LU86611A1 - 2-OXO-1 - (((SULFONYL SUBSTITUTE) AMINO) -CARBONYL) AZETIDINES - Google Patents

Description

2-oxo-1-Ç £ (substituted sulfonyl) amino_7-carbonyl 7-azetidines.

The compounds corresponding to the formula:? 2 5 R - NH J Rq 1 \ / 3 CH-

I I

^ C-N-C-NH-SO -R I

0 ^ 0 and their pharmaceutically acceptable salts exert antibacterial activity. In formula I and throughout this specification, the symbols have the meanings defined below: 0

X

15 -OH

l i ° i i R represents -A ^ -N N-A ^ -C-Ag- ^ ^ Nr, Ύ »o •. 20k 2 Ο Ä

Y -OH

/ - \ P I

5 -A ..- N Ν-Αο-0-Α_ · ^^ Ν · ^ „‘ A / “

i i AJ

-A.-N N-Ac ^ 1 5

Y

0 15 0

II OH

ΛΛ jQ

-A1 -N N-Ac ^ "X k 0 ^ ^ 0 Ä_„ 25 I | -NH-A „YYn S or

ö I

H

0 i

30 -OH

o || -NH-A.-C-A. ^^ N · ^; 4 6, ’

H

represents an acyl group derived from a carboxylic acid; 3 and Rg are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group or a tetragonal, pentagonal heterocycle , hexagonal or heptagonal (hereinafter referred to as R) or one of the radicals R „and R ^ represents a hydrogen atom and the other, an azido group, a halomethyl group, a dihalomethyl group, a tri-halomethyl group , an alkoxycarbonyl group, a 2-phenylethenyl group, a 2-phenylethynyl group, a carboxy group, a -CH group, ^ £ where ^ represents an azido group, an amino group (-NH2), a hydroxy group, a carboxy group , an alkoxycarbonyl group, an alkanoylamino group, a phenylearbonylamino group, a (substituted phenyl) carbonylamino group, an alkylsulfonyloxy group, a phenylsulfonyloxy group, a (substituted phenyl) sulfonyloxy group, a phenyl group, a substituted phenyl group, a cyano group , a group 20 0 1 1 -AC-NXgX ^, a group -S-Xg or a group -0-X2 (where A, X2, Xg and Xj have the meanings defined below) J, a group -S-X2 or a group -0 -X2 £ where X2 represents an alkyl group, a substituted alkyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, an alkyl (substituted phenyl) group, an alkanoyl group, a phenylalkanoyl group, a (phenyl substituted group ) alkanoyl, = a phenylearbonyl group, a (substituted phenyl) carbonyl group or a heteroarylcarbonyl group 77, a? 3? 3 group -0-CX ^ or a group -SCX ^ £ "where a radi- 4 or alternatively X ^ and X ^, taken together with the carbon atom to which they are attached, form a cycloalkyl group; and X ^ represents a formyl group, an alkanoyl group, a phenylcarbonyl group, a> 5 (substituted phenyl) carbonyl group, a phenyl-alkylcarbonyl group, a (substituted phenyl) alkylcarbonyl group, a carboxy group, an alkoxycarbo group - 0

H

nyle, an aminocarbonyl group (NH ^ -C-), a group

10 (substituted amino) carbonyl or a cyano (-C — N) group "J

0 11 or a group -AC-NX ^ X ^ {"where A represents a group -CH = CH-, a group - (CH2) m ~, a group - (CHg) -0 ^ a group - (CH2) m -NH-, or a group -CH2-S-CH2-, 15 m represents 0, 1 or 2, while X_ and X „are O / identical or different and each represent a hydrogen atom, an alkyl group, a phenyl group or a substituted phenyl group, or Xg represents a hydrogen atom and X ^, an amino group, a substituted amino group, an alkanoylamino group or an alkoxy group, or Xq and X7 taken together with the atom nitrogen to which they are connected, form a tetragonal, pentagonal, hexagonal or heptagonal hetero ring ^; A1 represents a single bond, 25 0 0 -NH-C-, -NH- or -NH-NH-C-; A2 represents a single bond, -NH-, 0 f -CH2-CH2-NH-, or -C-NH-NH-; Aq represents - (0Ho) - where p represents 0 o to. p oo or 1, -NH -C-NH-, -NH-C-NH-CH2-, -NH-CH2-, -0-CH2-0 0 -CH2-C-NH- or -CH2-C-NH-CH2-; 35 A4 represents -NH-, ~ (CH2) -NH-, 5

Ο Ο CH2X

-NH-C-NH-NH-, -C-NH-NH- or -N- where X represents a hydrogen atom, a carboxy group or a carbamoyl group and p represents 0 or 1, '5 while y represents 2, 3 or 4;

Ag represents a single bond, -CH ,, -, 0 -NH-CHp-, -N = CH- or -C-NH- (CHp) - where q represents d. îL q 0 or 1; 10 Ag represents a single bond, -CH = CH- or τ (0Η2) ^ where t represents 1, 2, 3 or 4.

The above symbols (for example, A ^, A2, Α ^, A ^, Ag and Ag) are used to represent groups of multiple atoms. These groups are introduced into the structural formulas represented in this specification in the order in which they are presented (i.e. from left to right). For example, if R represents 0

20 OH

I — I ί jT

-A ^ -N N —— ’and if A ^ represents Y at 25 0 11 -NH-C-, the group R should be

Ay "

30 0 | | I I

^ -NH-C-N N '^, ^ S> SsN, but not Y 4 0 6 λ- ·

: I — I

5 -C-NH-N N.—, Y "0

The definitions of the various terms used to describe the β-lactams of the present invention will be given below. These definitions apply to terms as used in this specification (unless they are otherwise limited in specific cases), either individually or as part of a larger group.

The terms "alkyl group" and "alkoxy group" refer to both straight chain and branched chain groups. Among these groups, those containing 1 to 10 carbon atoms are preferred.

The terms "cycloalkyl group" and "cycloalkenyl group" mean cycloalkyl groups and cycloalkenyl groups having 3, 4, 5, 6 or 7 carbon atoms.

The term "substituted alkyl group" refers to alkyl groups substituted by one or more (preferably 1, 2 or 3) azido groups, amino groups (-NH2), halogen atoms, hydroxy groups, carboxy groups , cyano groups, alkoxycarbonyl groups, aminocarbonyl groups, alkanoyloxy groups, alkoxy groups, phenyloxy groups, oxy (substituted phenyl) groups, mercapto groups, alkylthio groups, phenylthio groups, thio (substituted phenyl) groups, alkylsulfinyl groups or alkylsulfonyl groups.

The terms "alkanoyl group", "alkenyl group" and "alkynyl group" mean both straight and branched chain groups.

Among these groups, those containing 2 to 10 carbon atoms are preferred.

The terms "halogen" and "halo" denote fluorine, chlorine, bromine and iodine.

* The expression "substituted phenyl group" designates a phenyl group substituted by 1, 2 or 3 amino groups (-Nl · ^), halogen atoms, hydroxy groups, trifluoromethyl, alkyl (containing 1 to 4 10 carbon atoms) , alkoxy (containing 1 to 4 carbon atoms), alkanoyloxy, aminocarbonyl or carboxy.

