-1-iraidazolidinyl] -sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] J-2-oxo-ethylidene] -amino ] -oxy] [- 2-methylpropionic acid

0.7 g (0.85 ift mol) [3 S (Z)] -2-QQQi - (2-amino-4-thiazolyl) -2- 'LD ~ [[CD "B ¹ /4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) -methyl] -2-OXO-1-imidazolidinyl] -sulfonyl] -amino] -carbonyl]} - 2-dxo-3-azetidinyl] -amino] -2-oxoethylidene ] -amino] -oxy] -2-methylpropionic acid diphenylmethyl ester are dissolved in 1.4 ml of anisole.

j_5 'donated and cooled to -10 ⁰ C. The suspension is added trifluoroacetic acid and the solution then stirred for 1 hour at ^'0 -10 C. The solution is treated with 100 ml of ether and the precipitate is filtered off by suction, washed with ether and dried under reduced pressure.

The trifluoroacetic acid salt is dissolved in a mixture of methanol and water and the pH of the solution is adjusted to 6.5 by addition of 2N sodium hydroxide solution. The methanol is removed under reduced pressure and the aqueous solution is freeze-dried. There are obtained 0.5 g of the title compound. This is cleaned by MPLC. F. 250 ⁰ C (9 Zers.I.Beispiel di-sodium salt of Q3S (Z)] - 2-Q [_Ql - (2-amino-4-thiazolyl) -2-

OQ LD ~ [[[r ⁴ -di, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl] -2,3-dioxo-1-piperazinyl] -sulfonyl] -amino] -carbonyl] 2-oxo-3-azetidinyl] _ -amino] -2-oxoethyl-2-yl] -amino] -oxy] -2-methyl-propionic acid

A) 2- (Chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone hydrochloride

η in Od Q 7 Q i ", Q -I

A suspension of 3.21 g (10 mmol) of 2- (hydroxymethyl) -5- (phenylmethoxy) -1-phenylmethyl) -4- (1H) -pyridinone in 20 ml of chloroform is cooled to 0 ⁰ C and treated dropwise with 4, Added 65 ml (64 mmol) of thionyl chloride. The mixture is stirred for 10 minutes at 0 ° C and then heated for 1 hour unte.r reflux. The solvent is evaporated under reduced pressure and the residue is washed with PetroXether and dried under reduced pressure. There are obtained 3.66 g of the title compound with a mp of 85 ° C (dec.).

B) 2- (chloromethyl) -5- (phenylmethoxy) -1 - (phenylmethyl) -4-

(1H) -pyridinone

3.5 g (9.3 mmol) of 2- (chloromethyl) -5- (phenylmethoxy) -1 - (phe -] _ 5 nylmethyl) -4- (1 H) -pyridinone hydrochloride are dissolved in a mixture of water / ethyl acetate and the layers separated. The organic phase is washed twice with water. washed, dried over magnesium sulfate and evaporated under reduced pressure. The residue is digested with petroleum ether, filtered off with suction and dried under reduced pressure. There are obtained 2.27 g of the title compound with a mp of 115 to 120 ⁰ C (dec.).

C) N- (triphenylmethyl) -piperazine-2,3-dione

A mixture of 11.4 g (100 mmol) of 2,3-piperazinedione, 55.7 g (270 mmol) of bistrimethylsilylacetamide and 150 ml of acetonitrile is heated under reflux for 1 hour. Within 30 minutes, the mixture is added dropwise with 22.2 g (80 mmol) of triamine.

gO phenylmethyl chloride and then heated under reflux for 2 hours. After stirring overnight at room temperature, the clear solution is added with 21.6 ml of water. The resulting precipitate (3.13 g) is filtered off and the filtrate is concentrated under reduced pressure. The residue is digested with water and dried. There are obtained 25.5 g of the crude title compound which is concentrated from ethanol.

is stalled. The yield of the pure product with a F. of 230 to 235 ⁰ C is 12.19 g. ·

D) 1 - \ Jj , 4-Dihydro-4-oxo-5- (phenylmethoxy) -1 - (phenylmethyl) -2-pyridinylQ-methyl] -4- (triphenylmethyl) -2,3-piperazinedione

A solution of 4.19 g (11.77 mmol) of N- (triphenylmethyl) -piperazine-2,3-dione in 95 ml of anhydrous dimethylformamide is added 0.35 g (11.77 mmol) of sodium hydride (80% oil ). After hydrogen evolution ceases, the thick suspension is mixed with 4.0 g (11.77 mmol) of 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone in 25 mL anhydrous dimethylformamide, with a clear solvent.

] _5 solution arises. After 1 hour of stirring at room temperature, a precipitate begins to precipitate. After 2 hours, the crystals are filtered off, washed and dried under reduced pressure. There are obtained 5.13 g of the title compound with a mp of 165 to 168 ° C.

E) 1 - [! C, 4-Dihydro-4-oxo-5- (phenylmethoxy) -1 - (phenylmethyl) -

2-pyridinyl] -methyIJ-2,3-piperazinedione

A solution of 8.77 g (13.23 mmol) of 1 - [[1, 4-dihydro-4-oxo-5- (phenylmethoxy) -1 - (phenylmethyl) -2-pyridinyl] -methyl3-4- (triphenylmethyl ) -2,3-piperazinedione in 65 ml of dichloromethane is added dropwise at room temperature with 65 ml of formic acid. After stirring for 3 days, the volatiles are distilled off under reduced pressure and the residue OQ is digested twice with ether. There are 5.24 g of 1 - [[i, 4-dihydro-4-oxo-5- (phenylmethoxy) -1 - (phenylmethyl) -2-pyridinyl] methyl ^ -2,3-piperazinedione with a F. of 260-265 ° C.

F) (S) -Jj - [[[C ⁴ - [D - 4-dihydro-4-oxo-5- (phenylmethoxy) -1 (phenylmethyl) -2-pyridinyl-3-methyl] -2,3-dioxo i-piperazi

-810.86- 37853

nyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -carbamic acid phenylmethyl ester

A solution of 0.44 g (2.0 mmol) of (S) -3- [[ (1-phenylmethoxy) carbonyl] amino-Q-2-azetidinone in 25 ml of anhydrous ethyl acetate is added 0.28 g (2.0 mmol) of chlorosulfonyl isocyanate and the solution is stirred for 30 minutes at room temperature. The solution is, with 12 ml of dichloromethane, 0.61 g (6 mmol) of triethylamine and a previously stirred for 3 hours mixture of 0.83 g (2.0 mmol) of 1 - [[.1, 4-dihydro-4-oxo -5- (phenylmethoxy) -1 - (phenylmethyl) -2-pyridinyl] methyl] -2,3-piperazinedione and 1.59 g (8.0 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in 25 ml of anhydrous ethyl acetate. After 3 days of stirring at room temperature, the mixture is mixed with ice-water and the pH is adjusted to 1 with hydrochloric acid. The insoluble residue is filtered off and dried under reduced pressure. There are obtained 1.15 g of the title compound with 72 % purity.

-G) (S) -3-amino-N- [_ [4- ( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl] -2,3-dioxo 1 -piperazinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide-4-methylbenzenesulfonic acid salt

A solution of 0.98 g (1.32 mmol) of (S) - [i - [_ [[[[4 - [[1, 4-dihydro-4-oxo-5- (phenylmethoxy) -i- (phenylmethyl) 2-pyridinyl] -methyl'J-2,3'-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] 2-oxo-3-azetidinyl] -carbamic acid phenylmethyl ester in 20 ml dimethylformamide is reacted with 0.5 g ( 2.64 mmol) of p-toluenesulfonic acid and 0.5 g of palladium on charcoal (10 %) . Hydrogen is then passed through the mixture for 1 hour. The catalyst is filtered off, the solvent is distilled off under reduced pressure and the residue is digested with dichloromethane. 0.82 g of the title compound having a melting point 160-185 ⁰ C (dec.) Are obtained after drying.

H) [3S (Z)] - 2-LED- (2-Amino-4-thiazolyl) -2 - [[i - [[[[- [4 - [(1, 4-dihydro-5-hydroxy-4-oxo -2-pyridinyl) -methylJ-2,3-dioxo-1-piperazinyl] sulfonyl] amino carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic

A solution of 0.57 g (1.3 mmol) of (Z) -2-AmInO-Of - [{] 2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] -imino] -4-thiazoleacetic acid in 30 ml of dimethylformamide is added at -30 ⁰ C with 0.39 g (3.9 mmol) of triethylamine .and 0.31 g (1.3 mmol) Triphenylchlorphosphat. After stirring for 1 hour, 0.39 g (3.9 mmol) of triethylamine and 0.98 g (1.3 mmol) of (S) -3-amino-N- [_ [β- L (1,4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl) -methyl] -2,3-dioxo-1-piperazinyl] -sulfonyl] -2-oxo-1-azetidinecarboxamine-4-methylbenzenesulfonic acid salt. The mixture is stirred for 2 hours at -10 ⁰ C and 1.5 hours at 0 ° C. Then ¹ it is mixed with water and ethyl acetate and the pH adjusted to 1 with 3N hydrochloric acid. The precipitate is filtered off, washed with ethyl acetate and dried under reduced pressure. There are obtained 0.86 g of the title compound having a melting point from 130 to 190 ⁰ C (dec.).

I) Di-sodium salt of [3S (Z)] -2- [LL ¹ - (2-amino-4-thiazolyl) 2-one {- LLCD * - [(1,4-dihydro-5-hydroxy) 4-oxo-2-pyridinyl) -methyl] -2,3-dioxo-1-piperoyinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidyl] amino ] oxy] -2-methyl propionic acid

A suspension of 0.8 g (0.94 mmol) of [3S (Z)] -2- [LL ¹ ~ <2-amino-4-thiazolyl ] -2- ]] - (_ [. [. [ - \ j ¹ , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] -2-oxo-3 -azetidinyl] amino] -2-oxoäthyliden] amino] _- oxy] -2-methylpropionsäurediphenylmethylester in 1.4 ml of anisole is added at -10 ⁰ C with 7 ml of trifluoroacetic acid. After stirring for 1 hour, 30 ml of ether are added and the

-910PB- 378531

, resulting precipitate is filtered off and dried under reduced pressure. This trifluoroacetic acid salt is suspended in water and the pH of the solution is adjusted to 6.5 with 2N sodium hydroxide solution. The solution is freeze-dried, c. 0.66 g of the crude product is obtained, which is chromatographed on a macromolecular styrene-divinylbenzene copolymer under MPLC conditions together with a second sample prepared in the same way (total 1.55 g) becomes. There are obtained 0.34 g of the title compound. , Q A second column chromatography on macroreticular styrene-divinylbenzene copolymer obtained with 0.18 g.der title compound; "'" - a F. 242-270 ⁰ C.

Example 10

Di-sodium salt of {jS (Z ) ~ \ -2- [[[i - (2-amino-4-thiazolyl) -2-]] - LL [[3-O-C (1,4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl) -me thy-ler \\ amino] -2-oxo-1 -imidazolidinyl] sulfonyl] -amino} carbonyl]] -2-oxo-3-azetidinylJ - amine-2-oxoethylidene]] -aminoj-oxy]] 2-methylpropionic acid

A) 4,5-bis (phenylmethoxy) -2-pyridinearbonsäurepheny! Methyl ester

A suspension of 29.4 g (120 mmol) of O-benzylcomenamic acid; In 350 ml of dimethylformamide is added 21.5 g (156 mmol) of potassium carbonate and stirred for 1 hour at room temperature. The mixture is treated with 31 ml (264 mmol) of benzyl bromide and heated with stirring for 25 hours at 100 ⁰ C. After cooling to room temperature, the dimethylformamide is distilled off under reduced pressure _on the residue with ethyl acetate and triturated with brief heating to 60 ⁰ C. 40 g of the inorganic salts are filtered off and the filtrate concentrated to about 75 ml. The concentrate is chromatographed on silica gel, using ethyl acetate / petrol, ether 90/1, as eluent. There are obtained 35.5 g of the title compound with a mp of 116.7 ° C.

- «1086- 37853i

-96-B) 4, 5-bis- (.Phenylmethoxy) -2-pyridinemethanol

A suspension of 95 mg (25 mmol) of lithium aluminum hydride in 10 ml of ether and 10 ml of tetrahydrofuran is mixed with 1.06 g (25 mmol) of 4,5-bis (phenylmethoxy) -2-pyridincarbonsäurephenylmethylester in 3 portions at 0 ⁰ C added. After stirring for 20 minutes at 0 ^° C., the suspension is treated with 0.2 ml of saturated sodium bicarbonate solution, 0.2 ml of 10% potassium hydroxide solution and additionally with saturated sodium hydrogen carbonate solution until the inorganic precipitate flocculates. The clear organic phase is poured off and evaporated under reduced pressure. An oil is obtained which slowly crystallizes out. The yield is 0.6 g, mp 96.6 ° C.

"

C) 4,5-bis (phenylrethoxy) -2-pyridinecarboxaldehyde

A solution of 0.54 g (1.7 mmol) of 4,5-bis (phenylmethoxy) -2-pyridinemethanol in 15 ml of acetone is treated with 1.5 mg (17 mmol) of manganese dioxide and the mixture is stirred at room temperature overnight. The mixture is then filtered through a silica gel column (70 to 250 mesh, 60 to 200 μ) and the aldehyde eluted with acetone. The eluate is evaporated and the residue digested with petroleum ether. There are obtained 0.3 g of the title compound with a mp of-104.3 ⁰ C.

D) 1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinecarboxaldehyde

To a solution of 1.9 g (6.0 mmol) of 4,5-bis (phenylmethoxy) -2-pyridinecarboxaldehyde in 25 ml of anhydrous dimethylformamide is added 0.2 g of palladium on charcoal catalyst and hydrogen for 3 hours passed through the mixture. The catalyst is filtered off, the solvent is distilled off under reduced pressure and the residue is digested with ether. There are obtained 0.64 g of the title compound having a mp of 174-177 ° C (dec.).