The term "tetragonal, pentagonal, hexagonal or heptagonal heterocyclic" (denoted by "R") denotes substituted and unsubstituted aromatic and non-aromatic groups containing one or more atoms (preferably 1, 2 or 3) nitrogen, oxygen or sulfur. Among the substituents are the oxo group (= 0), the halogen atoms, the hydroxy, nitro, amino, cyano, trifluoromethyl groups, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 atoms carbon, alkylsulfonyl, phenyl, substituted phenyl, 2-furfurylidene-amino 0 ^^ CH = N- (^ ^), benzylidene-amino and substituted alkyl (the alkyl group having 1 to 4 carbon atoms). One type of "tetragonal, pentagonal, hexagonal or heptagonal heterocycle" is the group "heteroaryl". The term "heteroaryl" refers to the tetragonal, pentagonal, hexagonal or heptagonal heterocycles which are aromatic. Among the heteroaryl groups are the tetrazolyl, triazinyl, oxazolyl, pyrimidinyl, thiadiazolyl, thiazolyl, imidazolyl, 1,2,4-triazolyl, 1,2,3- 8 triazolyl, thienyl, pyrrolyl, furannyl and pyri- groups. substituted and unsubstituted dinyls. Among non aromatic heterocycles (i.e. fully or partially saturated heterocyclic groups) there are, for example, * hexahydroazepinyl, dihydrothiazolyl, tetrahydropyrimidinyl, pyrrolidinyl, oxazolidinyl, imidazo- substituted and unsubstituted lidinyl, piperazinyl, piperidinyl, thietanyl, oxetanyl and azetidinyl. Among the substituted tetragonal, pentagonal, hexagonal or heptagonal heterocycles there are, for example, 1-alkyl-3-azetidinyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidi- nyle, 3-benzylidene-amino-2-oxo-1-imidazolidinyl, 3-alkyl-2-oxo-1-imidazolidinyl, 3-phenyl (or substituted phenyl) -2-oxo-1-imidazolidinyl, 3-benzyl- 2-oxo-v * 1-imidazolidinyl, 3- (2-aminoethyl) -2-oxo-1-imidazo lidinyl, 3-amino-2-oxo-1-imidazolidinyl, 3- £ * (alkoxy-carbonyl) amino. 7-2-oxo-l-imidazolidinyl, 3-ΖΓ 2- £ “(al-20 coxycarbonyl) amino J7ethyl ^ 7-2-oxo-l-imidazolidinyle, 2-oxo-l-pyrrolidinyle, 2-oxo-3- oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1-hexahydro-azepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydro-furannyl, 2,3-dioxo-l- piperazinyl, 2,5-dioxo-1,25 piperazinyl, 4-alkyl-2,3-dioxo-1-piperazinyl and 4-phenyl-2,3-dioxo-1-piperazinyl.

The term "substituted amino group" means a group of the formula -NXgXg where Xg represents a hydrogen atom, an alkyl group, a phenyl group, a substituted phenyl group, a ς, phenylalkyl group or a group (phenyl substituted) - alkyl, while Xg represents an alkyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, a (substituted phenyl) -35 alkyl group, a hydroxy group, a cyano group, an alkoxy group, a phenylalkoxy group or amino group (-nh2).

The expression "acyl group" designates all the organic radicals deriving from an organic acid (that is to say a carboxylic acid) by elimination of the hydroxy group. Certain acyl groups are obviously preferred, but this preference should not be considered as a limitation on the scope of the present invention. Among the acyl groups there are, for example, acyl groups which have been used in the past to acylate β-lactam antibiotics including 6-amino-penicillanic acid and its derivatives, as well as acid 7 -aminocephalosporanic and its derivatives (see, for example, Cephalosporins and Penicillins, edited by

Flynn, Academie Press (1972), DE-0S-2,716,677 published October 10, 1978, Belgian patent 867,994, published December 11, 1978, patent of the United States of America 4,152,432 granted May 1, 1979, U.S. Patent 3,971,778 granted July 27, 1976, U.S. Patent 4,172,199 granted October 23, 1979 and British Patent 1,348,894 issued March 27, 1974). The parts of these references describing different acyl groups are mentioned here for reference. The following list of acyl groups is given to further illustrate the term "acyl group"; this list should not be considered * · ”as a list limiting this expression. Among the acyl groups there are, for example: c, (a) the aliphatic groups corresponding to the formula: 0

II

v ° - 35 where R represents an alkyl group, a cycloq group.

Alkyl, an alkoxy group, an alkenyl group, a cycloalkenyl group, a cyclohexadienyl group, or an alkyl group or an alkenyl group substituted by one or more halo-5 genes, as well as by one or more cyano, - nitro groups , amino, mercapto, alkylthio or cyanomethylthio.

1 (b) Carbocyclic aromatic groups corresponding to the formulas:

R

10 ° y- (Cti2> n-C- 15 l

R

20 ^ ° (Τ '· λ \ —0H2-0-C-

R

25 ° 'S- 0-CH2-C-

R

30 °. <7 ^ · · * Μ — S-CH2-C- or 11

R

2 -ch2-s-c- 5 where η represents 0, 1, 2 or 3; R ^, Rq and R ^ each independently represent a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, an amino group, a cyano group, a trifluoromethyl group , an alkyl group containing 1 to 4 carbon atoms, an alkoxy group containing 1 to 4 carbon atoms or an amino-methyl group; and R represents an amino group, a hydroxy group, a carboxy salt, a protected carboxy group, a formyloxy group, a sulfo salt, a sulfoamino salt, an azido group, a halogen atom, a hydrazino group, an alkylhydrazino group , a phenyl-hydrazino group or a group / 7 (alkylthio) thioxomethyl 77-thio.

Among the preferred cyclic carbon-aromatic acyl groups, there are those corresponding to the formulas: HO-U \\ - CH2-C-

Or1 CH2NH2 Π 30 HO - (/ y- CH-C- (Rg represents,

Re preferably a carboxy salt or a sulfo salt) and 12 / Γ \ - U 'V —- CH-C- (He represents, V = / Re preferably a carboxy salt or a sulfo salt).

5 (c) Heteroaromatic groups corresponding to the formulas: 0

Rf_ (CH2) n-C- 0 10 Rp-CH-C-

1 I

R

e 0

Rf-0-CH2-C- 0 15 Rf_S-CH2-C-

0 0 Il II

Rf-G - C- where n represents 0, 1, 2 or 3; R has the meaning defined above and R ^ represents a substituted or unsubstituted pentagonal, hexagonal or heptagonal hetero-cyclic ring containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen atoms, d and sulfur. Among the heterocyclic rings, there are, for example, the thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyri-midinyl, thiadiazolyl and tetrazolyl rings. Among the substituents are, for example, halogen atoms, hydroxy group, nitro group, amino group, protected amino group, cyano group, trifluoromethyl group, alkyl-containing groups 1 to 4 carbon atoms, alkoxy groups containing 1 to 4 carbon atoms or 0 hooc-ch-ch2-oc-nh- NH2 13

Among the preferred heteroaromatic acyl groups, there are the groups corresponding to the above formulas in which represents a 2-amino-4-thiazolyl group, a 2-amino-5-halo-4-5 thiazolyl group, a 4- group aminopyrimidin-2-yl, a 5-amino-1,2,4-thiadiazol-3-yl group, a 2-thienyl group, a 2-furanyl group or a 6-aminopyridin-2-yl group.

(d) 00 (2,3-dioxo-1-pipera-10 zinyl 4-substituted) carbonyl_7aminoJ7arylacetyl groups corresponding to the formula: 0 0 / - \ -C-CH-NH-C-N N-R.

In which R is an aromatic group (including g carbocyclic aromatic groups such as those corresponding to the formula:

R

Rb - ^ iyr ^ and heteroaromatic groups falling within the definition of R ^); and R 1 represents an alkyl group, a substituted alkyl group (in which the alkyl group is substituted by one or more halogen atoms, as well as by one or more cyano, nitro, amino or mercapto groups), an aryl group methylene amino (ie -N = CH-R where R has the gg 30 meaning defined above), • ï ς, 0

II

an arylcarbonylamino group (i.e. -NH-C-R

where R has the meaning defined above) or an alkylcarbonylamino group.

14

Preferred ce (2,3-dioxo-1-piperazinyl) carbonyl Jamino, 7arylacetyl groups include those in which Rh represents an ethyl group, a phenylmethylene-amino group or a "2-furylmethylene-aralno group.

(e) The (substituted oxlmino) aryl-acetyl groups corresponding to the formula: 0 -C-C = N-0-R.

10 R

g in which R ^ has the meaning defined above and Ri represents a hydrogen atom, an alkyl group, a cycloalkyl group, CH2 - (pH2) 1 2 or 3 ’

^ C- ^ COOH

A 2-pyrazolylmethyl group, a (2-oxo-3-pyrrolidinyl) methyl group, an alkylaminocarbonyl group, 0 I!

an arylaminocarbonyl group (i.e. -C-NH-R

g where R has the meaning defined above) or a

O

Substituted alkyl group (where the alkyl group is substituted by one or more halogen atoms, as well as by one or more cyano, nitro, amino, mercapto, alkylthio, aromatic (as defined by R), carboxy (including their salts) ), amido, o 25 alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihydroxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl, (dialcoxyphosphinyl or tetrazolyl).

Preferred (substituted oximino) arylacetyl groups include those in which R is a 2-amino-4-thiazolyl group. Also preferred are groups in which R is a methyl group, an ethyl group, a carboxymethyl group, a 1-carboxy-1-methylethyl group, a 2,2,2-trifluoroethyl group or a 1- group. carboxycyclopropyle.

(F) The (acylamino) arylacetyl groups corresponding to the formula: 0 0

He II

-C-CH-NH-C-R.

„· J

5 R

g

in which R has the meaning defined above S

and R. represents J

R

Rb 10 'V-1-0-, amino group, alkylamino group, (cyanoalkyl) amino group, amido group, alkylamido group, (cyanoalkyl) -amido group, 15 tjHs ° -CH2-NH-C - ('N -CH-CH2-C-NH-CH3

\ zzz / HO

-f ^> / AS02-N (CH2-CH2-0H) 2, ·

20 \ zZ-N \ - / \ - N

OH

OH OH

25 rîf * | Λ ~ λ ° 30 ho ^ C H ° -—! R 0 16

Among the preferred (acylamino) arylacetyl groups corresponding to the above formula, there are those in which R. is an amino group or a

J

amido group. Also preferred are the groups - 5 in which R is a phenyl group or an o - 2-thienyl group.

(g) The groups E E E 2-oxo-1-imidazolidinyl 3-substituted J7carbonylJ7amino j ^ rylacétyle corresponding to the formula: 10 0 ο ο ^ -C-CH-NH-C-N N-R,. I I k

Rg 0H2— C "2 in which R has the meaning defined above o 15 and Rk represents a hydrogen atom, an alkyl-sulfonyl group, an arylmethylene-amino group (ie" -N = CH- R where R has the meaning defined above), oo 0

II

-C-Rm (where Rm represents a hydrogen atom, an alkyl group or an alkyl group substituted by a halogen), an aromatic group (as defined for R above), an alkyl group or an alkyl group or substituted (where the alkyl group is substituted by one or more halogen atoms, as well as by one or more cyano, nitro, amino or mercapto groups).

The preferred 2-oxo-1-imidazolidinyl 3-substituted 7carbonylJ7aminoJarylacetyl CEE groups of the above formula include those in which R is a phenyl group or a 2- group

O

Thienyl. Also preferred are the groups in c, which R ^ is a hydrogen atom, a methylsulfonyl group, a phenylmethylene-amino group or a 2-furylmethylene-amino group.

The compounds of the present invention form basic salts with different inorganic and organic bases which also fall within the scope of the present invention. Among these salts are ammonium salts, alkali metal salts, alkaline earth metal salts, salts formed with organic bases, for example, dicyclohexylamine, benzathine, N-methyl -D-glucamine, hydrabamine and the like. Pharmaceutically acceptable salts are preferred, although other salts are also useful, for example, in isolating or purifying the product.

Certain compounds of the present invention can be crystallized or recrystallized from solvents containing water. In this case, hydration water may form. The present invention contemplates stoichiometric hydration products, as well as compounds containing varying amounts of water which can be formed by methods such as lyophilization.

The β-lactams of formula I contain at least one chiral center - the carbon atom at position 3 of the β-lactam ring to which the substituent acylamino ("R ^ -NH-") is attached. The present invention relates to the β-lactams which have been described above and in which the stereochemistry on the chiral center in position 3 of the β-lactam nucleus is the same as the configuration existing on the carbon atom in position 6 of naturally obtained penicillins (eg, penicillin G) and the configuration on the carbon atom in position 7 of naturally obtained cephamycins (eg, cephamycin C).

The scope of the present invention also includes racemic mixtures containing the β-lactams described above.

The β-lactams of formula I and their pharmaceutically acceptable salts exert activity against gram-positive and gram-negative organisms. The compounds of the present invention can be used as agents for combating bacterial infections (including urinary tract infections and respiratory tract infections) in mammals such as pets (e.g. dogs, cats, cows, horses and the like), as well as in humans.

To combat bacterial infections in mammals, a compound of the present invention can be administered to a mammal that requires it, in an amount of from about 1.4 mg / kg / day to about 350 mg / kg / day, preferably from about 14 mg / kg / day to about 100 mg / kg / day. All of the modes of administration which have been adopted in the past to distribute penicillins and cephalosporins to the site of infection are also contemplated for use with the β-lactams of the present invention. Among these modes of administration are oral administration, intravenous administration, intramuscular administration, as well as suppositories.

The β-lactams of formula I can be prepared from a 2-azetidinone protected on the amino group in position 3 and corresponding to the formula:? 2!

CH-C-R, II

30 I I

c, C-NH

o - ^ *

In formula II and throughout the specification, the symbol "R4" denotes an amino protecting group. These groups are well known in the art of β-lactam chemistry and the particular group chosen is not critical. Benzyloxycarbonyl, trityl and t-butoxycarbonyl groups are examples of protecting groups.

- 5 The reaction of a ß-lactam of formula II with an isocyanate corresponding to the formula:

o = c = n-so2-y III

in which Y is a group which moves away, such as chlorine, gives the corresponding compound corresponding to the formula:

RP

vNîu;

^ * CH-C-R0 IV

I I

15 _ N-C-NH-S02-Y

Preferably the reaction is carried out in an inert organic solvent, for example, ethyl acetate, tetrahydrofuran, dimethoxyethane, dichloromethane, acetonitrile or mixtures of these solvents. The displacement of the group which moves away "Y" with the desired group "R" can be carried out using the appropriate nucleophile corresponding to the formula:

25 RH V

optionally in the presence of a base (for example, triethylamine), to obtain the corresponding compound corresponding to the formula:? 2 30; c, R4-NH --- R3

N-C-NH-SO ^ -R

0 ^^ S

VI

20

Alternatively, displacement of the departing group can be accomplished by reaction of a compound of formula IV with a protected form of a compound of formula V. After the displacement reaction, the protecting groups can be removed by adopting well known techniques to obtain one; compound of formula VI.

Protected forms of a compound of formula V, as well as all of the reagents described herein, which contain a 3-hydroxy-4-pyridone moiety, include compounds in which the hydroxy group is protected, compounds in which the group hydroxy and the nitrogen atom of the nucleus are protected, as are the compounds in which the two oxygen atoms of pyridone are protected. Among the protecting groups there is, for example, the silyl group - (for example, the trimethylsilyl group), the benzyl group and the acyl group (for example, the acetyl group). If a silyl group is used, subsequent de-protection can be carried out by adopting hydrolysis or cleavage by the intervention of a fluoride. If a benzyl group is used, subsequent deprotection can be carried out by hydro-genolysis. If an acyl group is used, subsequent deprotection can be carried out by hydrolysis.

Deprotection of a compound of formula VI by adopting conventional techniques gives the corresponding key intermediate product corresponding to the formula: 21 h m2

CH C-R3 VII

5 C_N-C-NH-SO -R

it ^ 0 ^ 0 or one of its salts. Of course, the particular deprotection reaction adopted will depend on the protective group ("R ^") present. If, for example, R ^ is a t-butoxycarbonyl protecting group, deprotection can be carried out by treatment of a compound of formula VI with an acid (e.g. formic acid or trifluoroacetic acid). If, for example, R ^ is a benzyloxycarbonyl protecting group, deprotection can be carried out by catalytic hydrogenation of a compound of formula VI. Alternatively, the protecting group R 1 may be removed simultaneously with the other protecting groups of pyridone immediately after the displacement reaction described above.

Well-known acylation techniques can be adopted to convert an intermediate product of formula VII to a corresponding product of formula I. Among these techniques there is, for example, the reaction of a compound of formula VII with an acid carboxylic acid (R ^ OH), or a carboxylic acid anhydride or a corresponding carboxylic acid halide. The reaction with a carboxylic acid proceeds most easily in the presence of a carbo-diimide such as dicyclohexylcarbodiimide, as well as of a substance capable of forming an active ester in situ, for example, N-hydroxybenzotriazole.

When the acyl group (R ^) contains reactive functionality (e.g. amino or car-boxy groups), it may be necessary to first protect these functional groups and then carry out the acylation reaction and finally, to deprotect the product obtained.

Another process for preparing the compounds of formula I is to first acylate (the acylation techniques have been described above) a 3-amino-2-azetidinone having the formula:? 2 io _______; wine

-C-RQ

I I

^ C NH

- 15 to obtain an intermediate product corresponding to the formula:? 2

R ^ -NH J IX

CH-C-R

2 ° He

_NH

0 0

II

An activator group -C-NH-SO2-R can be introduced in position 1 of a compound of formula IX 25 (by adopting the methods described above) to obtain the corresponding product of formula I. When the acyl side chain " R ^ "contains a reactive functionality (for example, amino groups), it may be necessary to protect these 30 functional groups first ^ then add the activating group in position 1 and finally deprotect the product obtained.