-810.86- 378b3-I

E) Di-sodium salt of [3S (Z)] J -2- [] [D - (2-amino-4-thiazolyl) ² "LD" LLCL ³ -LLd, 4-dihydro-5-hydroxy-4-oxo 2-pyridinyl) -methylene] ^ -aminoj-2-oxo-1-imidazolidinyl]] sulfonyl]] amino] carbonyl ^ -2-oxo-3-azetidinyl-3-amino-2-oxoethylidene]] - amino] oxy -] - 2-methylpropionic

A solution of 0.64 g (1.1 mmol) of [3S (Z)] - 2- [£ [2 - [[i - [[[(3-amino-2-oxo-1-imidazole id inyl) - sulfonyl]] -amino]] -carbonyl] -2-oxo-3-azetidinyl]] - amino] -1 - (2-amino-4-thiazolyl) -2-oxoethyl -] - - -] -] - amino] - oxy ]] - 2-propionic acid in 15 ml of anhydrous dimethylformamide is added with 0.18 g (1.3 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxaldehyde. After stirring for 4.5 hours, an additional 0.02 g (0.14 mmol) of the above compound is added. After stirring overnight at Räumte; Temperatur'wird the solvent is evaporated under reduced pressure and the residue taken up in 30 ml of water, filtered and the solution was freeze-dried. The crude product (0.82 g) is dissolved in 5 ml of water and chromatographed on macroreticular styrene-divinylbenzene copolymer resin using water as eluent. There are obtained 0.22 g of the pure product with a mp of 248 ° C (dec.).

Example 11

Di-sodium salt of [3S (Z fj-2-LLD ~ (2-amino-4-thiazolyl) -2-LD-LLLL ⁴ "LL ( ¹ -4-dihydro-5-hydroxy-4-oxo-2-pyridinyl ) -carbonyl]] -amino]] -2,3-dioxo-1-piperazinyl-1-sulfonyl] -amino-carbo-n-butyl] -2-oxo-3-azetidinyl] -1-amino-2-oxoethylidene-1-amino oxy-2-methylpropionic acid

A) 4,5-bis (phenylmethoxy) -2-pyridinecarboxylic acid

A solution of 11.8 g (28 mmol) of 4,5-bis (phenylmethoxy) -2-pyridincarbonsäurephenylmethylester in 115 ml Tetrahydrogc furan is added with 16 ml of water and 35 ml of 1N potassium hydroxide solution. After stirring overnight at room temperature, 115 ml of water are added.

-810.86- 378531

The pH of the solution was adjusted to 2.5 with 1N hydrochloric acid. The acid is filtered off, washed with water and dried under reduced pressure. There are obtained 8.6 g of the title compound having a melting point of 203.6 ⁰ C.

B) N- (2,3-dioxo-1-piperazinyl) -4,5-bis (phenylmethoxy) -2-pyridinecarboxamide

IQ A suspension of 7.1 g · (21, 17 mmol) of 4,5-bis (phenylmethoxy) -2-pyridinecarboxylic acid, 0.29 g (2.12 mmol) of hydroxybenzotriazole and 2.73 g (21.17 mmol ) N-Aimopiperazine-2,3-dione in 140 ml of anhydrous dimethylformamide is added after stirring for 15 minutes with 4.8 g (23.3 mmol) of dicyclohexylcarbodiimide. After stirring for 21 hours at room temperature, the cyclohexylurea (4.0 g) is filtered off and the solvent is evaporated off under reduced pressure. The solid residue is digested with 240 ml of tetrahydrofuran for 40 minutes, filtered, washed with tetrahydrofuran and dried under reduced pressure. There are obtained 7.76 g of the title compound with a mp of 231.1 ⁰ C.

C) (S) - | j - [[[[[4 - [[£ 4,5-Bis (phenylmethoxy) -2-pyridinyl] carbonyl] amino-2,3-dioxo-1-piperazinyl] sulfonyl ] -incq -carbonyl]] ^ -oxo-S-azetidinyl-1-carbamic acid phenylmethyl ester

A suspension of 2.02 g (9.18 mmol) of (S) -3- [(J-phenylmethoxy) carbonyl] amino] -2-azetidinone in 130 ml of ethyl acetate is treated with 1.43 g (10 mmol) of chlorosulfonyl isocyanate and after 1 hour of stirring at 0 ⁰ C with 2.79 g (27.54 mmol) of triethylamine. This mixture is stirred with a solution of 4.10 g (9.18 mmol) N- (2,3-dioxo-1-piperazinyl) -4,5-bis (phenylmethoxy) -2-pyridinearboxamide previously stirred for 1.5 hours and 5.4 g (27.54 mmol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in 150 ml of ethyl acetate.

37853

V ti tem ο

After stirring overnight at room temperature, the solution is mixed with 220 ml of ice water and the pH is adjusted from 2 to 3 with 3N hydrochloric acid. When the separated organic phase is treated with brine, the title compound precipitates. The precipitate is filtered off, washed with water and dried under reduced pressure. There are obtained 5.35 g. 2.5 g of this product are digested for 1 hour with a mixture of 25 ml of water and 37.5 ml of acetone at a pH of 6.3. There are obtained 2.12 g of the title compound.

D) (S) -N- [4- [Q3-amino-2-oxo-1-azetidinyl) -carbonyl] amino] sulfonyl] -2,3-dioxo-1-piperazinyl J-1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinecarboxamide

,

A solution of 1.54 g (2 mmol) of (S) - {Ί - [££ [4- [5] -5-

(phenylrnethoxy) -2-pyridinyl] carbonyl] amino] -2,3-dioxo-1-piperazinyl] -sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] -carbamic acid phenylmethyl ester in 30 ml of dimethylformamide on 0.77 g of palladium-on-charcoal is added and the mixture is hydrogenated for 45 minutes. The catalyst is filtered off through Hyflo and the resulting solution, without isolating the title compound, used in the next step.

E) [3S (Z)] - 2 - [[[_ 1- (2-Amino-4-thiazolyl) -2-] - [[- [[[[- 4 - [[(1, 4-dihydro-5-hydroxy 4-oxo-2-pyridinyl) carbonyl] amino] 2, 3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene ] - amino] -oxy] -2-methylpropionic acid diphenylmethyl ester

A solution of 0.88 g (2.0 mmol) of (Z) -2-amino-CC- \ J ~ 2- (di-

phenylmethoxy) -1,1-dimethyl-2-oxoethoxy] -imino] -4-thiazoleacetic acid in 20 ml of dimethylformamide is treated with 0.60 g (6.0 mmol) of triethylamine and at -30 ⁰ C under nitrogen with gc 0.54 g (2.0 mmol) of triphenylchlorophosphate. After 1 hour of stirring at -30 ⁰ C, the mixture is added dropwise

-FiMflifi- 378Ü3-I

0.20 g (2 mmol) of triethylamine and of the dimethylformamide solution of (S) -N- [4- [JJj 3-amino-2-oxo-1-azetidinyl) -carbonyl] -amino] -sulfonyl] -2, 3-dioxo-1-piperazinyl] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide. The mixture is stirred for 2 hours at -10 ⁰ C and 17 hours at 0 ⁰ C. The solvent is distilled off under reduced pressure and the residue is extracted by shaking in 40 ml of ethyl acetate and 20 ml of ice-water. When the pH of the solution is adjusted to 1.5 with dilute hydrochloric acid, an oil separates, which is separated from the solvent and dried under reduced pressure. There are obtained 1.35 g of the title compound.

F) Di-sodium salt of [3S (zQ-2 - [. [[I - (2-amino-4-thiazolyl) -2-LD-CLLC ⁴ ~ [[ ⁽¹ -4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl) - carbonyl] amino J-2,3-dioxo-1-piperazinyl] -sulfonyl] amino]] carbonyl *] -2-oxo-3-azetidinyl-3-amino] -2-oxoethylidene] - amino] oxy] -2-methyl propionic acid

A mixture of 2.6 ml anisole and 13 ml trifluoroacetic acid. is treated with 1.3 g (1.48 mmol) of \ JS (Z)] -2- [Q Q1- (2-amino-4-thiazolyl) -2-LD-LLLII ⁴ "LL ^ ¹ /4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonyl! Amino] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] [- amind] -2-oxoäthyliden] amino]] -.. oxy] -2-methylpropanoic acid are added at -10 ⁰ C and the mixture stirred for 2 hours at 0 ⁰ C. the volatiles are distilled off under reduced pressure and the residue triturated with ether are. After drying, 1.06 g of the trifluoroacetic acid salt are obtained The trifluoroacetic acid salt is suspended in 20 ml of water and the pH of the suspension is adjusted to 6.5 with 1N sodium hydroxide solution The freeze-dried solution gives 1.10 g of the crude product, which is added to macroreticular styrene Divinylbenzene copolymers are chromatographed under MPLC conditions using water as the eluent, yield 0.48 g, and the product becomes twice more

-mnafi- 37853-I

with other samples, which were prepared in the same way, chromatographed. The second column chromatography is carried out on macroreticular styrene-divinylbenzene copolymer, the third on organogen. Each time, water is used as the solvent. The final yield is 0.10 g, mp> 300 ° C.

Example 12

Q3S (Z)] - 3- [[(2-amino-4-thiazolyl) - [(2-fluoroethoxy) -imino] -acetyl] -amino-N- [3-Q 1, 4-dihydroxy] 5-hydroxy-4-oxo-2-pyridinyl) carbonyl] "- amino] -2-oxo-1-imidazolinyl] -sulfonyl] -2-OXO-1-azetidinecarboxamidoethyldiiospropylamine salt

A solution of 0.33 g (1.4 mmol) of (Z) -2-hm ± no-C (- [(2-fluoroethoxy) -imino] -4-thiazole acetic acid in 5 ml of anhydrous dimethylformamide is added 0.19 g g (1.4 mmol) of N-hydroxybenzotriazole and 0.18 g (1.4 mmol) of N-ethyl-diisopropylamine was added. the solution is added at 0 ⁰ C with 0.29 g (1.4 mmol) of dicyclohexylcarbodiimide and the The mixture is stirred for 1 hour, then it is treated with a solution of 0.8 7 g (1.6 mmol) of (3S) -3-amino-N- [1 -] - [ 1 - 4-dihydro-5-hydroxy 4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide trifluoroacetate (1: 2) salt (see Example 1, G ) and 0.41 g (3.2 mmol) of N-ethyldiisopropylamine in 3 ml of anhydrous dimethylformamide and stirred at 0 ⁰ C for 2 hours. The mixture is stirred for an additional 16 hours at room temperature. The dicyclohexylurea is filtered off and the solvent is evaporated under reduced pressure. The oily residue is digested with water until the product has completely crystallized out. The solid (0.82 g) is filtered and the filtrate adjusted to pH 6.1 and lyophilized. The solid is suspended in 40 ml of water and the pH of the suspension is adjusted to 6.0 with 0.25N sodium hydroxide solution. The insoluble material is filtered off and the filtrate

, freeze-dried. 2 portions of the freeze-dried product are combined (about 0.6 g) and macroreticular

-B10.86- 378531

Styrene-divinylbenzene copolymer chromatographed using water and water / acetonitrile 95: - 5 serve as eluent '. After freeze-drying, the appropriate fractions give 0.22 g of the title compound with a mp of 163

δ to 165 ^° C.

Example 13

Tri-sodium salt of [_3S (Z) J -2- [££} - (2-amino-4-thiazolyl) -2-Qj - QQCÜ.2 - (carboxymethyl.) -2- [_ (1, 4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino ^ -sulfonylj-amino - carbonylj-

2-oxo-3-azetidinyl "] amino] -2-oxoethylidene] -amino] -oxy] -2- methylpropionic

A) N, O-Dibenzyl-comenamyl chloride hydrochloride

A suspension of 16.77 g (50 _, 0 mmol) of N, O-Dibenzylcomenaminsäure in 360 ml of anhydrous dichloromethane is added at 0 to 5 ° C in portions with 11.45 g (55.0 mmol) of phosphorus pentachloride. After stirring for 1 hour at room temperature, the precipitate is collected by suction, washed with 20 ml of anhydrous dichloromethane and dried under reduced pressure. There are obtained 15.02 g of the title compound with a mp of 126 to 127 ° C (dec.).

B) [2 - "[J-phenylmethoxy) -carbonylj-hydrazino-1-acetic acid-1-ethylacetate

A stirred solution of 6.65 g (0.040 mol) of N-Q-phenylmethoxy) -ca'rbonylj-hydrazine in 40 ml of dimethylformamide is treated with a solution of 8.58 g (0.044 mol) of tert-butyl bromoacetate in 20 ml of dimethylformamide and a Solution of 8.2 ml (0.048 mol) of N, N-diisopropylethylamine in 8 ml of dimethylformamide. The mixture is stirred for one day at room temperature and then the solvent is distilled off under reduced pressure. The residue is taken up in ether and water. The organic layer is washed with three times

-810.86- 37853Ί

Washed with water, dried over magnesium sulfate and evaporated under reduced pressure. There remains an oil (10.6 g) which is purified by column chromatography on silica gel using ethyl acetate / toluene (1: 1) as eluent. The appropriate fractions are evaporated under reduced pressure and the residue is stirred with petroleum ether. There are obtained 6 * 0 g of the title compound with a F. of 61 to 62 ° C.

C) Qi - [I , 4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl]] carbonyl] -2-Q (phenylmethoxy) carbonyl] hydrazino-1-acetic acid 1,1-dimethylethyl ester

A solution of 11.2 g (40.0 mmol) of Q 2 - [(phenylmethoxy) -]

X5 carbonyl]] - hydrazinoQ-acetic acid 1, 1-dimethylethyl ester in 60 ml of anhydrous acetonitrile is treated with 15.6 ml (80.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide. After stirring at room temperature for 30 minutes, the clear solution is evaporated under reduced pressure and the residue is dissolved in 45 ml of anhydrous dichloromethane. This solution is added at room temperature to a suspension of 15.61 g of N, O-dibenzylcomenamyl chloride hydrochloride in 60 ml of anhydrous. Given dichloromethane. After stirring overnight, the reaction mixture is evaporated under reduced pressure. There remains a residue, which is stirred with 10 ml of methanol, evaporated under reduced pressure and then chromatographed on silica gel, using ethyl acetate and ethyl acetate / methanol (10: 1) as the eluent. After evaporation under reduced pressure, the appropriate fractions give a solid foam, which becomes crystalline upon stirring with ether. The yield is 12.7 g, mp 177-178 ° C (dec.).