Yet another synthesis for preparing compounds of formula I is the use of a 3-azido-2-azetidinone having the formula: 23? 2 i ^ CH-C-Rg

5. C_NH X

0 0 11; An activator group -C-NH-SOg-R can be introduced in position 1 of a compound of formula X (by adopting the methods described above) to obtain the corresponding compound corresponding to the formula:? 2 N3 \ ^ CH-0-R,

15 II

C_N-C-NH-S02-R XI

* 0 0

Reduction of an intermediate product of formula XI gives the corresponding intermediate product corresponding to the formula:? 2 NH2 ^ v. ;

^ CH-C-R0 VII

I I

25 C_N-C-NH-S02-R

0 ^ δ

The reduction can be carried out by catalytic hydrogenation (for example, with palladium carbon or platinum oxide) or with reducing agents such as zinc or triphenylphosphine. As described above, from these key intermediates (compounds of formula VII), by adopting conventional acylation techniques, it is possible to prepare the products of formula I.

24

Alternatively, a 3-azido-2-azetidinone of formula X can be reduced to the corresponding 3-amino-2-azetidinone having the formula:? 2 5 nh2 \;

^ CH 0-Ro VIII

I I

_NH

The reduction can be carried out by catalytic hydrogenation (for example, with palladium carbon or platinum oxide) or with reducing agents such as zinc or triphenylphosphine. A 3-amino-2-azetidinone of formula VIII can be reacted as described above (i.e. it is first subjected to acylation and then to treatment as described above above to enter 0

II

an activating group -C-NH-SOg-R in position 1) to obtain the products of formula I.

According to another synthesis with a view to preparing the compounds of formula I in which R2 and R ^ each represent a hydrogen atom, a 6-acylaminopenicillanic acid corresponding to the formula is used:

VNHV

CH-CH C (CH,) „

I I I

> _ N_CH-COOH XII

30 0 ^ - or a salt thereof, as starting material. By adapting the methods described in the literature, 3-acylamino-2-azetidinone can be obtained from the corresponding 6-acylaminopenicillanic acid of formula XII: see, for example, Chem. Share, Special 25

Publication No. 28, page 288 (1977), The Chemistry of Penicillins, Princeton University Press, page 257 and Synthesis, 494 (1977).

As described in the literature, 5 6-acylaminopenicillanic acid or a salt thereof can be desulfurized to give a compound corresponding to the formula:

R1-NH

^ CH-CPL XIII

10 I I

^ C_N-CH-CH (CH)

0 COOH

by reduction using Raney nickel. The reaction can be carried out in water under reflux conditions.

The replacement of the carboxy group of a compound of formula XIII by an acetate group with subsequent hydrolysis gives the corresponding 3-acylamino-2-azetidinone corresponding to the formula:

20 R - NH

1 \ _

CH-CH0 XIV

i i

_NH

By treating a compound of formula XIII with cupric acetate and lead tetracetate in an organic solvent (for example, acetonitrile), the carboxy group is replaced by an acetate group. The hydrolysis of the compound obtained can be carried out using potassium carbonate in the presence of sodium borohydride. 0

II

An activating group -C-NH-SO ^ -R can be introduced in position 1 of a compound of formula XIV (by giving products of formula I in which 35 R ^ and Rg each represent a hydrogen atom) 26 adopting the methods described above.

Yet another variant of the synthetic methods described above for preparing a compound of formula I in which R2 and Rg each represent a hydrogen atom, consists in first desulfurizing 6-aminopenicillanic acid, acylating the compound obtained to obtain a compound of formula XIII, then proceed as described above to first obtain a 3-acylamino-2-azetidinone of formula XIV, then a product of formula I.

The azetidinones of formula I can also be prepared from amino acids corresponding to the formula:

OH

15 “W L * R2

^ CH-C-R3 XV

^ C_OH

The amino group is first protected (with a protective group "R4", for example, the t-butoxycarbonyl group). The carboxy group of the protected amino acid is then reacted with an amine corresponding to the formula:

25 Z-0-NH2 XVI

in which Z represents an alkyl group, a benzyl group or a triphenylmethyl group, in the presence of a carbodiimide, to obtain a compound corresponding to the formula:

30 OH

V® L \ NR2

^ CH C-Rg XVII

C_NH-O-Z

35 0ίίί: ^ 27

The hydroxy group of a compound of formula XVII is converted to a departing group ("OL") with a reagent such as methane-sul-fonyl chloride or a pyridine-SO ^ complex.

5 The completely protected compound corresponding to the formula:

: OL

R.-NH XVIII

CH- C - Rq

10 I

V, C_NH-O-Z

is cyclized by treatment with a hash, for example, potassium carbonate. Preferably, the reaction is carried out in an organic solvent or in a mixture of an organic solvent and water under reflux conditions and it gives a compound corresponding to the formula: R4-NH sr2 20 ^ CH C * - Rg

^ C_N-O-Z XIX

Alternatively, the cyclization of a compound of formula XVII can be carried out without first converting the hydroxy group to a group which is moving away. Treatment of a compound of formula XVII with triphenylphosphine and azodicarboxylate m s. of diethyl gives a compound of formula XIX.

Examples of methods for converting a compound of formula XVIII into a compound of formula XIX are described in J. Amer. Chem. Soc., 102, 7026 (1980) and J. Org. Chem., 47, 5160 (1982).

The two methods described above for the cyclization of a compound of formula XVII give rise to the inversion of the stereochemistry on the carbon atom containing the substituents and when these are not identical.

Removal of the protecting group from position 1 of an azetidinone of formula XIX can be carried out via sodium reduction when Z is - an alkyl group, to give an intermediate product corresponding to the formula: VN »^ R2 10 CH C - R,

I I

_NH II

(at least one of the radicals Rg and R ^ is a hydrogen atom). If Z is a benzyl group, catalytic hydrogenation (for example, with palladium on carbon) will initially give the corresponding N-hydroxy compound which, when treated with titanium tri-chloride, gives an intermediate product of formula II . If Z is a triphenylmethyl group, formic acid or a mixture of water and 70% acetic acid will initially give the corresponding N-hydroxy compound.

0 fl 25 An activator group -C-NH-S02-R can be introduced in position 1 of a compound of formula II by adopting the methods described above and the; compound obtained can be deprotected and acylated.

- The nucleophiles of formula 30 V can be prepared in which R represents 29 Λ / * I I: X J.

5 -Α ^ -Ν N-A ^ -C-Ag N "^, while Α ^ and Τ *

Ag each represents a single bond, reacting a silylated derivative of 2-imidazolidinone

10 I I

(HN NH), or the anion of 2-imidazolidinone formed

V

O

with a strong non-nucleophilic base, with an activated derivative 15 suitably protected from an acid corresponding to the formula: 0 H0 il ΤΠ s

20 [I I__Ag-C-OH XX

H

to obtain, during deprotection, the corresponding compound corresponding to the formula: 25 1 i i o fi ij

HN N-C-A _- ^ \ N ^ XXI

N / 6

T

30 0

The reaction can be carried out in an inert organic solvent such as dimethylformamide, acetonitrile, dichloromethane or tetrahydro-furan. The acid of formula XX can be activated with dicyclohexylcarbodiimide or a combination of dicyclohexylcarbodiimide and hydroxybenzotriazole.

An activated and suitably protected derivative of a compound of formula XX can also be the corresponding acid chloride (prepared with reagents such as phosphorus pentachloride, thionyl chloride, oxalyl chloride - or the triphenylphosphine / carbon tetrachloride) or a mixed anhydride (prepared with reagents such as diphenylphosphoryl chloride, pivaloyl chloride or isobutyl chloroformate).

The compound of formula XX in which Ag is a single bond, can be prepared as described in the literature; see Helv. Chem. Acta, 15 43, 469 (1960) and J. Med. Chem., 17, 1 (1974).

The compound of formula XX in which Ag represents -CH = CH- can be formed by oxidizing

I N CH2-0H XXII

t

H

(with appropriate protection) in corresponding aldehyde-25 corresponding to the formula: 0 ho Y |] ° N H ch xxiii 30

’I

H

(with appropriate protection), by reacting the aldehyde with a protected derivative on the carboxy group 31

I (/ \\ ή— P = CH-C-OH XXIV

and by deprotecting to obtain 5 0 HO Π Ύιΐ -

l | IJ ___ CH = CH-C-OH

XXV

10 a.m.

The compounds of formula XX in which

Ag represents ^ represents 2, 3 or 4, can be formed by conjugation of a compound of% formula XXIII (with appropriate protection) with a Wittig reagent corresponding to the formula:

—P = CH "(CH2) t ^ C-OH XXVI

; (with appropriate protection on the carboxy group), then by subsequent hydrogenation of the exocyclic double bond obtained and deprotection to obtain 0

hov JL

25 °

(I I ^ (CH2) t-C-0H

XXVII

H

where t represents 2, 3 or 4.

30 The compounds of formula XX in which

Ag represents - (CHg) ^ - and t represents 1, can be formed by reaction of an appropriately protected compound corresponding to the formula: 32 Ο Η0

I I. CHnL XXVIII

\ ^ a 5 ι Η: (where L is a group which moves away such as a chloride,

(Bromide, methane-sulfonyloxy group or toluene-sulfonyloxy group) with cyanide, then by subsequent hydrolysis and deprotection to obtain the compound of formula XXVII where t represents 1. A compound of formula XXVIII can be prepared from a compound of formula XXII (with appropriate protection) by methods well known in the art (for example, thionyl chloride or methane sulfonyl chloride / triethylamine).

The nucleophile of formula V in which R represents, 0 20 / \> ° H I I ° Ij.

-A ^ -N Rf-Ag-C-Ag * ^, A ^ is a single bond at 0 and A ^ represents -NH-, can be prepared by reacting an activated and optionally protected derivative of a compound of formula XX with 1-amino-i-1 2-imidazolidinone (HN N-NH ,,) to obtain, during 30% of deprotection: 33%

he oh

xxix i — i? 1 1 5 HN -Ν-ΝΗ-Ο-Α ^^ Ύν ^ T ή

- O

The nucleophiles of formula V in which Λ I-1 S 1) R represents -A1 -N N-A.-C-A ,, ^, k. is 1 'w' 26, 1

Y

A single bond and A ^ represents -CH ^ -CH ^ -NH-, can be prepared by reacting an activated and optionally protected derivative of a compound of * formula XX with 1- (2-aminoethyl) -2 -imidazolidi-

20 I — I

none (HN rj-CH2CH2NH2) to obtain, during the Π 0 deprotection: 25 0 Ù ° h

YY / XXX

I-1 2 XJ

HN N-CH0-CH0-NH-C-Ac - ^ \ N ^ V 2 2 6,

H

0

The nucleophiles of formula V in which R represents 34 JL “1 1 ° Ji j 5 -A1-N N-A ^ -C-A- '·" ’^, A. is a liai- 1 W 2 6, 1

T

- 0 0 11 its simple and A2 represents -C-NH-NH-, can be prepared by reacting 10 / T ~ \ 2 2 y— ch2-oc-nh-nh-c-ci xxxi with a silylated form of 2 -imidazolidinone, the anion of 2-imidazolidinone formed with a strong non-nucleophilic base or with 2-imidazolidinone in the presence of an organic base to obtain

?,?, \ I

\ 'Vch2-o-c-nh-nh-c-n NH XXXII

20 \ zm / Nn [| 0 The catalytic hydrogenation of the compound of formula XXXII gives the · compound corresponding to the formula: o i — 1

25. H0N-NH-C-N N-H XXXIII

V

0 which can be coupled with an activated and optionally protected derivative of a compound of formula XX to give, during deprotection: 35 rV “j I ο ° Π Π χχχιν 5 ΗΝ NC-NH-NH-C-Ac- ^^ N ^ Y "= 0

Alternatively, the compound of formula XXXIII can be prepared by first reacting 10-chlorocarbonyl-2-imidazolidinone with hydrazine protected by the t-butoxycarbonyl group to obtain I I s s

HN. N-C-NH-NH-C-O-C (CH0) _ XXXV

X / O o

15 T

0 and by deprotecting the compound of formula XXXV.

The nucleophiles of formula V can be prepared in which R represents 20 0 -A1 -N N-Ap-C-A - "^, A. represents 1 CD, 1

25 V

0 0 1! -NH-C- and A2 represents a single bond, making; react a compound corresponding to the formula: 30 0

-OH XXXVI

21 I 2 J J

Cl-C-N N-C-A *

35 H

0 36 (with appropriate protection) with hexamethyl-disilazane to obtain, during hydrolysis and deprotection, a compound corresponding to the formula: 0

5 JL

oh xxxvii SI — IS Jfjr H_N-C-N N-C-A “^ Y” 10 0

Compounds of formula XXXVI can be prepared (with appropriate protection) by reacting a silylated form of a compound of formula XXI (optionally protected) with phosgene.

Alternatively, a compound of formula XXXVII can be prepared by reacting a protected form of a compound of formula XXI with chlorosulfonyl isocyanate, this reaction being followed by the hydrolysis of the intermediate product obtained, as well as cleavage of protective groups.

The nucleophiles of formula V in which R represents 0 can be prepared

25 —OH

I-1 2 1 JJ 2 -A.-N N-A0-C-Ac, A, represents -NH-C- 1 v / 2 6,!

Y

i o 30 and A2 represents -NH-, by reacting a silylated form of compound 37

I I

HN N-NH-Prot XXXVIII

Y

0 5 where the symbol Prot can be a protecting group for the amino group such as a t-butoxycarbonyl group or - a benzyloxycarbonyl group, with phosgene to obtain 0 | -1

10 Cl-C-N N-NH-Prot XXXIX

V

0 which can be reacted with hexamethylsila-zane to obtain, during deprotection: 15 ° | -1

NH0-C-N N-NH. XL

Y

The reaction of the compound of formula XL with 20. an activated and possibly protected form of a compound of formula XX gives, during deprotection: 0 25 if i 2 JCjT xli NH0-CN N-NH-C-Ac ^ N "^! Y * * 0 - As a variant, a compound 30 of formula XL can be prepared by reacting the compound corresponding to the formula: 38 1 1

ΗΝ N-N = CH-Sf y XLII

II

0 - 5 with chlorosulfonyl isocyanate to obtain, during hydrolysis:

IF I

h2n-c-n n-n = ch—. y xliii 10 0

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

It is possible to prepare the nucleophiles of formula V in which R represents 15 0

OH

ri s Xf '-A ^ -N N-A2 “C-Ag ^ Nr, A ^ represents

8 p.m.

0 0

II

-NH-C- and A2 represents -CH2-CH2-NH-, by first deprotecting l- (aminocarbonyl) -3- £ "2- £ £ (t-butoxy) -25 carbonylJ7amino, 7ethyl.7- 2-imidazolidinone and by coupling the compound obtained with an activated form of a compound of formula XX (possibly protected) to obtain, after deprotection: 0

30 II 0H

o | -1 o jf JJ XLIV

HoN-0-N. N-CH0-CH0-NH-C-Ac <X'K> ^ N ^ 2 2 6,

T

35 0 39

The nucleophiles of formula V in which R represents 0 can be prepared

AT

5 —OH

I I ° Ij, -A -N N-A0-C-Ac, A. represents 1 2 6, 1

Y

0

10 0 O

II II

-NH-C- and A2 represents -C-NH-NH- by reacting a silylated form of a compound of formula XXXIV (optionally protected) with phosgene, then with hexamethyldisilazane to obtain, during hydro- 15 lysis and deprotection: 0

ilÎT0H

o | | ο o II JJ xlv

20 H0N-C-N N-C-NH-NH-C-A / ^^ ÎT

2 Y 6 »0

Alternatively, a compound of formula XLV can be prepared by reacting a protected form of a compound of formula XXXIV with chlorosulfonyl isocyanate, then hydrolyzing the intermediate product obtained and cleaving the protecting groups. As a variant, compound XXXII can be reacted with chlorosulfonyl isocyanate, in order to then proceed to the hydrolysis of the intermediate product formed in order to obtain: 40 I I ο ο

5 NH2C0N N-C-NH-NH-C-0-CH2— (f \\ XLVI

T w 0

Deprotection of the XLVI compound by hydro-genolysis gives: 10 0 | -------- 1 0

NH-CN N-C-NH-NH0 XLVII

V

o which can be coupled with an activated and possibly protected derivative of a compound of formula XX to obtain, during deprotection, a compound of formula XLV.