D) Ql-Hd, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazineC-acetic acid 1,1-dimethylethyl ester

37853-1

A suspension of 7.17 g (12.0 mmol) \ j - [[i, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] -2- \\ phenylmethoxy) -carbonylj -hydraζinoj-acetic acid 1,1-dimethyl ethyl ester in 400 ml of methanol is hydrogenated in the presence of 1.6 g PaI-ladium-on-charcoal (10 %) for 40 minutes. The catalyst and the precipitated product are filtered off and washed thoroughly with 300 ml of anhydrous dimethylformamide to dissolve the precipitated product. From the combined filtrates, the solvents are removed under reduced pressure. There remains a residue which crystallized with stirring with ether (1.68 g, mp 221 ⁰ C, dec.) Recrystallization from methanol gives the pure compound in a yield of 1.26 g, mp 225 ° C, sintering point 229 ° C (decomp.).

, '

E) (3S) - [i - [(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -2- [X [2-oxo-3 [[(phenylmethoxy ) -carbonyl} -amino-1-azetidinyl] -carbonyl] -amino] -sulfonyl] -hydrazino] -acetic Acid 1, 1-Dimethyläthylester 20

A suspension of 3.2 g (11.0 mmol) of [1- ( 1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] acetic acid 1,1- Dimethyl ethyl ester in 120 ml of anhydrous ethyl acetate is treated with 9.0 ml (46.2 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide. It is stirred for 1 hour at room temperature, whereby a clear solution is formed (solution A).

A suspension of 2.42 g (11.0 mmol) of (S) -3 - [[(phenylmethoxy) carbonyl] amino] -2-azetidinone in 80 ml of anhydrous ethyl acetate is added, with 0.99 ml (11, 0 mmol) chlorosulfonyl isocyanate added with stirring. The mixture is stirred for 1 hour at room temperature and cooled dann'auf 0 ⁰ C. Solution A is added at 0 ° and stirred overnight at room temperature. After the addition of 4 ml of triethylamine, the mixture is introduced under reduced pressure.

-310.86- 378531

steamed. The residue is dissolved in 10 ml of methanol / water (4: 1). The solution is poured into a mixture of 30 ml of methanol / water, keeping the pH at 2. There remains a residue (10.25 g), which becomes crystalline on stirring with a few ml of water and methanol. The precipitate is purified by successive washing with stirring with isopropanol / water (4: 1), methanol, methanol / ether (1: 1) and ether. The yield after drying under reduced pressure is 2.39 g.

F) - (S) -3-amino-1 - [ε [2- (carboxymethyl) -2-Γ_ (1,4-dihydro-5-

hydroxy-4-oxo-2-pyridinyl) carbonyl]} hydrazino]] sulfonyl] [-amino]] carbonyl]] [-2-azetidinone trifluoroacetate salt

c A mixture of 7.0 ml of trifluoroacetic acid and 1.66 ml thioanisole at 0 ⁰ C with 2.39 g (3.9 mmol) of (3S) - [i - [_ (1, 4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) carbonyl} -2- Γ_ · Γ _ [] [] 2-οχο -3 - ΓΓ (phenylmethoxy) carbonyl "} amino] -1-azetidinyl] -carbonyl ]] -sulfonyl]] -hydrazino] -acetic, 1-1, 1-dimethylethyl

2Q ester added. After stirring overnight at room temperature, the solution is evaporated under reduced pressure. The residue is washed successively with stirring with ethyl acetate, ethyl acetate / petroleum ether (1: 1), Petro'läther and dichloromethane and then dried under reduced pressure. The crude salt is used in the next step without further purification. The yield is 2.15 g.

G) [3 S (Z)] -2- [[Ql- (2-amino-4-thiazolyl) -2- [JJ - [[[[2- (carboxymethyl) -2- [_ { 1, 4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) -

OQ carbonyl]} - hydrazino]] sulfonyl]] amino]] carbonyl] -2-oxo-3-azetidinyl]] - amino]] - 2-oxoethylidene]} amino]] oxy]] -2-methyl 1-propionic acid diphenylmethyl ester ·

A -30 ⁰ C cold mixture of 1, 42 g (3.24 mmol) of (Z) -2-Amigc no-Of- [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoäthoxy] -iminol 4-thiazole-acetic acid and 1.81 ml (12.96 mmol) of triethylamine

378531

in 30 ml of anhydrous acetonitrile is added 0.70 ml (3.24 mmol) of diphenylchlorophosphate (solution A).

A suspension of 2.13 g (about 3.3 mmol) of crude (S) -3-amino-1-CCLC ^ - (carboxymethyl) -2- [ 1,4-dihydro-5-hydroxy-4-oxo -2-pyridinyl) carbonyl] hydrazino]] sulfonyl] aminocarbonyl]} 2-azetidinone trifluoroacetate salt in 30 ml of anhydrous ethyl acetate is added at room temperature with 3.27 "ml (12.96 mmol). Bistrimethylsilylacetamide is added.

Stirring the clear solution is cooled and poured into the -30 ⁰ C cold solution A. The mixture is stirred for 1 hour at -1O ⁰ C and for 1 1/2 hours at 0 ° C and then evaporated under reduced pressure. The residue is stirred with a few ml of water and the pH of the solution is adjusted to 2 by addition of dilute hydrochloric acid. The precipitate is filtered off, washed with water, redissolved in water / acetone at pH 5.5 to 6.0 by the addition of dilute sodium hydroxide solution and purified by MPLC on a macroreticular styrene-divinylbenzene copolymer using a water-methanol gradient (0 to 100%) is eluted. Freeze-drying the appropriate fractions gives 270 mg of the purified products. A suspension of the salt. In a few ml of cold water is acidified to pH 2 with dilute hydrochloric acid to precipitate the free acid. This is collected by suction and dried under reduced pressure. There are obtained 0.19 g with a F. of> 180 ⁰ C (dec.).

H) [3S (Z)] - 2-Q [[i- (2-amino-4-thiazolyl) -2- [fi-Q [[[2-carboxymethyl) -2- [j 1, 4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) -carbonylj-hydrazino] -sulfonyl] -amino] -carbonylJ-2-oxo-3-azetidinyl] -amino]] -2-oxoethylidene] -aminoj-oxyj-2- methyl-propionic acid trifluoroacetic salt

A cold stirred solution of 0.62 ml (8.0 mmol) of trifluoroacetic acid and 0.087 ml (0.8 mmol) of thioanisole is added at -10 ° C

-810.86- 378531

slowly with 0.17 g (0.2 mmol) of Q3S (Z)]. -2- [[Ql - (2-Amino-4-thiazolyl) -2-Q [1 - [[[Q2- (carboxymethyl) -2 - [(1,4-dihydro-5-hydroxy-4-oxo) 2-pyridinyl) carbonyl] -hydrazinoj-sulfonyl '} amino]] carbonyl] -2-oxo-3-azetidinyl ~ j-amino] -2-oxo-ethylidene] amino]] - oxy] -2-methylpropionäurediphenylmethylester , It is stirred for a further 15 minutes at 0 ⁰ C. The suspension is evaporated under reduced pressure at -5 ° C and the residue is stirred with anhydrous ether. The residue is collected by suction, washed with anhydrous water and dried under reduced pressure. There are obtained 0.14 g with a F. of> 230 ° C (dec.).

I) Tri-sodium salt of [3 S (Z)] -2-QQQi - (2-amino-4-thiazolyl) -

2- Uj - Q [[[2- (carboxymethyl) -2-Q (1,4-dihydro-5-hydroxy-4-2-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] amino] - carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidyl] amino] oxyj-2-methylpropionic acid

115 mg (0.146 mmol) of the JJS (Z)] -2- [[Q 1 - (2-amino-4-thiazolyl) 2-Q [1 - [[[Q 2 - (carboxymethyl) -2 - [(1, 4 -dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazinojsulfonyl] amino] carbonyl] 2-oxo-3-azetidinyl] amino] -2-oxoethylidyl] amino] oxy ] -2-methylpropionic acid trifluoroacetic acid salt are suspended in 1.5 ml of water and the pH of the suspension by dropwise addition of dilute sodium hydroxide solution

5.5 set. The solution is added sequentially over 2 columns of macroreticular styrene-divinylbenzene copolymer (0.05 to 0.1 mm) and cross-linked dextran gel (25 to 100 μm) and eluted with water. The corresponding fractions are combined and lyophilized. There are obtained 100 mg of the title compound.

By S. Piel 14

Di-sodium salt of Q3S (Z)] -2- [[qi - (2-amino-4-thiazolyl) -2- [Ql - [[[[3- [[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) acetyl] amino] -2-oxo-i-imidazolidinyl] sulfonyl] amino] -

η - »η ο C.

carbonyl] ^ -oxo-S-azetidinyl] amino] ^ -oxoethylideneQ-amino] oxyj-2-methylpropionic acid

A) 2- (Cyanomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone

A suspension of 2.0 g (6 mmol) of 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone in 20 ml of acetonitrile is charged with 3.9 g (60 mmol ) Potassium cyanide and 0.1 g

[j 8 ~] Crown-6 offset. The mixture is heated under reflux for 2.5 hours. The salts are filtered off by suction and the filtrate is evaporated under reduced pressure.

The remaining residue is purified by column chromatography on silica gel using ethyl acetate / methanol (8: 2) as eluent. The yield of the title compound is 0.55 g, mp. 175 to 180 ^° C.

B) 1,4-Dihydro-5-hydroxy-4-oxo-1- (phenylmethyl) -2-pyridine acetic acid

A mixture of 2.45 g (7.16 mmol) of 2- (cyanomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (1H) -pyridinone and 40 ml of concentrated hydrochloric acid (37 %) becomes 4 hours stirred at 70 ⁰ C and then evaporated under reduced pressure. The

The residue is suspended in 15 ml of ice-cold water and the pH of the suspension is adjusted to 2.0 by addition of 5N sodium hydroxide solution. The precipitate is filtered off, washed with ice-water and ether and dried under reduced pressure (1.71 g). The crude acid is dissolved in 20 ml of 0.5N Na

• Tronlauge dissolved, re-precipitated by acidification with 2N hydrochloric acid to pH 1.8, collected by suction and washed with ice-water. The yield is 1.52 g, mp 231-235 ° C.

O "7 Q κ Q Λ

250

C) 1,4-Dihydro-5-hydroxy-4-oxo-N- (2-oxo-1-imidazolidinyl) -1 - (phenylmethyl) -2-pyridineacetamide

A suspension of 9.29 g (35.83 mmol) of 1,4-dihydro-5-hydroxy-4-OXO-1- (phenylmethyl) -2-pyridine acetic acid, 0.28 g (1.79 μm MoI). N-Hydroxybenzotriazole, 0.22 g (J, 79 mmol) of N-dimethylaminopyridine, 3.62 g (35.83 mmol) of N-aminoimidazolidinone and 8.13 g (39.41 mmol) of dicyclohexylcarbodiimide in 115 ml of anhydrous dimethylformamide is washed with Added 4.99 ml (35.83 mmol) of triethylamine. It is stirred overnight at room temperature. The precipitated dicyclohexylurea is filtered off, washed with dimethylformamide and the filtrate is evaporated under reduced pressure. There remains a residue which becomes crystalline when stirred with 110 ml of dichloromethane. The precipitate is collected by suction and dried under reduced pressure. A suspension of this crude product in 65 ml of anhydrous acetonitrile is treated with 14.0 ml (71.6 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide. After stirring for 30 minutes at room temperature, the undissolved dicyclohexylurea is filtered off and the filtrate is evaporated under reduced pressure. The oily residue is boiled in 70 ml of methanol for 15 minutes and then cooled. The precipitation is by - -. Suck, collected successively with methanol, methanol / ether. ( ^1: 1) and ether and dried under reduced pressure. The yield is 8.7 g, sintering point 242 ° C, mp 260 to 265 ° C (dec.).

D) Sodium salt of (S) - [i -LLLL ^3- ECD-4-dihydro-5-hydroxy-4-oxo-1- (phenylmethyl) -2-pyridinyl-3-acetyl]] - amino-2-oxo-1 -imidazolidinyl-C-sulfonyl-] -amino-carbonyl-2] -oxo-3-azetidinyl-1-] -carbamic acid phenyl-methyl ester

A suspension of 3.42 g (10.0 mmol) of 1,4-dihydro-5-hydroxy-3g 4-oxo-N- (2-oxo-1-imidazoiidinyl) -1- (phenylethyl) -2 -pyridineacetamide in 50 ml of anhydrous Essigsaureathyiester is with

Λ - 1 Λ Γ * / "Ί I

250

-1 ΙΟΙ 5.86 ml (30.0 mmol) of N-methyl-N-trimethylsilyltrif luoracidamid and stirred for 1 hour at room temperature (solution A).

A solution of 2.20 g (10.0 mmol) of (S) -3 - [[(phenylmethoxy) carbonyl]] - amino *] -2-azetidinone in 50 ml of anhydrous ethyl acetate is added under stirring to 0.90 ml ( 10.0 mmol) of chlorosulfonyl isocyanate and the mixture was stirred for 1 hour at room temperature. It is then cooled to 0 ° C and the solution A is added with stirring at 0 ⁰ C. After stirring overnight at room temperature, the mixture is evaporated under reduced pressure and the residue taken up in a few ml of methanol and water. The pH of the solution is adjusted to 5.5 by addition of dilute sodium hydroxide solution and the filtered solution is freeze-dried. An MPLC is performed on a macroreticular-styrene-divinylbenzene copolymer eluting with water / acetone (8: 1). Subsequently, the corresponding pure fractions are freeze-dried. There are obtained 0.40 g of the title compound. The non-pure fractions are subjected to a second MPLC while maintaining the same conditions. The yield is 0.60 g.

E) (S) -N- [3- [X (J 3-amino-2-oxo-1-azetidinyl) -carbonyl "] -aminosulfonyl] -2-oo-ω-imidazolidinyl"] -1, 4-dihydro-5-hydroxy-4-oxo-2-pyridineacetamide, trifluoroacetate salt

A solution of 0.90 g (1.3 mmol) of the sodium salt of (S) - | j - HELL ³ -LLD <4-dihydro-5-hydroxy-4-oxo-1 - (phenylmethyl) 2-pyridinyl "] -acetylj-amino "] -2-oxo-1-imidazolidinyl] -sulfonyl"] -amino "] - carbonyl"] -2-oxo-3-azetidinyl "] -carbamic acid phenylmethyl ester in 13 ml of anhydrous dimethylformamide containing 0.50 ml (6.5 mmol) trifluoroacetic acid is hydrogenated in the presence of 0.15 g of palladium on carbon (10 %) for 20 minutes. The catalyst is filtered off

ο -7 ο;. '. ο Λ

and washed with a few ml of dimethylformamide. The filtrate is evaporated under reduced pressure. There remains an oily residue which becomes crystalline when stirred with a few ml of ethyl acetate. The yield is 0.675 g, mp> 150 ° C (decomp.)

Simply stirring this crude title compound in anhydrous ethyl acetate for 1 hour followed by filtration, washing with ethyl acetate and drying under reduced pressure improves the purity. The yield is 80%, mp> 165 ° C (dec.).

F) [3S (Z) 3-2 - [[[i- (2-Amino-4-thiazolyl) -2- [qi - [[[t 3 - [[- (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) acetyl]] amino] -2-oxo-1-imidazolidinyl]} sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] -amino] oxy] -2-methyl-propionic acid diphenylmethyl ester

A suspension of 0.75 g (1.35 mmol) of (S) -N- [_3- [LD 3-amino-2-oxo-1-azetidinyl) -carbonyl] amino-sulfonyl] -2-oxo-1 -imidazolidinyl] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridineacetamide trifluoroacetate salt in 12 ml of anhydrous ethyl acetate is treated with 1.1 ml (4.45 mmol) of bis-trimethylsilylacetamide. After 1 hour of stirring at room temperature, the clear solution is evaporated under reduced pressure and the oily residue dissolved in 12 ml of anhydrous ethyl acetate (solution A).

A -30 ⁰ C cold suspension of 0.60 g (1.35 mmol) of (Z) -2-amino-of £ [2- (diphenylmethoxy) -1, 1-dimethyl-2-oxoäthoxy] imino] - 4-thiazoleacetic acid in 12 ml of anhydrous acetonitrile is treated with 0.57 ml (5.4 mmol) of triethylamine and then with 0.29 ml (1.35 mmol) of diphenylchlorophosphate. It is stirred for 1 hour at -30 ⁰ C and an additional hour at 0 ⁰ C. The solvent is removed under reduced pressure and the residue is stirred by stirring with a few ml of water.

-810.86- 37853

precipitated at ⁰ ° C. The precipitate is collected by suction, washed with cold water, suspended in pH 2 water by addition of a few drops of dilute hydrochloric acid, filtered off, washed successively with water, methanol and ether and dried under reduced pressure. The yield is 1.07 g, mp> 180 ° C. (dec.). This crude product is used in the next step without further purification.

G) Di-sodium salt of [3S (Z)] -2- [[[i - (2-amino-4-thiazolyl) ^2- LD-CECC ³ "[D ¹ -4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) -acetylQ-amino-2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methyl-propionic acid!

A -10 ⁰ C cold solution of 2.0 ml of anisole in 10 ml of trifluoroacetic acid is crude with 1.01 g (1.17 mmol) £ 3S (Z)] - 2- [£ \ j - (2-amino-4 -thiazolyl) -2- [[1-LCCC ^ - [D 1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -acetyl] -amino] -2-oxo-1-imidazolidinyl] -sulfonyl] -amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoäthyliden] -amino] -oxy] -2-methylpropionsäurediphenylmethylester. After stirring for 20 minutes at -10 ⁰ C, the solvent is under reduced pressure at +10 ⁰ C abgedampft..Der residue is stirred with a few ml of dichloromethane, filtered off and stirred once more with a few ml of dichloromethane. The residue is collected by suction, washed with hexane and dried under reduced pressure. The crude product (1.06 g) is suspended in a few ml of water / acetonitrile and then dissolved by adjusting the pH to 6.0 by the addition of 1N sodium hydroxide solution. After concentration under reduced pressure, the aqueous solution is chromatographed by MPLC on macroreticular styrene-divinylbenzene copolymer eluting with water. The appropriate fractions are combined and freeze-dried. The yield is 0.10 g, mp> 255 ° C.

mn OC. Q7 P, Κ! Ή

Example 15

Di-sodium salt of [3S (Z)] -2- [_ \ - (2-amino-4-thiazolyl) -2-LE ¹ -LCCEI ³ - [C ³ - ⁽¹ , 4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl) -1-oxo-2-propenyl] -amino] -2-oxo-1-imidazolidinyl] -sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] amino] oxy] -2-methylpropionic acid

A) 2 - ((1-Hydroxy-1-methoxy) -methyl) -5- (phenylmethoxy) -4- (1H) -pyridinone

9.0 g of 2- (hydroxymethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone and 26 g of manganese dioxide (activated) are stirred in 100 ml of methanol overnight at room temperature. There are crystals of the product. After boiling the reaction mixture for 10 minutes and hot filtration through HyfIo, the filter cake is washed twice with 50 ml of boiling methanol. The combined filtrates are evaporated and the residue is stirred with 50 ml of ethyl acetate. There are white crystals of the product. The yield is 9.7 g,

F. 156 ⁰ C (Zers.).

B) 3- | ~ 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -2-propenoic acid ethyl ester

0.5 g of p-toluenesulfonic acid, 6.26 g of 2- (1-hydroxy-1-methoxymethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone and 8.35 g of carboethoxymethylenetriphenylphosphorane are dissolved in 100 ml of dioxane for 3 hours stirred at 70 ⁰ C. It forms a clear dark-colored solution. Evaporation of the solvent under reduced pressure leaves an oily residue of the title compound and triphenylphosphine oxide. The residue is dissolved in 30 ml of isopropanol, whereupon crystals of the product begin to precipitate. The solution is left overnight in the refrigerator. The crystals are then filtered off, washed with ether and recrystallized from isopropanol. The yield is 5.72 g, mp 188 ° C.

-81186- 37853-1

C) 3- [i, 4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -2-propenoic acid

1.5 g of 3- (j, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] 2-propensäureäthylester stirred and 0.29 g of potassium hydroxide in 30 ml of ethanol for 2 hours at 50 ⁰ C. After After evaporation of the solvent, the residue is dissolved in 100 ml of water and filtered, the filtrate is treated with 2N hydrochloric acid until the pH reaches 5. The crystals of the title compound precipitate out of solution and are filtered off, washed with water and concentrated The yield is 1.14 g, - F. 236 ° C.

D) 3-Ql, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl]] - N- (2-OXO-1-imidazolidinyl) -2-propenamide

10.85 g of 3- [j, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl]] -2-propenoic acid, 1 g of N-hydroxybenzotriazole, 0.01 g of N, N-dimethylaminopyridine and 8 , 24 g of dicyclohexylcarbodiimide are stirred for 30 minutes in 100 ml of dimethylformamide. After cooling to 0 ° C, 4 g N-aminoimidazolidinone are added and stirring is continued for 1 hour at 0 ^0C and 10 hours at room temperature. The resulting suspension is heated to 60 ⁰ C and filtered. It is resuspended in 50 ml of dimethylformamide, heated to 60 ⁰ C and filtered again.

The combined filtrates are evaporated at 40 ⁰ C (oil vacuum). The oily residue is stirred with 50 ml of water containing 2 g of sodium bicarbonate. After filtration, the solid is washed with water, acetone and ether.

After drying, 12.3 g of the solid are obtained. It is stirred together with 8 g of p-toluenesulfonic acid in 100 ml of dichloromethane for 1 hour. Filtration gives 12.98 g of a white solid. This compound is suspended in water. The recrystallization from water / dimethylformamide gives 8.49 g of the title compound with a mp of 271 ° C.

-81 (186- 37853

1. E) (3S) - [i -LLEC ³ -CC ^3- D - 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl-1-oxo-2-propenyl] -amino '] - 2-oxo-i-imidazolidinyl] -sulfonyl]] -amino] -carbonyl] -2-oxo-3-azetidinyl]] carbarninsäurephenylmethylester 5

3.55 g of 3- [i, 4-dihydro-4-oxo-5- (phen, ylmethoxy) -2-pyridinyl] N-2- (2-OXO-1-imdiazolidinyl) -2-propenamide are dissolved in 100 ml Essigsäureäthylester suspended and treated with 6.3 g of N-methyl-N- (trimethylsilyl) trifluoroacetamide. After stirring for 1 h HO, a clear solution is obtained. The solution is then within 10 minutes to a cooled to 0 ⁰ C solution of 3.3 g of (S) -1 - [L (Chlorsulf onyl) amino] carbonyl] -3-LL ^ phenylmethoxy) carbonyl] - amino] -2-azetidinone in 50 ml of ethyl acetate. After stirring overnight, the solvent is evaporated and the oily residue is stirred for 1 hour with 50 ml of isopropanol. The resulting precipitate is filtered off and washed with isopropanol and ether. The yield is 5.91 g.

F) (3S) -3-amino-N-EC ³ -CD ¹ , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -1-oxo-2-propenyl] amino] -2-oxo -i-imidazolidinyl] sulfonyl] -1-azetidinecarboxamide, trifluoroacetate salt

6.8 g of ⁽³ S) -) ^j-3 LLLC -LL ^3- D, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinylJ-1-oxo-2-propenyl] amino] - 2-oxo-1-imidazolidinyl] -sulfonyl] -amino] -carbonylj-2-oxo-2-azetidinyl] -carbamic acid phenylmethyl ester are stirred overnight at room temperature in 60 ml trifluoroacetic acid / thioanisole (3: 1). After evaporation of the resulting solution. One third of its volume is added to 50 ml of isoproanol and 10 ml of ether. The (3S) -3-amino-N- Uj- [D ¹ -4-dihydro-5-hydroxy-4-oxo-2-pyridinyl] -1-oxo-2-propenyl] amino] -2-OXO- 1-imidazolidinyl] sulfonyl-1-azetidinecarboxamide trifluoroacetate salt precipitates as a white precipitate. It is washed several times with ether and dried. The yield is 4.30 g.

η -in η η ο "7 η :; η j

-1 1 δ-G) di-sodium salt of the JJS (Z ) "] -2- [[qi - (2-amino-4-thiazolyl) 2 [D - [L [D- Uj ~ ( ¹ - 4-dihydro 5-hydroxy-4-oxo-2-pyridinyl) 1-oxo-2-propenyl] amino]] -2-o xo-1-imidazole id inyl] -sulfonyl "] -amino-carbonyl] -2- oxo-3-azetidinyl] amino]] -2-oxoethylidene} amino-oxy] -2-methylpropionic acid

2.2 g of (Z) -2-amino-0f - [[2- (diphenylmethoxy) -1, 1-dimethyl-2-oxoethoxy] -imino] -4-thiazoleacetic acid and 1.5 g of triethylamine are dissolved in 150 ml of acetonitrile solved. The solution is added dropwise at C "-30 ⁰ with 1.4 g of diphenyl chlorophosphate and then the mixture was stirred 1 hour, 3.3 g of (3S) -3-amino-N -. [[3 - [[(1, 4-dihydro -5-hydroxy-4-oxo-2-pyridinyl) -1-oxo-2-propenyl'2-amino'3-2-oxo-1-imidazolidinyl] sulfonyl] 1-azetidinecarboxamide 2.0-trifluoroacetate salt are suspended in 1 00 ml of ethyl acetate and 6 ml of N-methyl-N- (trimethylsilyl) trifluoroacetamide treated and subse-. ßend stirred for 1 hour at room temperature. The solution is stirred at -30 ⁰ C within 15 minutes dropwise to added the activated acid. It is then stirred for 1 hour at -10 ⁰ C and 30 minutes at 0 ⁰ C. the solvent is stirred evaporated under reduced pressure and the residual oil with ice water at pH 2 (2N phosphoric acid). the ice water is discarded and the residue washed again with ice water and then dissolved in 100 ml of tetrahydrofuran.

The solution is dried over sodium sulfate and the filtrate is then evaporated. The diphenylmethyl ester of the title compound is isolated as a solid foam in a yield of 1.81 g.

1.5 g of product are stirred C for 30 minutes in 30 ml trifluoroacetic acid / anilines sol at 0 ^0th After the addition of 100 ml of ether, 1.7 g of the trifluoroacetic acid salt of the title compound are isolated by filtration. This is dissolved in 10 ml of water and treated with sodium bicarbonate solution until the pH reaches 5.5. The filtered solution is coated on macroreticular styrene-divinylbenzene copolymer

O "7 O;." O!

-1 1 ΤΙ. (400 g) using water as eluent. The appropriate fractions contain 0.64 g of the product, a bioautography yields a small amount of a bioactive by-product, and the product is subjected to a second column chromatography on Merck Lobar C with water as the eluent The corresponding fractions contain 0.17 g of the title compound.

Example 16

Di-sodium salt of [3S (Z ) J -2-C [Ij - (2-amino-4-thiazolyl) -2-CD - CELL ² - D - (1, 4-dihydro-5-hydroxy-4-oxp 2-pyridinyl) -1-oxo-2-propenyl] -hydrazino-Q-sulfonyl] -amino-carbonyl] -2-oxo-3-azetidinyl] -amino-2-oxoethylidene] -amincQ -oxy "] -2 -methyl propionic acid!