It is possible to prepare the nucleophiles of formula V in which R represents 20 0

_OH

i i ° i i I I "y -A ^ -N \ represents -NH-

25 J] H

0 and Ag represents a single bond, coupling the compound of formula XXXVIII to an activated form of a; compound of formula XX (optionally protected) and by cleaving the protecting group to obtain: 41

rV

i i s JL Jj

5 H0N-N N-C-A.YYnY XLVIII

Y * o

It is possible to prepare the nucleophiles of formula V in which R represents 10 0

A OH

^ d Ό, Ai represents -NH- 15 Π "0 and A2 represents -NH-, by coupling a monoprotected derivative (preferably, with a t-butoxycarbonyl group or a benzyloxycarbonyl group) of 1,3-20 diamino -2-imidazolidinone with an activated form of a compound of formula XX (possibly protected) and by deprotecting the compound formed to obtain: 0

25 A_ OH

| | 0 | I XLIX

H0N-N N-NH-C-A ΥΎ N Y

As a variant, a compound of formula XLIX can be formed by nitrosation of a protected form of a compound of formula XXIX, then by reduction of the nitroso group and cleavage of the protecting groups.

We can prepare nucleophiles of for-35 mule V in which R represents Ο 42

X

r ^ Y- oh I l? X J.

5 -A ^ -N N-Ag-C-Ag ^ N- ^, A ^ represents -NH-

X H

0 and Ag represents -CHg-CHg-NH- by nitrosation of a compound of formula XXX (with appropriate protection) 10 to obtain a compound corresponding to the formula: 0

π s jY

15 0 = N-N N-CH0-CH0-NH-C-Ac ^ \ N ^

Y

0 (with appropriate protection), as well as by reduction - and deprotection of this compound to obtain: 20 0 jl

lll — 0H

I I ° I I 11 h2n-n n-ch2-ch2-nh-c-a6 ^ N '

25 DD H

0

The nucleophiles of formula V can be prepared in which R represents 0 30

OH

I | ο [Γ]] -A ^ -N N-Ag-C-Ag "', A1 represents -NH-

35 H

0 43 Ο

II

and A2 represents -C-NH-NH- by nitrosation, reduction and deprotection of a protected derivative of a compound of formula XXXIV. The compound obtained corresponds to the formula: 5 0 i — ιο o rr

HCN-N N-C-NH-NH-C-A ^ T ^ N · ^ LU 10 Ύ 6 H

o

Alternatively, a compound of formula LU can be prepared by reacting a compound of formula XXXVIII with phosgene to obtain: I-I °

Prot-NH-N N-C-Cl HIM

V

o - which, upon reaction with a monoprotected hydrazine in the presence of a base, gives i-I s

Prot-NH-N N-C-NH-NH-Prot LIV

V

0 25 (The two protecting groups must be different). Selective elimination of the hydrazide protecting group gives: I 1 °

Prot-NH-N N-C-NH-NH „LV

V

o

Coupling a compound of formula LV with an activated and optionally protected form of a compound of formula XX (with subsequent deprotection) gives a compound of formula LU.

44

The nucleophiles of formula V in which R represents 0 can be prepared

X

5 S OH

I I ii „A ^ -N N-A ^ -C-Ag ^^ sN ^, A ^ represents Y k o

10 0 II

-NH-NH-C- and A ^ represents a single bond, reacting a compound of formula XXXVI (preferably one of its protected derivatives) with hydrazine (preferably in monoprotected form) in the presence of a base or with a silylated form of monoprotected hydrazine or hydrazine to obtain a protected derivative of formula: 0 20 rrt — oh

ο i i ° Ü JJ

H0N-NH-C-N N-C-A-Y ^ N- ^ LVI

Y "0 25 which can be unprotected by adopting conventional techniques.

Alternatively, a compound of formula XXXV (either one of its silylated derivatives or one of its anions ^ formed by reaction with a strong base) can be reacted with an activated form of the compound of formula XX (with appropriate protection). then carrying out a deprotection to obtain a compound of formula LVI.

The nucleophiles of formula V can be prepared in which R represents Ο 45

r-ι s JjT

5 -A ^ -N Ν-Α ^ -Ο-Αρ * ^, A ^ represents Y "

O

O

II

-NH-NH-C- and Ag represents -NH-, by selective removal of the non-hydrazide protecting group from a compound of formula LIV, while then coupling with an activated and optionally protected compound from formula XX, with subsequent deprotection / to obtain a compound corresponding to the formula: 15 0

° l— | »IV0H

- H „N-NH-C-N N-NH-C-A / ^^ N ^ LVII

2/6

20 Ύ] H

0

The nucleophiles of formula V in which R represents 0 can be prepared

25 II

-OH

i i? X JT

A1 A2 C A6 ^, A1 represents T π 1 30 0 c 0

II

-NH-NH-C- and A2 represents -CHg-CHg-NH- by reacting successively a compound of formula XXX (or one of its protected derivatives) with phosgene, then with hydrazine (or one of its monoprotected derivatives) 46 in the presence of a silylating agent such as N-methyl-N- (trimethylsilyl) trifluoroacetamide / to obtain, during deprotection:

: 5 rV

0 | | 0 I I

H „N-NH-C-N · N-CH0-CH0-NH-C-A -‘ ^ S ^ NxX LVIII

d w ^ d 2 o,

π H

10 o

Alternatively, a protected derivative on the amino group of 1- (2-aminoethyl) - 2-imidazolidinone (optionally silylated) can be reacted with phosgene and then with a monoprotected hydrazine derivative in the presence of a base. or a silylating agent (for example, N-methyl-N- (trimethylsilyl) trifluoracetamide or bis- (trimethylsilyl) acetamide) to obtain a protected derivative of the compound corresponding to the - formula: 20 _

s I I

HpN-NH-C-N N-CH -CH2-NH LIX

Y

0 2g The groups used to protect the terminal amino groups in a compound of formula LIX should be chosen such that the protecting group on the aminoethyl group can be selectively removed. The mono-deprotected compound obtained can be coupled with an activated form of an acid of formula XX (or one of its protected derivatives) to obtain (after deprotection) a compound of formula LVIII.

The nucleophiles of formula 35 V can be prepared in which R represents 47 iV "

1 1 n DD DD

g -A ^ -N N-A ^ -C-Ag N ^, A ^ represents V “0 0 0

II II

-NH-NH-C- and A ^ represents -C-NH-NH- by reacting the compound of formula XXXII (optionally in the form of one of its silylated derivatives) with phosgene to obtain a protected derivative of the responding compound to the formula: 15 0 | d 0

H2N-NH-C-N N-C-Cl LX

T

0 ς which can be coupled with a protected hydrazine derivative to obtain a protected derivative of ° | -1 0

H.N-NH-C-N N-C-NH-NH „LXI

T

The groups used to protect the terminal amino groups in a compound of formula LXI should be chosen such that one of the protecting groups can be selectively removed. The mono-deprotected compound obtained can be coupled with an activated and optionally protected form of an acid of formula XX to give (after deprotection) a compound corresponding to the formula: Ο 48

i ^ S-0H

01 ........ ι ° ο I I]

H0N-NH-C-N N-C-NH-NH-C-A _ ^ \ n ^ LXII

Ύ k o

The nucleophiles of formula V in which R represents 0 can be prepared

10 A

OH

/ ~ λ 2 A.J

-A, -N N-A0-C-Ae by adopting W. ά

15 0 ^ S

methodology described above for the preparation of nucleophiles of formula V in which R represents 0

20 II

OH

1 1 ° Jo -A. -N N-A0-C-A_ N ^, but substituting Y * 25 0 the appropriate reagents of 2,3-piperazine-dione for the reagents of 2-imidazolidinone.

The nucleophiles of formula V in which R represents '30 0 can be prepared

A OH

± Q "A1 is a simple reason

35 | d H

0 49 and Ag is a single bond, using an appropriately protected derivative of the compound 0 5 HO- I llo

G-OH LXIII

H

A compound corresponding to the formula 10 can be prepared: -vs | l \\ NH2 lxiv 15

H

by converting a protected form of the compound corresponding to the formula: - 0

20 II

HO -p 0 Π Π c-nh-nh2 lxv!

H

25 in a protected form of the compound of formula LXIV by the method of K. Heyns et al., Chem. Ber., 87, 1440 (1954), while then carrying out a deprotection to obtain the compound of formula LXIV as it is.