A) 3- | j, 4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -2-

propenoic acid, 2-Q1,1-dimethyläthoxy) -carbonylQ hydrazide

1.36 g of 3- [i, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -2-propenoic acid, 0.75 g of N-hydroxybenzotriazole, 0.01 g of N, N-dimethylaminopyridine and 1.06 g of dicyclohexylcarbodiimide are stirred in 20 ml of dimethylformamide at 0 ^° C. for 20 minutes. Then 0.66 g of N- (tert-butoxycarbonyl) -hydrazine are added. After stirring overnight, the resulting dicyclohexylurea is filtered off and the filtrate is washed with 10 ml of dimethylformamide. The filtrate is evaporated to dryness and the residue is suspended in 30 ml of water. Subsequently, 1 g of sodium bicarbonate is added and after stirring the title compound is filtered off. Recrystallization from dimethylformamide / water gives white crystals in a yield of 1.47 g with a mp of 141 ^° C.

B) 3-yl, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] j-2-propenoic acid hydrazide

- fs 10.8 6 - 378531

3.86 g of 3-Ql, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl]] - 2-propenoic acid 2-Q (1,1-dimethylethoxy) carbonyl] hydraid stirred at 0 to 5 ° C in 30 ml of trifluoroacetic acid 'half an hour. The trifluoroacetic acid salt of the title compound precipitates after addition of 50 ml of diethyl ether. The salt is suspended in 30 ml of water, stirred with 2 g of sodium bicarbonate for 20 minutes, and then the title compound is filtered off. It is washed with water and dried to give a beige powder in a yield of 2.75 g.

C) (3S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridine

, carboxylic acid 2- [_Q [_Q2-oxo-3-QQ (phenylmethoxy) carbonyl] -

amincQ -1-azetidinyl] -carbonyl-amino-sulfonyl-hydrazide 15

2.86 g of 3-Ql, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl]] -2-propenoic acid hydrazide and 8.1 g of N-methyl-N- (trimethylsilyl) trifluoroacetamide are stirred for 1 hour in Stirred 50 ml of ethyl acetate. The clear solution obtained is within 10 minutes at 0 ⁰ C with a solution of 3,27g (S) -I- [Q Chlorsulf onyl) amino carbonyl]] -3- {_ [_ {phenylmethoxy) carbonyl] ] -aminoJ-2-azetidinone. After stirring overnight, the solvent is evaporated and the residue is stirred with 50 ml of isopropanol and one drop of acid. The title compound is filtered off and washed with isopropanol and ether. The yield is 5.42 g.

D) (3S) -3-Ql, 4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl] -2-propenoic acid 2-QQQ (3-amino-2-oxo-1-azetidinyl) -carbonyl] ] amincT [-sulfoneyl]] - hydrazide trifluoroacetate salt

5.2 g of (3S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid 2-, Q [[] Q 2 -oxo-3 - [Q (phenylmethoxy) carbonyl] amino ]] -1-azetidinyl]] - carbonyl]] - amino]] sulfonyl] hydrazide are stirred in 50 ml trifluoroacetic acid / thioanisole (3: 1) at room temperature overnight. The clear solution becomes

-fliflßfi-

4L-J W α £ & a

with a mixture of 100 ml ether / isopropanol (8: 2)

added. The resulting precipitate is filtered off and washed with ether. The yield is 4.01 g after drying

 5

E) The di-sodium salt of [3S (Z)] -2- [[[/ I - (2-amino-4-thiazolyl) 2LD-QCLI ² - [3- (1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl) -1-oxo-2-propenyl] hydrazino] sulfonyl] amino] carbonyl] 2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] 2 -methylpropionic

1.5 g of (Z) -2-amino-Of-Q '[2- (diphenylmethoxy) -1, 1-dimethyl-2-oxoäthoxy] _i imino] -4-thiazoleacetic acid and 1 g of triethylamine are in-100 ml Acetonitrile dissolved. The solution will be. at -30 ⁰ C added dropwise with 1 g of diphenylchlorophosphate and the mixture then stirred for 1 hour.

2.0 g of (3S) -3- [1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl] -2-propenoic acid 2- [Eq 3-amino-2-oxo-1-azidinyl ) -carbonyl] amino ^ -sulfonyl] hydrazide trifluoroacetate salt and 5.5 ml of N-methyl-N- (trimethylsilyl) trifluoroacetamide are stirred in 50 ml of ethyl acetate at room temperature for 1 hour. The erhaltene.klare solution is cooled and added dropwise at -30 ⁰ C to the activated acid. The mixture is stirred for 1 Stunde'bei -3O ⁰ C, 30 minutes at -10 ⁰ C and 1 hour at 0 ⁰ C. The solvents are then evaporated under reduced pressure and the residue is stirred with 50 ml of isopropanol. The resulting solid is filtered off and stirred with 100 ml of ice water for 20 minutes at pH 2 (phosphoric acid). After filtration, the diphenylmethyl ester of the title compound is obtained, which is washed three times with 50 ml portions of ice-water and dried (1.78 g). 1.5 g of the ester are stirred at 0 ^° C. for 30 minutes with 50 ml of trifluoroacetic acid / anisole (4: 1). After addition of 150 ml of ether, the trifluoroacetic acid salt of the free acid of the title compound is distilled off.

-810.86- 378531

-ίσοι filtered (1.65 g).

1 g of this product is suspended in 5 ml of water and the pH is adjusted to 6.0 with sodium bicarbonate. The clear solution is then chromatographed on 400 g of macroreticular styrene-divinylbenzene copolymer with water as eluent. There are obtained 413 g of the title compound. 400 mg of the product are rechromatographed on Merck Lobar C with water as eluent. The yield is 160 mg.

Example 17

Di-Sodium salt of [3S (Z Γ) -2-ECC ¹ - (2-amino-4-thiazolyl) -2-EX ¹ "CC [EE ² ""LD ¹ '4-dihydro-5-hydroxy-4-" oxo-2-pyridinyl) carbonyl} amino] ethyl] amino] sulfonyl]] amino] carbonyl "] 2-oxo-3-azetidinyl] _-amino] -2-oxoethylidyl] amino] -oxy ] -2-methylpropionic acid

A) N- (4-methoxybenzyl) -O-benzylcomenarnic acid 20

10 g of O-benzylcomenoic acid and 10 ml of 4-methoxybenzylamine in 60 ml of water are refluxed for 4 hours. The reaction mixture is adjusted to pH 2 with 2N hydrochloric acid at room temperature. There are obtained 15 g of crystals. Recrystallization from dioxane gives 12.3 g of the title compound with a mp of 175 ^° C.

B) 1, 4-Dihydro-1 - [( 4-methoxyphenyl) methyl] -4-oxo-5- (phenylmethoxy) -N- [2 - [(phenylmethyl) -amino-ethyl] -2-pyridinecarboxamide

3.69 g of N-Q4-methoxypheriyl) -methyl J-O-benzyl-comenamic acid, 1.50 g of N-hydroxybenzotriazole and 2.05 g of dicyclohexylcarbodiimide are stirred for 1 hour at room temperature in 50 ml of dioxane. A solution of 1.35 g of N-benzylethylenediamine in 5 ml of dioxane is added dropwise. To

-810.86- 378531

rf & <M? W

Stirring overnight, the resulting dicyclohexylurea is filtered off and the dioxane is evaporated from the filtrate The oily residue is dissolved in 50 ml of dichloromethane and extracted with two 50 ml portions of 1 above sodium hydrogencarbonate and then washed with water. After drying the dichloromethane solution over sodium sulfate, the solution is evaporated. The residual solid is recrystallized from ethanol. There are obtained 4.2 g of crystals of the title compound with a mp of 112 ° C.

C) N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2-pyridin-aτ-Ηπν ami-rl-η- -t-η 1 iir> 1 QnI fAnat-Ssl -7

carboxamide ρ-toluenesulfonate salt

9.95 g of 1,4-dihydro-1 - * (4-methoxyphenyl) -methyl ^ -4-OXO-5- (phenylmethoxy) -N- 2- (phenylmethyl) -amino] -ethyl) - 2-pyridinecarboxamide and 7.7 g of p-toluenesulfonic acid in 100 ml of methanol are treated with 3 g of palladium on charcoal (10 %) and hydrogen is passed through the reaction mixture for 6 hours at 45 to 50 ^° C. Subsequently, argon 10 The mixture is filtered and the filtrate is evaporated to give beige crystals of the title compound, which are washed first with 20 ml of cold methanol and then with 50 ml of ether, yield 10.5 g, mp. 271 ⁰ C.

D) N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamine dihydrochloride

5.42 g of N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide p-toluenesulfonic acid salt are dissolved in 50 ml of formic acid and then 7.5 ml of formic acid / hydrogen chloride gas (2 , 2 equivalents of hydrogen chloride) and 15 Omlit added. There are obtained white crystals. After filtering and washing with 200 ml of ether are 2.60 g

-122 of the title compound having a mp of 287 ° C.

E) (3S) - [i - [[[[[[2- [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl]] -amino] -ethyl] -amino] ] -sulfonyl]] -amino]] carbonyl]] -2-oxo-3-azetidinyl J -carbamic acid phenylmethyl ester

4.38 g of (S) -3- {] [] (phenylmethoxy) carbonyl]) amino]] -2-azetidinone are suspended in 50 ml of ethyl acetate and admixed at room temperature with 2.83 g of chlorosulfonyl isocyanate. After stirring for 30 minutes, a clear solution is obtained.

5.40 g of N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide dihydrochloride in 50 ml of acetonitrile are added together with 24 g (6 equivalents) of N-methyl-N- (Trimethylsilyl) trifluoroacetamide bei.50 ⁰ C stirred for 1 hour. The volatiles are evaporated under reduced pressure. The remaining oily residue is mixed with 50 ml of 2Q ethyl acetate.

The solutions prepared as above are cooled to 0 ^° C. and the second solution is added with stirring to the first solution. After stirring overnight, 200 ml of isopropanol are added with stirring at 0 ^° C. The title compound is obtained in the form of beige crystals in a yield of 8.77 g with a melting point of 145 ^° C.

F) (3S) -N - [[_ [j] [] (3-amino-2-oxo-1-azetidinyl) -carbonyl] -amino] -sulfonyl] -aminoj-ethyl] [1,4-dihydro -5-hydroxy-4-oxo-2-pyridinecarboxamide-2 _/ 0-trifluoroacetate salt

2 g of (3S) - [J - [CLCC ² - [[C, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] J-ethyl] amino] sulfonyl] - amino] -carbo-3g nyl] -2-oxo-3-azetidinyl] carbamic acid phenylmethyl ester in 20 ml of thioanisole / 40 ml of trifluoroacetic acid at 0 C ⁰

No QR.

25U I

Stirred for 12 hours. After addition of 100 ml of ether, fine white crystals of the title compound are filtered off. They are washed with 50 ml of isopropanol and 100 ml of ether.

There are obtained 2.12 g of the title compound with a mp of 136 ° C (dec.).

G) [3S (Z) l-2 - [[[i- (2-amino-4-thiazolyl) -2 - [[i - [[[[[[2- [_ [_ [ 1, 4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) -carbonyl]] amino] -ylyl-amino]] -sulfonyl]] -aminoj-carbonyl] -2-oxo-3-azetidinyl]] -amino]] -2 -oxoethylidene-3-amino]] oxy] -2-methylpropionic acid diphenylmethacrylate:

4.40 g of (Z) -2-amino-0f- [_ [2- (diphenylmethoxy) -1, 1-dimethyl-2-oxoethoxy-imino] -4-thiazoleacetic acid and 3 g of triethylamine] are added in 150 ml Acetonitrile dissolved. The solution is added dropwise at -30 ⁰ C with 2.8 g of diphenyl chlorophosphate and the mixture is then stirred for 1 hour.

6.13 g of (3S) -N- [££ [[(3-amino-2-oxo-1-azetidinyl) carbonyl] amino]] sulfonyl]] amino]] ethyl Q -1, 4-dihydro 5-hydroxy-4-oxo-2-pyridinecarboxamide-2.0-trifluoroacetate salt and 17 g of N-methyl-N- (trimethylsilyl) trifluoroacetamide are stirred for 2 hours in 100 ml of ethyl acetate. The solvent of the clear solution is distilled off under reduced pressure and the remaining oily residue for 2 hours at 30 ⁰ C evaporated (oil vacuum <0.01 mm). The residue is again dissolved in 100 ml of ethyl acetate and added dropwise at -30 ⁰ C within 30 minutes to the activated acid. The mixture is stirred at -1O ⁰ C for 1 hour and at 0 ⁰ C for 1 hour. The solvent is evaporated and the remaining oily residue is stirred with ice-water at pH 3 (2N phosphoric acid). The ice-water is discarded and the residue is washed again with ice-water and dried. There are obtained 7.8 g of beige crystals.

-810.86- 378531

H) Di-sodium salt of the JJS (Z)] -2- [QQi - (2-amino-4-thiazolyl) j "[j - [[[[[2 - [[(1,4-dihydro-5-hydroxy 4-oxo-2-pyridinyl) carbonyl] amino] ethyl] amino] sulfonyl] amino] carbonyl] 2-oxo-3-azetidinyl] amino] -2-oxoethylidyl] amino] oxy ] -

2-methylpropionic

3 g of [3S (Z)] - 2-QQQi- (2-amino-4-thiazolyl) -2- [qi- [QQ [[2-QQ (1,4-dihydro-5-hydroxy-4-oxo) 2-pyridinyl) -carbonyl] -amino] -äthy l] -aminin] -sulfonyl ] --amino] -carbonyl] -2-oxo-3-azetidinyl] amino] 2-oxoethylidyl] amino] -oxy] 2-Methylpropionsäurediphenylmethylester are stirred for 30 minutes in 30 ml of trifluoroacetic acid / anisole. The trifluoroacetic acid salt of the free acid is isolated after precipitation with ether. 7.9 g of this product are suspended in 20 ml of water and the pH

Value of suspension with sodium bicarbonate adjusted to 6.0. After stirring for half an hour, the suspension is filtered and the solution chromatographed on macroreticular styrene-divinylbenzene copolymer with water as eluent. The yield is 0.24 g. This product is again chromatographed on a Merck Lobar C column. The yield is 0.078 g, mp 275 ° C (dec.).