A compound of formula LXV 30 can be prepared from an appropriately protected form of a compound of formula LXIII by conversion to an ester (such as ethyl ester or methyl ester), by reaction with hydrazine and by deprotection.

Alternatively, an activated and suitably protected form of a compound of formula LXIII can be reacted with a mono-protected hydrazine to obtain, upon deprotection, a compound of formula LXV.

During the reaction of the compound of formula 5 LXIV (or of an appropriately protected derivative thereof) with 2- (chlorethyl) isocyanate v. optionally in the presence of a base (such as triethylamine) or a silylating agent, during deprotection, the compound corresponding to the formula 10 is obtained: 0

-OH

° 1 r

15 Cl-CHg-CH ^ NH-C-NH "'' ^ LXVI

H

By treatment of the compound LXVI (or of one of its appropriately protected derivatives) with a base, during deprotection, the compound 20 corresponding to the formula: 0 is obtained

He oh

ÇY LXVH

25 HN n / ^ N ^ Y »0

It is possible to prepare the nucleophiles of formula V in which R represents 30 0

π JuT

-Α1-Ν N-A5, A ^ represents a link

35 Y H

0 51 its simple and A5 represents -CHg-, by reacting the compound corresponding to the formula: v,

It IL ^ CH2NH2 LXVIII

H

(or a derivative in which the pyridone is suitably protected, while the primary amine is unprotected) with 2- (chloroethyl) isocyanate to obtain the compound corresponding (during deprotection) to the formula: 0 15 Jl

-OH

0 I | J LXIX

Cl-CHg-CHg-NH-C-NH-CHg ***** ^ N ^

- H

20 By treating the compound LXIX (or one of its appropriately protected derivatives) with a base, the compound corresponding to the formula: 0 25 l is obtained]

OH

| | I I LXX

HN

Y "30 0

A compound of formula LXVIII can be prepared from a compound of formula XXVIII (with appropriate protection) by treatment with an azide, reduction of the azide and deprotection.

52

The nucleophiles of formula V in which R represents 0 can be prepared

5 OH

I I X JT

-A1-N N-Ac * ^, A represents a simple sound Y 4 0 10 and Ag represents -N = CH- or -NH-CHg, by condensing 1-amino-2-imidazolidinone with the aldehyde corresponding to formula XXIII (possibly protected) to obtain (after deprotection), the compound corresponding to formula 15 '0 JL.

i i X JT

HN N-N = CH * LXXI

8 p.m.

0

By reduction of the compound of formula LXXI (optionally protected) by catalytic hydrogenation or by using sodium cyanoborohydride, the compound corresponding to the formula: 0 is obtained

I I JuT

30 HN N-NH-CH * ---- ^ N * ^ LXXII

Y * 0

It is possible to prepare the nucleophiles of formula V in which R represents Ο 53 oh π jr jr 5 -A ..- N N-Ac * ^^ sN ^, A. represents a link 1 5 »1 ïï

Y O O

II

its simple and A ,, represents -C-NH-CCH ^) - by making

w c »CJ

reacting l-chlorocarbonyl-2-imidazolidinone with a compound corresponding to the formula 0

fjt-OH

H II LXXIII

15

H

(or one of its appropriately protected derivatives) in the presence of a base or with a silylated derivative of a compound of formula LXXIII to obtain, after deprpro-20 ’tection, the compound corresponding to the formula: 0

-OH

I-IS 1 Γ

25 HN N-C-NH- (0Ho) LXXIV

Y ’- 0

The nucleophiles of formula can be prepared; V in which R represents Ο 54 —ΟΗ ι — ι X JT s.

5 -Α ^ -Ν Ν-Α, .- ^^ νΝ ^ and represents -NHC- Π Α Ο by reacting an appropriately protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII 10 or LXXIV with phosgene to obtain a protected derivative of

if ι JlT

Cl-C-N N-Ac — LXXV

Y * 0 which can be reacted with hexamethylsila-20 zane to obtain, during deprotection and hydrolysis: 0

A OH

LXXVI

Y * 0: As a variant, nucleophiles of formula V can be prepared in which R represents 55 I-I JET s 5 A ..- N N-Aj.'NN / and A. represents -NHC- 1 5 , 1 *

Y H

0 by reacting an appropriately protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII 10 or LXXIV with chlorosulfonyl isocyanate to obtain, during hydrolysis and deprotection, a compound of formula LXXVI.

The nucleophiles of formula V can be prepared in which R represents 15 0 oh

I — I XT

-A.-N N-A, - ^ »INr and A. represents -NH-,

1 5. 1 20 Y H

0 by nitrosation of an appropriately protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII or LXXIV (for example, with nitrous acid), by reduction of the compound obtained (using, for example , zinc under acidic conditions) and by deprotection to obtain 0

30 LXXVI I

I I i JT

H2N-Ns ^ N-A5 - ^^ \ n ^ Y ή 0 56

Alternatively, the compounds of formula LXXVII can be prepared in which represents 0

II

-C-NH- (CHp) - by reacting a compound of formula 5 XXXIX with an optionally protected form of a compound of formula LXIV or LXVIII in the presence of a base or of a silylating agent to obtain, during deprotection: 0

10 JL

-OH

I-12 d Γ

H0N-N N-C-NH- (CH „) LXXVIII

Y q "15 0

Alternatively, the compounds of formula LXXVII in which represents -N = CH-or -NH-CHg- can be prepared by reacting the mono-protected 1,3-diamino-2-imida-zolidinone with a compound of formula XXIII (or one of its protected derivatives) and by deprotection of the product to obtain the derivative of formula LXXVII in which Ag represents -N = CH-. The reduction of this derivative gives the compound of formula LXXVII in which Ag represents -NH-CH ,, -.

The nucleophiles of formula V can be prepared in which R represents Λ-- i i JL Jl -A ^ -N N-A & and A ^ represents Y "0 0

II

35 -NH-NH-C- by reacting a compound of formula 57 LXXV (with appropriate protection) with a mono-protected hydrazine in the presence of a base or of a silylating agent. After deprotection, the products correspond to the formula: 5 0

sr-i JjT

H-N-NH-C-N N-Αγ LXXIX

Y = 0

The nucleophiles of formula V in which R represents 0 15 can be prepared

ΓΛ AJ

-A1-N N-Ap. , An represents a simple bond \ / έ 20 0 0 and A ,. represents a single bond or by reacting a compound of formula LXIV or LXVIII (or ion of its appropriately protected derivatives) with aziridine or an activated aziridine (activated with groups such as acyl group or group sulfonyl) to obtain, when. deprotection: 0

30 | jy— OH

h2n-ch2-ch2-nh (ch2) 0j1 '^ N "n ^ lxxx

H

58

A compound of formula LXXX (or an appropriately protected derivative thereof) can be converted into the desired piperazine-dione of formula 5 0

/ “Λ lV ° H

HN N- (CH9) n LXXXI

v je, ±, 10> -4, by reaction with a dialkyl oxalate (and, if necessary, with subsequent deprotection).

We can prepare nucleophiles of for-15 mule V in which R represents

/ -Λ DD

20 -A1 -N, A1 represents a simple line and ^ 0 ^ 0 and A ,. represents -N = CH- or -NHCHg- by adopting the methodology described above for the preparation of nucleophiles of formula V in which R represents 0

: »R-1 JÔT

-A ^ -N NA ^ / "^, A ^ represents a single sound Y-link and A & represents -N = CH- or -NHCH ^ -, but substituting 1-amino-2,3-piperazine -dione to 59 l-araino-2-imidazolidinone. The compounds obtained should correspond to the formulas: 0

T 5 —OH LXXXII

/ - \ J | I

„HN Ν-Ν = 0Η · ^ \ ν ^ and 4 * k 10 0

A OH

LXXXIII

15 "

The nucleophiles of formula V in which R represents

O

20 II

OH

, XJ

-A.-N Ν-Ακ ^, A. is a bond X * 25 O '^ 0 0

II

simple and A & represents -C-NH- (CH2) ^ - by reacting an optionally protected derivative of formula: / - \ 0

30 HN N-C-Cl LXXXIV

^ —4¾.

o r o with a compound of formula LXXIII (or an appropriately protected derivative thereof) in the presence of a base 35 or a silylating agent. The intermediate product 60 obtained can be deprotected to obtain: 0

/ \ u dd

HN N-C-NH- (CH) LXXXV

^ —4 q ή 0 '0

We can prepare nucleophiles of form-10 mule V in which R represents 0

/ - \ X jT

15 -A ..- N NA- and A1 represents -NH- "0 ^ ^ 0 by nitrosation of a protected derivative of a compound corresponding to the formulas LXXXI, LXXXII, LXXXIII or 20 LXXXV (for example, with the acid nitrous), by reduction of the compound obtained (using, for example, zinc under acidic conditions) and by deprotection to obtain: 0

25 II

AT

H „N-N N-Ac ^ LXXXVI

H

30 0 ^ 0

As a variant, the compounds of formula LXXXVI can be prepared in which A ^ represents -N = CH-or -ΝΗ-ΟΗ ^ - by reacting the mono-protected 1,4-diamino-2,3-pipé-razine-dione with a compound of formula 35 XXIII (or one of its protected derivatives) and deprotecting the product to obtain a compound of formula LXXXVI in which represents -N = CH- which can then be reduced to a compound of formula LXXXVI in which represents -NH-CHg-. Alternatively, reduction of -N = CH- may precede deprotection.