, Example 18

Di-sodium salt of [2S \ jC (, 3β (Z)]] -2-Q [qi - (2-amino-4-thiazolyl) -2-Q _- Ij - [QQQ3-QQ (1, 4 -dinydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] -sulfonyl] amino] carbonyl] -2-methyl-4-oxo 3-azetidinyl] amino] -2-oxoethylidene] -amino] oxy] -2-methyl thypropionic acid

A) (2S-trans) -Qi-QQQQ3QQQ1, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2-oxo-i-imidazolidinyl] sulfonyl] - amino] carbonyl] -2-methyl-4-oxo-3-azetidinyl] -carbamic acid phenylmethyl ester

2.35 g of (3S-trans) - (4-methyl-2-oxo-3-azetidinyl) -carbamic acid phenylmethyl ester and 1.41 g of chlorosulfonyl isocyanate

-8186- 378531

Stirred for 1 hour at 0 ° to 5 ° C in 50 ml of ethyl acetate. A clear solution is obtained (solution A). 3.28 g of 1, '4-dihydro-4-oxo-N - ^ -oxo-i-imidazolidinyl) -5- (phenylmethoxy) -2-pyridinecarboxamide and 6 g of N-methyl-N- (trimethylsilyl) trifluoroacetamide become 1 Stirred at 40 ⁰ C in 50 ml of ethyl acetate (solution B).

The cooled (0 ⁰ C) solution A is added within 30 minutes with stirring with solution B. After stirring overnight, the solvent is evaporated off and the oily residue is stirred with 50 ml of isopropanol and 1 drop of acetic acid. The title compound is obtained as a beige precipitate with a mp of 163 ° (dec.) In 4.3 g yield. ,

B) (2S-tr ans) -N- [3 - [[[( ^3- amino-2-methyl-4-oxo-1-azetidinyl) -

carbonyl-amino-sulfonyl-2-oxo-1-imidazolidinyl] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinearboxamide di-p-toluenesulfonate

5.9 g of (2S-trans) - [i - [[[[3 - [[i, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2 -oxo-1-imidazolidinyl] -sulfonyl] -amino] carbonyl] ^ -methyl ^ -oxo-S-azetidinyl] -carbamic acid phenylmethyl ester in 50 ml of dimethylformamide and 3.8 g of hydrated p-toluenesulfonic acid and 2.5 g of palladium on charcoal (10 %) are hydrogenated at room temperature for 1 hour. After filtration over Hyflo, the dimethylformamide is distilled off under reduced pressure. The oily residue is stirred with 100 ml of dichloromethane.

-Q 5.8 g of the title compound immediately precipitate as white crystals.

C) The di-sodium salt of [2S- [lOC, 3β (Z fQ -2- [[JJ - (2-amino-4-thiazolyl) -2- [[i - [[[[.3- [[(1 , 4-dihydro-5-hydroxy-4-oxo-2-ol

", - pyridinyl) carbonyl] amino-2-oxo-1-imidazolidinyl] -sulfonyl 13-amino]] carbonyl] -2-methyl-1, 4-oxo-3-azetidinyl]] -amino] 2 -oxoäthyliden] -aminc] oxy] -2-methyl-propionic acid!

-8.10.86- 37853 ·!

, 4.40 g of (Z) -2-amino-0f-ε [2- (diphenylmethoxy) -1, 1-dimethyl-2-oxoethoxy] -imino] -4-thiazoleacetic acid and 3.0 g of triethylamine are dissolved in 150 ml Acetonitrile dissolved. The solution is added dropwise at -30 ⁰ C comparable with 2.8 g of diphenyl chlorophosphate

c- and stirred for 1 hour, ο

7.90 g of (2S-trans) -N- [β- [f Q 3-amino-2-methyl-4-oxo-1-azetidinyl) carbonyl] amino] sulfonyl] -2-oxo-1 Imidazolidinyi] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide di-p-toluene _in sulfonate and 2.02 g of triethylamine are stirred for 5 minutes at -20 ⁰ C in 50 ml of dimethylformamide.

The suspension and solution prepared as described above are combined at -30 ⁰ C and 1 hour at -30 ⁰ C,

Stirred at -10 ° C for 1 hour and at 0 ° to 10 ° C overnight.

The solvents are then distilled off under reduced pressure and the residue is stirred with 100 ml of ice-water at pH (phosphoric acid). The diphenylmethyl ester of the title compound is filtered off and washed with water.

The yield of a beige powder is 6.13 g. Λ U

2 g of the ester are stirred for 30 minutes at 0 ^° C. in 30 ml of trifluoroacetic acid / anisole (4: 1). After addition of 100 ml of ether precipitates the trifluoroacetic acid salt of the free acid. It is suspended in 10 ml of water and the pH of the suspension is adjusted to 6.0. After filtering, the filtrate is passed through a macroreticular styrene-divinylbenzene copolymer column with water as eluent. The yield is 0.48 g.

A second column chromatography on Merck Lobar C with water as eluent gives 0.17 g of the title compound.

Example 19

Potassium salt of JJS (Z) "} - 2-amino-N- [i- [.LCC ³ - [(J ¹ -4-dihydro-5-35

hydroxy-4-oxo-2-pyridinyl) carbonyl] amino J-2-oxo-1-imidazo

-810.86- 37853-i

lidinyl [-sulfonyl] amino] carbonyl] -Z-oxo-B-azetidinyl] -O- (methoxyimino) -4-thiazole acetamide

A suspension of 0.6 g of (Z) -2-amino- (methoxyimino) -4-thiazoleacetic acid (0.003 mol) is treated at room temperature with 2.14 ml (0.009 mol) of tributylamine. The suspension is cooled to -30 ⁰ C and added at this temperature, 0.66 ml (0.003 mol) of diphenylchlorophosphate. The reaction mixture is stirred for 1 hour at -30 ⁰ C (mixture A).

A suspension of 1.62 g (0.003 mol) of (3S) -3-amino-N- [Q3-QQ1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] -amine ] -2-OXO-1-imidazolidinyl] sulfonyl] -2-OXO-1-azetidinecarboxamide in 20 ml of ethyl acetate is treated at room temperature with 2.6 ml of bis-trimethylsilylacetamide. It forms a clear brownish solution, which is stirred for 1 hour at room temperature and then cooled to 0 ⁰ C (solution B).

Solution B is added dropwise with stirring to the mixture A, while the temperature is maintained at -30 ⁰ C (about 10 minutes). The mixture is stirred at -10 ⁰ C for 1 hour and at 0 ⁰ C for a further 1 1/2 hours and then evaporated under reduced pressure. The syrupy residue is dissolved in 50 ml / 25 acetone. The solution is treated with 6 ml of 1M potassium ethylhexanoate to precipitate 3.0 g of the crude product. The addition of ether to the filtrate gives a further 0/2 g of the crude product. Chromatography of the crude product on macroreticular styrene-divinylbenzene copolymer yields 1.85 g of the title compound.

Example 20

Q3S (Z)] - 2- [ε- (2-amino-4-thiazolyl) -2- [ _i [iQ [[Q3- [Q (1,4-dihydro-5-hydroxy-4-oxo) 2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidyl] amino] oxy ] -2-methylpropionic acid

-iUO.86- 378531

2.2 g of the disodium salt of the [3 S (ZQ -2- [ γ] - (2-amino-4-thiazolyl) -2- [i - [[_ [[. 3 - [[(1, 4 -dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] _ -amino] -2-oxo-1-imidazolidinyl] -sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl-J-amino ] -2-Oxoäthyliden _ [_- amino] -oxy] -2-methylpropionic acid (see Example 1) are dissolved in 20 ml of acetone / water (1: 1) and the pH of the solution is adjusted to 2 with 2N hydrochloric acid. Chromatography on the macroreticular styrene-divinylbenzene copolymer gives 0.7 g of the title compound.

B e s p-i el 2 1

Sodium salt of the JJS (Z)] -2- [ε- (2-amino-4-thiazolyl) -2-LD-LLLD-EB ¹ > 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl] -carbonyl] -amino "] -2-oxo-1-imidazolidinyl] -sulfonyl] -amino] -g-carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] oxyJ_-N- hydroxy-2-methylpropanamids

4.72 g of (Z) -2-amino- <y- ZD, 1-dimethyl-2-oxo-2-Q (triphenylmethoxy) -amino "] -ethoxy ^ 1-imino] -4-thiazoleacetic acid become 2Q in 55 suspended ml of acetonitrile and treated at -30 ⁰ C with 3.7 to 2 ml Triäthylarnin. After 10 minutes of stirring, 1.97 ml of diphenylchlorophosphate was added. The mixture is then yet a further 90 minutes stirring (solution A).

8.9 ml of (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] -amino] -2-oxo 1-Imidazolidinyl] -sulfonyi ~ [-2-oxo-1-azetidincarboxamid be suspended in 70 ml of acetonitrile and treated with 7.7 ml of bis-trimethylsilylacetamide. After stirring for 1 hour at -10 ⁰ C and 1 1/2 STUN

_q at ^{0 0} C, a clear solution is obtained. The solvent and the resulting Trifluoressigsäuretrimethylsilylester are evaporated under reduced pressure and the residual oil dissolved in 70 ml of ethyl acetate (solution B).

The stirred solution B becomes at -20 ° C within 30 minutes

mixed with solution A. After 1 1/2 hours stirring at -10 ⁰ C and 1 hour of stirring at 0 ⁰ C, the reaction is complete.

The solvents are distilled off under reduced pressure and the oily residue is stirred with 300 ml of ice-water whose pH has been adjusted to 4.0 with T0% phosphoric acid. The formed Fes'tstoff is filtered off, washed with water and dried overnight under reduced pressure. The yield is 9 g of crude product.

4.5 g of the crude product are stirred for 1 hour at 0 ^° C. with 45 ml of formic acid (98 %) and 4.5 ml of dichloromethane. By precipitation with diethyl ether, 2.3 g of the title compound are obtained.

Example 22

Di-Sodium salt of [3S (Z)] -2- [QQ - (2-amino-4-thiazolyl) -2-LD - LCLC ² -LL ³ "LL ⁽ i -4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) -. carbonyl] amino] -2 ^ oxo-1-imidazolidinyl] carbonyl] hydrazino] sulfonyl] -amine] -carbonyl] [-2-oxo-3-azetidinyl] -amino] 2-oxoethylidene] -amino] -oxy] -2-methylpropionic acid

A) 2- [Jj. Phenylmethoxy) carbonyl] amino] -2-imidazolidinone

26 g (0.257 mol) of 1-amino-2-imidazolidinone are dissolved in 200 ml of water and the solution is then covered with 200 ml of ethyl acetate, followed by stirring with 43.8 g (0.257 mol) of chloroform / benzyl ester in which the pH of the solution is kept at 8.5 to 9 by addition of saturated sodium bicarbonate solution After stirring overnight at room temperature, the title compound is filtered off, washed first with water and then with ethyl acetate. The yield is 46.7 g. F. 140 bis'i44 ° C.

-810.86- 37853-

25 U u »

B) 1 - £ [(phenylmethoxy) carbonyl] amino] -3-chlorocarbonyl) -2-imidazolidinone

A suspension of 69.9 g (0.297 mol) of 2 - [[(phenylmethoxy) carbonyl] amino] -2-imidazolidinone in 1 liter of dichloromethane is treated with a solution of 35 g of phosgene in 200 ml of dichloromethane. The mixture is stirred overnight at room temperature to give a clear solution. The solvent is removed under reduced pressure and the syrupy residue digested with ether. The yield is 76.0 g, -F. 102 to 105 ⁰ C.

C) 3-β-Q-phenylmethoxy-carbonyl] -amino] -2-oxo-1-imidazolidinecarboxylic acid 2-Γ_ (1, 1-dimethylethoxy) carbonyl] hydrazide

1.5 liters of ethyl acetate are added at room temperature with 76 g (0.255 mol) of 1 - [_ [_ { phenylmethoxy) carbonyl] -aminol ~ 3- (chlorocarbonyl) -2-imidazolidinone. After cooling to 0 ° to 5 ⁰ C, a solution of 39.6 g (0.9 mol) of N- (tert-butoxycarbonyl) hydrazide and 41.8 ml (0.3 mol) of triethylamine in 150 ml of ethyl acetate added within 30 minutes. The mixture is stirred overnight. The precipitate is filtered off, dried, stirred with 800 ml of water to remove triethylamine hydrochloride, filtered, washed with water and dried. The yield is 71.2 g, mp 195-198 ° C.

D) 2- [3- [_] - , 4-Dihydro-4-oxo-5- (phenylmethoxy-2-pyridinyl-1-carbonyl-amino) -2-OXO-1-imidazolidinyl] -carbonyl] -hy- "-carboxylic acid -1,1-dimethyläthylester

31.5 g (0.08 mol) of 3- [ε (phenylmethoxy) carbonyl-amino] -2-oxo-1-imidazolidines arbonsäure-2- [_ { 1, 1-dimethylethoxy) carbonyl] hydrazide be in Dissolved 400 ml of dimethylformamide. Then the solution is mixed with 16 g of palladium-on-charcoal (10 %) and hydrogen is stirred through the

£ 7 F) 31

Conducted reaction mixture. After 1 hour, the catalyst is filtered off. The filtrate is charged with 19.62 g (0.08 mol) of O-benzylcomenamic acid, 0.48 g of dimethylaminopyridine and 0.64 g of N-hydroxybenzotriazole. The mixture is stirred for 1 hour at room temperature and then treated with a solution of 18.13 g (0.088 mol) of dicyclohexylcarbodiimide at room temperature. Then the mixture is stirred overnight. The precipitate of dicyclohexylurea is filtered off and the filtrate evaporated under reduced pressure. The residue is digested with water, which was added to adjust the pH to 7.5 sodium bicarbonate. The precipitate is filtered. There are obtained 36 g of the title compound.

E) 3- [[I, 4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2-oxo-1-imidazolidinecarboxylic acid hydrazide

300 ml of trifluoroacetic acid at -10 ⁰ C under stirring with 36 g of 2- \ Jjß- [JJJ, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2-oxo 1-imidazolidinyl] carbonyl] - hydrazinecarboxylic added. Das.Gemisch is stirred for 1 hour at 0 ⁰ C and the trifluoroacetic acid removed under reduced pressure. The residue is digested with ether, it will hold 41 g of the trifluoroacetate salt of the title compound he. The trifluoroacetate salt is cooled in water

suspended and the pH of the suspension adjusted to 7 by the addition of 2N sodium hydroxide solution. The precipitate is filtered off. There are obtained 21.9 g of the title compound.

F) 3 - [[(1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinecarboxylic acid hydrazide

21.9 g of 3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2-oxo-1-imidazolidinecarboxylic acid hydrazide are suspended in 250 ml of acetonitrile. The suspension is mixed with 75 ml of bis-trimethylsilylacetamide and the

η Hn ο ο O7n;: oj

Stirred mixture until a solution. The solution is mixed with 10 g of palladium on charcoal (10 %) and hydrogen passed through the vigorously stirred mixture. Debenzylation is complete after 1 hour. After filtering off, the precipitate of the title compound is mixed with 15 ml of methanol and 10 drops of acetic acid. The yield is 10.8 g. This crude product is stirred with 150 ml of ethanol, whereby 8.8 g of the title compound mit'einem F. <205 ⁰ C (dec.) Are formed.

G) (S) - [i - [_ [Q [2 - [[3-I] qi, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo -i-imidazolidinyl] carbonyl] hydrazine /] -sul.f onyl] _-amino] carbonyl "] -2-oxo-3-azetidinyl] J carbamic acid phenylmethyl ester

A suspension of 5.9 g (0 ^ 02 mol) crude 3- [_ [_ (1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo i-imidazolidincarbonsäurehydrazid is with 14.9 ml (0.08 mol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide was added and the mixture stirred at 50 ⁰ C stirred until a solution is formed (solution a).

A suspension of 4.4 g of (S) -3-ε-Q-phenylmethoxy) carbonyl] amino] -1-azetidinone (0.02 mol) in 160 ml of methyl acetate is added at room temperature with 1.76 ml of chlorosulfonyl isocyanate. The mixture is stirred for 1 hour (solution B).

Solution B is mixed with solution A while cooling with ice. After stirring for 1 hour, the mixture is treated with 2.8 ml (0.02 mol) of triethylamine and then stirred overnight at room temperature. There are once again added to 2.8 ml (0.02 mol) of triethylamine and then ice water. The mixture is stirred vigorously for 1 hour and the layers are then separated. The aqueous phase is acidified to pH 3 and the precipitate is filtered off. The yield of crude

-1 33 title compound is 5.3g.

The crude product is dissolved in acetone / water and the pH of the solution is adjusted to 6.5 by addition of 2N sodium hydroxide solution. After removal of the acetone under reduced pressure, the aqueous solution is filtered and lyophilized. There are obtained 5.5 g of the crude sodium salt of the title compound. Chromatography of the crude sodium salt on macroreticular styrene-divinylbenzene copolymer gives 0.64 g of 2o pure product. This is dissolved in water and acidified with 2N hydrochloric acid, the title compound precipitating in 0.5 g yield.

H) (S) -N- [3 - [[2 - [[Q3-amino-2-oxo-1-azetidinyl) -carbonyl ic amino]] sulfonyl]] hydrazino- ^1- carbonyl]] - 2-oxo 1-imidazolidinyl]] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide

A mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid is treated with 0.5 g of (S) - [j - LLCL ² - LG ³ - CQ ¹ '4 -dihydro-5-hydroxy-4-oxopyridinyl] carbonyl ] -amino] T-2-oxo-1-imidazolinediyl]] - carbonyl]] hydrazino]] sulphonyl]] aminocarbonyl]] -2-oxo-3-azetidinyl]] carbamic acid phenylmethyl ester. The mixture is stirred overnight at room temperature and then evaporated under reduced pressure. The residue is digested with acetic acid ethyl ester. The title compound is obtained in quantitative yield.

, I) [] 3S (Z)]] -2- £ [[1-Q2-amino-4-thiazolyl] -2- (CQ - CCCC ² "CC ³ -

LL ^, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl]} - oQ amino] -2-oxo-i-imidazolidinyl]] carbonyl] hydrazino]] sulfonyl]] amino]] - carbonyl-2-oxo-3-azetidinyl] -amino]] -2-oxoethylidene] -amino]] oxy] [- 2-methylpropionic acid diphenylmethyl ester

A solution of 0.35 g (0.0008 mole) of (Z) -2-amino-ethyl- [[2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy] imino-4-thiazole

-ftiflßfi-

1. Acetic acid in 10 ml of acetonitrile is mixed with 0.34 ml of triethylamine. The mixture is cooled to -30 ° C and treated with 0.17 ml of diphenylchlorophosphate. The reaction mixture is stirred for 1 hour at -30 ⁰ C (solution A).

A suspension of 0.008 mole of (S) -N- [ 3-QjE-QQQ (3-amino-2-oxo-1-azetidinyl) -carbonyl-amino] -sulfo-nyl-hydrazino-2-carbonyl] 2-oxo 1-imidazolidinyl] -1,4-dihydro-5-hydroxy-4-oxopyridinecarboxamide in 6 ml of ethyl acetate is treated with 0.7 ml of bis- trimethylsilylacetamide (solution B).

Solution A is added at -30 ⁰ C with solution B. .If the mixture for 2 hours at -10 ⁰ C and stirred for 1 hour at 0 ⁰ C and then evaporated under reduced pressure. After treating the residue with water, 0.7 g of title compound having a melting point of 155 ° C. (dec.) Is obtained.

J) of di-sodium salt of Q3S (Z)] - 2- Q [Q - (2-amino-4-thiazolyl) ² -LE. ¹ - [[[[2- QQ ³ "LQ ⁽¹ 4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl) carbonyl]] -amino] -2-oxo-i-imidazolidinyl] carbonyl] hydrazino] -sulfonyl] amino-carbonyl] -2-oxo-3-azetidinyl] -amino ] -2-oxoäthylidenJ-aminoJ-oxy-J-2-methylpropionic

A suspension of 0.7 g (0.00077 mol) of [_3S (Z ) J-2- Q [[1 - [2-amino-4-thiazolyl] -2-QQi -QQ [[2- QQ3- Q 1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] _ -amino] -2-oxo-1-imidazolidinyl] carbonyl] hydrazino] sulfonyl] amino] carbonyl J-2 oxo-3-azetidinyl] amino] -2-oxoäthyliden] -amino] -oxy] -2-methylpropionsäurediphenylmethylester in 1 ml of anisole is treated with 6 ml of trifluoroacetic acid at -10 ⁰ C added. The mixture is kept for 1 hour at -10 ⁰ C and then treated at -10 ⁰ C with ether. The trifluoroacetate of the free acid of the starting material precipitates in a yield of 0.5 g.

The precipitate is suspended in water while cooling and the pH of the suspension is reduced by addition of 2N sodium hydroxide.

lye adjusted to 5.5. After freeze-drying, 0.55 g of the crude product is obtained. The crude product is purified by chromatography on macroreticular styrene-divinylbenzene copolymer. The yield of purified title compound is 0.1 g.

Example 23

Di-Sodium salt of [3S (Z)} - 2- [[(j - (2-Amino-4-thiazolyl) -2- [il ] [[QCC.2- [_ { 1, 4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl) -carb- ^η Υΐ] - ^ - methylhydrazino] -sulfonyl]] -amino-carbonyl] -2-oxo-3-azetidinyl ^ -amino-TJ-2-oxoethylidyl] -amino ] -oxy] -2-methyl-1-propionic acid

A) 1, 4-Dihydro-4-oxo-5- (phenylmethoxy) -1 - (phenylmethyl) -2-pyridinecarboxylic acid 1-methylhydrazide

0.15 mol of N, O-Dibenzylcomenamylchlorid are under ice. Cooling suspended in 150 ml of dichloromethane. The suspension is mixed with 26.2 ml (0.5 mol) of methylhydrazine and then with 150 ml of acetonitrile. The mixture is stirred overnight at room temperature. The turbid solution is evaporated under reduced pressure and the residue digested with 300 ml of water. The resulting solid is filtered off and dried to give 26.3 g of crude product.

Recrystallization of the crude product from water gives 12.7 g of the pure title compound with a mp of 138 to 142 ° C.

B) (S) -1,4-Dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinecarboxylic acid-1-methyl-2-Q [ε [2-oxo-3- [Γ (phenylmethoxy) carbonyl ^ amino] -1-azetidinyl]] carbonyljamino] sulfonyljhydrazide

1.82 g (0.005 mol) of 1, 4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinecarboxylic acid 1-methylhydrazide are suspended in 20 ml of ethyl acetate. The suspension

-Q-in OC O "7 η; - ο ι

250

is added at room temperature with a total of 1.85 ml (0.01 mol) of N-methyl-N- (trimethylsilyl) trifluoroacetamide. The mixture is stirred for 4 hours at 50 ^° C. (suspension A).

1.1 g (0.005 mol) of (S) -3-C (phenylmethoxy) carbonyl] amino] -2-azetidinone are suspended at room temperature in 40 ml of ethyl acetate and admixed with 0.5 ml of chlorosulfonyl isocyanate. The mixture is stirred at room temperature for 1 hour to form a solution (solution B).

Solution B is added under ice-cooling with 1.2 ml of triethylamine and then with 20 ml of dichloromethane and suspension A. The suspension is stirred overnight at room temperature. The slightly turbid solution is mixed with 30 ml of dichloromethane and 20 ml of water and the mixture is then stirred for 1 hour at room temperature.

The pH of the aqueous phase is 6.5 to 7. It is mixed with 60 ml of ethyl acetate, the organic phase separated and the aqueous phase washed twice with a mixture of dichloromethane / ethyl acetate (1: 3). The. combined organic phases are dried over magnesium sulfate and evaporated. There are obtained 4.5 g of a syrup, which crystallized on standing over the weekend. After treatment with ether, 2.6 g of the title compound are obtained.

C) 1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid 2-LTB 3-amino-2-oxo-1-azetidinyl) carbonyl] amino] sulfonyl] -1-methylhydrazide trifluoroacetate -Salt

A solution of 2 g of (S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinecarboxylic acid-1-methyl-2- [[Ε-2 ° ^C] ~ 3- [ε (phenylmethoxy) carbonyl] amino] -1-azetidinyl] carbonyl] amino] sulfonyl] _ hydrazide in 60 ml of dimethylformamide is added

Added 1.1 ml of trifluoroacetic acid and then with 1 g of palladium-on-charcoal (10 %) . After purging with nitrogen, hydrogen is bubbled through the solution for 60 minutes with stirring. The catalyst is filtered off and the filtrate is evaporated under reduced pressure. The residue is digested with ether to give 1.1 g of the title compound in a yield of 86.6 % .

D) £ 3S (Z)] - 2- [ε- (2-amino-4-thiazolyl) -2- [lj - [[¢ 2-1-j1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) carbonyl] -2-methylhydrazino] _ -sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -. amino] -2-oxoäthyliden] -aminoJ-oxy] -2-methylpropanoic

A suspension of 0.88 g (0.002 mol) of (Z) -2-amino-QT- [[2- (diphenylmethoxy) -1-, 1-dimethyl-2-oxoethoxy] -imino] -4-thiazole acetic acid in 30 ml acetonitrile with 0.7 ml ( "0.005 mol) of triethylamine and then at -30 ⁰ C with 0.44 ml (0.002 mol) of diphenyl chlorophosphate was added. The mixture is 1 hr at -30 ⁰ C. (solution A).

A suspension of 1.2 g (0.002 mol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid 2- [_ [_ [{ 3-amino-2-oxo-1-azetidinyl) carbonyl] -amino] -sulfonyl] -1-methylhydrazide trifluoroacetate salt in 30 ml of ethyl acetate is treated with 2 ml (about 0.008 mol) of bis-trimethylsilylacetamide at room temperature, which forms a clear solution after 30 minutes (solution B).

Solution A is added dropwise within 10 minutes at -30 ° C with solution B. The temperature is for 1 hour at -10 ⁰ C and held for another hour at 0 ⁰ C. The solvent is evaporated and the residue is treated with water. It will be after filtering and drying

2.4 g of the crude title compound.

378531

E) Di-Sodium salt of] - 3S (Z)] -2- [[[i - (2-Amino-4-thiazolyl) 2] CD - LCEC ² -D ¹ -4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) -c-arbonyl] [- 2-methyl thyhydrazinoQ-sulfonyl] amino-carbonyl '] 2-oxo-3-azetidinyl] -amino] -2-oxoethylidyl] -amino] -oxy] 2'-methylpropionic acid

A mixture of 20 ml of trifluoroacetic acid and 4 ml of anisole at -10 ⁰ C with 2.4 g of the crude [_3S (Z) ~ \ -2- [[Qi - (2-amino-4-thiazolyl) -2- [ [i-CLCC ² "D ¹ -4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -2-methylhydrazino] sulfonyl] amino] carbonyl] _ 2-oxo-3-yl azetidinyl] amino] -2-oxoäthyliden] amino] oxy] -2-methylpropanoic acid was added. the mixture is stirred for 1 hour at -10 ⁰ C and the reaction. then the product by addition of ether at -1O ⁰ C precipitated. The yield is 1.12 g of the crude trifluoroacetate of the title compound.

By adding 2N sodium hydroxide to a suspension in acetone / water, the crude product is converted to the sodium salt and lyophilized. The sodium salt is purified by chromatography on macroreticular styrene-divinylbenzene copolymer, eluting with water. The yield is 0.25 g.

Example 24 (3S) -2- [Q] - (2-Amino-4-thiazolyl) -2- [Jj - [! [[[1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl ) -methyl] -amino] -sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylid ~ [-amino] oxy] -2-methylpropionic acid

A) 2- (hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one

A suspension of 56.8 g (0.4 mol) of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one in 400 ml of methanol is mixed with 16 g (0.4 mol) of sodium hydroxide in 200 ml of warm methanol and then treated with 50.6 g (46 ml, 0.4 mol) of benzyl chloride.

378531

delt. The mixture is refluxed for 3 1/2 hours, cooled and poured into 1 liter of water. The resulting solid is filtered a-b and washed with about 1.5 liters of water, 200 ml of ethanol and 400 ml of hexane. After drying under a high vacuum, the weight of the product is 55.7 g.

B) 1,4-Dihydro-2- (hydroxymethyl) -5- (phenylmethoxy) -4-pyridinone

A mixture of 9.65 g (41.59 mmol) of 2-hydroxymethyl-5- (phenylmethoxy) -4H-pyran-4-one, 95 ml of concentrated ammonia and 20 ml of ethanol is heated at reflux overnight. A further 75 ml of ammonium hydroxide are added and the mixture is then refluxed for 2 hours and cooled. The resulting brown solid is filtered and washed with water until the wash is neutral. The crude product is suspended in ethanol, filtered, washed with ethanol and hexane and dried under reduced pressure. The yield of Tielverbindung is 7.61 g.

20 "

C) 1- (Chloromethyl) -1,4-dihydro-5- (phenylmethoxy) -4-pyridinone hydrochloride

A suspension of 3 g (12.99 mmol) of 1,4-dihydro-2- (hydroxy-. Methyl) -5- (phenylmethoxy) -4-pyridinone in 15 .ml of chloroform is cooled under argon to 0 ⁰ C and treated with 6.1 ml (83.62 mmol) of thionyl chloride. After a few minutes, a homogeneous solution is formed. After stirring for a further 5 minutes, a cream solid precipitates. The cooling bath is removed and the mixture heated at reflux for 45 minutes. The mixture is cooled to 0 ^° C. and the white suspended product is filtered, washed with chloroform and hexane and dried under reduced pressure. The yield of the title compound is 3.65 g

 35

-310.86- 37803Ί

-140-D) 2- (azidomethyl) -1,4-dihydro-5- (phenoxymethyl) -4-pyridinone

A mixture of 3.59 g (12.54 mmol) of 1- (chloromethyl ί-1,4-dihydro-5- (phenylmethoxy) -4-pyridinone hydrochloride, 4.08 g (62.7 mmol) of sodium azide and 2, 19 ml (12.54 mmol) of diisopropylethylamine in 60 ml of dimethylformamide is stirred at room temperature for 3 1/2 days under argon. There are added again 4.08 g of sodium azide and the mixture then for 2 hours at 45 to 50 ⁰ C heated. After the After cooling, the reaction mixture is poured into 500 ml of water to precipitate an insoluble white solid, the pH of the supernatant is lowered from 8.5 to 7.5 with dilute hydrochloric acid and the white solid is then filtered. After washing with water, acetone and hexane, the solid is dried under reduced pressure The yield of the title compound is 2.81 g.

E) 2- (aminomethyl) -4-OXO-5- (phenylmethoxy) -pyridine

A suspension of 2.030 g (7.93 mmol) of 2- (azidomethyl) -1,4-dihydro-5- (phenoxymethyl) -4-pyridinone and 200 ml of platinum oxide is stirred in 100 ml of dimethylformamide for 6 hours at room temperature in a hydrogen atmosphere. The catalyst is filtered off and the solution is concentrated under reduced pressure. There are obtained 1.5 g of the title compound as a gray powder.

F) (3S) -1- [ε [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl-D-me-thyl-amino-sulfonyl]] amino-carbonyl "] - 2-oxo-3- [ε (phenylmethoxy) carbonyl] amino] azetidine

A stirred suspension of 2.330 g (10.13 mmol) of 2- (aminomethyl) -4-OXO-5- (phenylmethoxy) -pyridine in 60 ml of ethyl acetate is charged with 3.76 ml (20.26 mmol) of N-methyl-N - (Trimethylsilyl) trifluoroacetamide added. The resulting solution is stirred for 30 minutes at room temperature and then

-81 (186- 378Ü31

O ⁰ C cooled. At the same time, a stirred suspension of 2.288 g (10.sup.-13 mmol) of (S) -3- {_ { phenylmethoxy) carbonyl] amino] -2-azetidinone in 60 ml of ethyl acetate with 882 uLiter (10.13 mmol ) Added chlorosulfonyl isocyanate. ,

The resulting solution is stirred for 30 minutes at room temperature and then cooled to 0 ⁰ C and 4.23 ml (30.39 mmol) of triethylamine and a solution of silylated 2- described above (aminomethyl) -4-OXO-5- ( phenylmethoxy) -pyridine. The mixture is stirred for 2 days at room temperature.

The mixture is concentrated under reduced pressure and the residue is dissolved in acetonitrile / water (40:60). The pH of the solution is adjusted to 2.9 with the separation of a thick oil. After cooling to 5 ° C, the oil solidifies. The solid is separated, washed four times with water and dried under reduced pressure. There are obtained 3.4 g of the crude title compound. The crude product is dissolved in a small volume of dimethylformamide and ^au f a column (1 liter) was applied on macroreticular styrene-divinylbenzene copolymer. The column is eluted with a gradual gradient of acetone / water. The desired EStoff is eluted at about 65 % acetone. The appropriate fractions are combined and lyophilized.

25. There are obtained 2.69 g of the title compound.

G) (3S) -2 - [[[i- (2-amino-4-thiazolyl) -2 - [[i - [[[L [U, 4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) -methyl] -amino] -sulfonylj-amino] -carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidyl] amino] oxy] -2-methylpropionic acid diphenylmethyl ester

912 mg (1.64 mmol) of (3S) -1 - [[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl] -amino] sulfonyl] amino] -carbonyl] -2-OXO-3-Γ ((phenylmethoxy) carbonyl] amino] azetidine, 625 mg (3.28 mmol) of p-toluenesulfonic acid monohydrate and 190 mg of 10%

RififlK-378531

Palladium on charcoal in 16 ml of dimethylformamide are stirred in a hydrogen atmosphere until 3.28 mmol (73 ml) of hydrogen are consumed (about 3 hours).

A stirred solution of 846 mg (1.804 mmol) of (Z) -2-nC.2- (diphenylmethoxy) -1,1-dimethyl-2-oxoäthoxyj-imino] -4-thiazoleacetic acid in 16 ml of dimethylformamide at -20 ⁰ C. with 374 uLiter (1.804 mmol) of diphenyl chlorophosphate and 450 uLiter (3.28 mmol) of triethylamine.

The solution is stirred for 1 hour at -20 ⁰ C and then added with the above-described mixture of the hydrogenated compound. Then 921 uLiter (6.6 mmol) of triethylamine are added. The resulting mixture is then stirred for 1 hour at -20 ⁰ C and overnight at 5 ° C. The catalyst is filtered off, the volatiles removed under reduced pressure and the resulting oil dissolved in a small volume of acetone / water (75:25, pH 5.2) and added dropwise to a stirred suspension of 20 ml Dowex 50x2-400 (K ⁺ ) in acetone / water (35:65). After 40 minutes, the mixture is filtered and the filtrate is lyophilized to give 2.1 g of a solid. The solid is dissolved in a small amount of acetonitrile / water (40:60, pH 5.6) and applied to a column (800 ml) of macroreticular styrene-divinylbenzene copolymer.

'gene. Elution is gradual with an acetonitrile / water gradient. The desired product is eluted at about 30 % acetone tril. The appropriate fractions are combined and lyophilized to give the title compound

30. receives.

H) (3S) -2 - [[[i- (2-Amino-4-thiazolyl) -2-] - [[[[[[(1, 4-dihydro-5-hydroxy-4-oxo-2 -pyridinyl) -methyl] -amino] -sulfonyl] -amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethyl] -aminoj-oxy] -2-methylpropionic acid

-810.86- 378531

-1 43-

A stirred suspension of 131 mg (0.113 mmol) (3S) of 2-OZD- (2-amino-4-thiazolyl) -2- £ jj - [] [X [] [] (1, 4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) -methylj-amino-sulfonyl-amino-1-carbonyl-2-oxo-3-azetidinyl-J-amino-2-oxo-ethylidene-1-arninoj-oxy-2-methylpropionic acid diphenylmethyl ester in 3 ml of dichloromethane and 0.3 ml of anisole is added dropwise at 0 ⁰ C with 4.7 ml of trifluoroacetic acid. After stirring at 5 ^° C. for 45 minutes, 2 ml of toluene are added and the volatiles are then removed under reduced pressure. The resulting oil is washed three times with 4 ml of hexane and the solid is then digested with 10 ml of ether. The solid is washed once with 10 ml of ether and then dried under reduced pressure. The above reaction and work-up are carried out with 0.166 mmol of (3S) -2 - [[JJ - (2-amino-4-)].

^ 5 thiazolyl) -2- [i- £ [£ CLD ^1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methylj-aminoj-sulfonylj-aminoj-carbonylj-2-oxo-3-azetidinylj amino-2-oxoethylidene-aminoamino-oxy | -2-methylpropionäurediphenylester repeated. The crude solids are combined, dissolved in 2 ml. Acetonitrile / water (40:60, pH 2.5) and chromatographed on a column (200 ml) of macroreticular styrene-divinylbenzene copolymer. For the elution, an acetonitrile / water gradient is used. The desired product is eluted with acetonitrile / water (20:80). The appropriate fractions are combined and lyophilized. There are obtained 103 mg of the title compound as a white solid with a mp of 180 ⁰ C (dec.).

-310.86- 378t ^: 3i

Claims (2)

Invention claim: (1) a compound of general formula VII ^R 2 I ² (VII) NH ₂ 1 NC-NH-SO ₉ -R acylated with an R -acyl radical derived from an R-carboxylic acid, or (2) one. -CO-N the general formula IX 1. Process for the preparation of Verbindungen_der general formula I. R, R ₁ -NE ^V CH. -NC-NH-SO ₂ -R or pharmacologically acceptable salts thereof, in which ι-ι s jrV ^oK R -A _n -N NA ₂ -C-Ar ^ N ^ 9 o Q- NA ₂ -CA ^ N-A.- W 3 I / \ [L l A-N N-A, - -N ^ ¹ VlV => I OH OAER -NH-A, -C-A means R _{1 represents} an acyl radical derived from a carboxylic acid; R ₂ and R 1 have the same or different meanings and each represents a hydrogen atom, an alkyl radical, an alkenyl radical, an alkynyl radical, a cycloalkyl radical, a - ° 10 «B-378531 Phenyl group, a substituted phenyl group or a 4-, 5-, 6- or 7-membered heterocycle (hereinafter denoted by R), or one of R ₀ and R _{3 is} a hydrogen atom and the other is an azido, halomethyl, Dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethyl, 2-phenylethynyl, carboxyl ·, -CH x - (wherein X is an azido, amino, hydroxyl, carboxyl, alkoxycarbonyl, alkanoylamino, Phenylcarbonylamino, (substituted phenyl) carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl 0
nyl-, cyano-, -AC-NXgX-, -SX «or a -0-X ₀ -ReSt , indicates (where A, X ₀ , X ^ and X_ are as described below Eg / • are defined), an -SX "or -O-X ₀ -ReSt (wherein X" is an alkyl, substituted alkyl, phenyl, substituted phenyl, phenylalkyl, substituted phenylalkyl, alkanoyl, phenylalkanoyl, substituted phenylalkanoyl, phenylcarbonyl, substituted phenylcarbonyl or a Heteroarylcarbonyl radical), an -O-C-X. or ^X 3 * 5 -SCX.-Rest (where one of the radicals X ₃ and X. a water * 5 And the other is a hydrogen atom or an alkyl radical, or X and X together with the carbon atom to which they are attached represent a cycloalkyl radical, and X ₁ is a formyl, alkanoyl, phenylcarbonyl, substituted phenylcarbonyl radical, Phenylalkylcarbonyl, substituted phenylalkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, substituted aminocarbonyl or cyano radical), 0
or an -AC-NX ₅ X ₇ -ReSt, (where A is a -CH = CH-, - (CH ₀₎ -, - (CH ") -O-, - (CH") NH-, or -CH _{O O} -S-CH group be-2m zm cm ZZ m is 0, 1 or 2 and X _g and X _{7 are the} same or different and each represents a hydrogen atom, an alkyl group, a phenyl group or a substituted phenyl group, or X _{5 is} a hydrogen atom and X _{7 is} a. Amino group, substituted amino group, an alkanoylamino group or an alkoxy group or X ₅ and -810HK-37853-1 ] _ X ₇ together with the nitrogen atom to which they are attached denote a 4-, 5-, 6- or 7-membered heterocycle); , 0 0 A represents a single bond, -NH-C-, -NH- or -NH-NH-C-; '0 A _{2 is} a single bond, -NH-, -CH ₂ -CH ₂ NH- or -C-NH-NH-; A _{3 is} - (CH ₂ ) -, where ρ is 0 or 1, or 0 0. -NH-C-NH-, -NH-C-NH-CK ₂ -, -NH-CH ₂ -, -O-CH ₉ - 0 0 il 'ii
-CH ₂ C-NH- or -CH ₉ -C-NH-CH ₂ -; NH-, NH A ₄ -NH-, - (CH ₂ ) -, - (CH ₂ ) -NH-, -NH-C-NH-NH-, -C-NH-NH- CH.X I ² or N-, wherein X represents a hydrogen atom, a carboxyl group or a carbamoyl group, ρ is 0 or 1, and γ is 2, 3 or 4; A is a single bond, -CH ₉ -, -NH-CH ₉ -, -N = CH- or 0 -C-NH- (CH ₂ ) - where q is 0 or 1; and Ag is a single bond, -CH = CH- or - (CH ₉ ), -, where t is 1,2, 3 or 4, characterized by, that (2) one. -CO-NH-SO R activation group in a compound \: h (Ji-R ₃ c NH introduces. -Q in Q R-