The nucleophiles of formula V in which R represents 0 can be prepared

10 _OH

ΛΛ XJ

-A -N N-Ar ^ and A. represents ο 'ο 15 0

II

-NH-NH-C- by reacting an appropriately protected derivative of a compound of formula LXXXI, LXXXII, LXXXIII or LXXXV with phosgene to obtain 0

20 II

S / - \ J1 dd

Cl-C-N N-Ac ‘^ \ n ^ LXXXVII

^ —4. k 25 0 * ^ ^ 0 which can be reacted with hexamethyldisilazane to obtain, during deprotection and hydrolysis: 0 30 ji

—OH LXXXVI II

> 35 0 0 62

As a variant, it is possible to prepare the nucleo-philes of formula V in which R represents 0

5 —OH

/ - \ XJT 2

„-A., -N N-A ^ and A. represents -NHC

X * 0 ^ 0 10 by reacting an appropriately protected derivative of a compound of formula LXXXI, LXXXII, LXXXIII or LXXXV with chlorosulfonyl isocyanate to obtain a compound of formula LXXXVIII during hydrolysis and protection.

The nucleophiles of formula V in which R represents 0 iYh -NH-A / ^^^ N and A. represents - (CH0) - have o | o d. p

H

have been described (see formulas LXIV and LXVIII).

The nucleophiles of formula '25 V in which R represents 0 can be prepared

not a word

r ^^ v — oh

II

y h 30 -NH-Ag * ^ and A ^ represents -NH-C-NH- or

H

0! 1 -NH-C-NH-CH2- by reacting a compound of formula XXXI with a compound of formula LXIV or LXVIII (possibly protected) in the presence of a base or a silylating agent, to then proceed with the elimination of either protective group.

Alternatively, nucleo-philes of formula V may be prepared in which R represents 50

OH

X JJ o -NH-Ag ‘^> s ^ N and represents -NH-C-NH-

10 a.m.

0 11 or -NH-C-NH-CHg- from an appropriately protected form of a compound of formula LXIV or LXVIII by reaction with phosgene, this reaction being followed by treatment with a monoprotected derivative of hydrazine in the presence of a base or of a silylating agent, as well as by deprotection.

The nucleophiles of formula V can be prepared in which R represents 20 0 jY 0 -NH-Ag ’^^ N ^ and Α ^ represents -CH2-C-NH- or

25 h

-CH ^ -CO-NH-CH ^ - by coupling an activated and N-protected derivative of glycine with a compound of formula LXIV or LXVIII (possibly protected), this coupling being followed by deprotection.

30 The nucleophiles of formula V can be prepared in which R represents Ο 64

A OH

^ and represents -NH-CHg- in

H

„Reacting a possibly protected aldehyde derivative of formula XXIII with hydrazine or mono-protected hydrazine, this reaction being followed by a reduction of the carbon-nitrogen double bond, with subsequent deprotection.

Alternatively, a mono-protected hydrazine can be mono-alkylated on the free amino group with a compound of formula XXVIII (with appropriate protection) to then carry out deprotection in order to obtain a nucleophile of formula V in which R represents 0 i

20 r ^ V- OH

1 JT

-NH-A2 ,,,,,,,, ^> S> SsN ,, ^ and A ^ represents -NH-CHg-.

H

The nucleophiles of formula 25 V can be prepared in which R represents 0

jY

30 -NH-A ^^^ N ^ and A ^ represents -O-CH ^ - in weak-

H

able to react an appropriately protected derivative of the compound of formula XXII with N-hydroxyphthalimide under Mitsunobu conditions (presence of triphé-nylphosphine and diethyl azodicarboxylate) to obtain a protected derivative of compound 0 H ° \ il 0 5 JJ ^ ch2-on lxxxix H 0 * which can be deprotected in a compound of formula 0

10 HO II

\AT

(I JJ ^ CH2-0-NH2 xc

3 p.m.

Alternatively, the compound of formula XG can be prepared by reacting a compound of formula XXVIII (with appropriate protection) with N-hydroxy-phthalimide in the presence of a base.

The nucleophiles of formula V in which R represents Λ- can be prepared

25 0 I DD

-NH-A ^ -C-Ag '^^ N and A4 represents -NH-, in

H

reacting a mono-protected hydrazine with an activated and optionally protected derivative of an acid of formula XX to obtain, after deprotection, a compound of formula 66: JCV “

NH ^ -NH-C-A ^^^ N ^ XCI

2 6,

5 hrs

Alternatively, the compounds of formula XCI can be prepared by reacting a carboxylic acid ester of an appropriately protected derivative of a compound of formula XX with hydrazine, followed by deprotection.

The nucleophiles of formula V in which R represents -! {y "-NH-A ^ -C-Ag ^ \ N / and A4 represents - (CH ,,) -

H

and p represents 0, by reacting ammonia or hexamethyldisilizane with an activated and optionally protected derivative of an acid of formula XX to obtain, after deprotection, a compound corresponding to the formula: 0

25 "OH

s 1 Γ

NHL-C-A - ^^ N ^ XCII

2 6,

H

The nucleophiles of formula 30 V can be prepared in which R represents Ο 67

ο jfV0H

5 -NH-A ^ -C-Ag ^^^ vN ^ and A ^ represents “(CHg) ^ -,

H

while p represents 1, by treatment of an appropriately protected activated derivative of a compound of formula XX with diazomethane, then with hydrochloric acid to obtain a protected derivative of a compound corresponding to the formula: 0 15 0 fl Jj L. -CH0-CA „X '\ n ^ xciii b 2 6,

H

in which "L ^" represents chlorine. A compound of formula XCIII in which chlorine represents can then be treated with an iodide or bromide salt (such as sodium iodide or lithium bromide) to obtain a protected derivative of a compound of formula XCIII in which represents bromine or iodine. By displacement of the group "Lb" 25 which moves away (L ^ representing chlorine, bromine or iodine) with an azide, then by reduction and deprotection, we obtain: 0

30 -OH

s 1 r

NH0-CH0-C-Ac ^ XSs ^ Nx ^ XCIV

2 2 6,

H

The nucleophile of formula 35 V can be prepared in which R represents Ο 68 Ι ^ Ν — ΟΗ Ο Π 1 5 -NH-A ^ -C-Ag '^' ^ N '^ and Α ^ represents - (CH2) y- NH- Η. by reacting a compound (possibly mono protected) of formula:

NH2- (CH2) y-NH2 XCV

10 with an activated and optionally protected derivative of an acid of formula XX to obtain, after deprotection, a compound corresponding to the formula; 0 fi

15 —OH

o Jf j

NH0- (CH0) -NH-C-A / ^ \ N ^ XCVI

^ ^ y 6,

H

The nucleophiles of formula 20 V can be prepared in which R represents 0

X

-OH

0 I I 0 25 -NH-A ^ -C-Ag '^^ N and A ^ represents -NH-C-NH-NH-

H

by reacting a compound of formula XCI (with appropriate protection) with a compound corresponding to the formula: 30 0

Prot-NH-NH-C-Cl XCVII

in the presence of a silylating agent, then removing the protective groups.

The nucleophiles of formula 35 V can be prepared in which R represents 69 o jrV0H ο 5 -NH-A ^ -C-A6 ‘^ V's-N '^ and A ^ represents -C-NH-NH-

H

0 11 by reacting NH2-C-NH-NH2 (in the presence of a base or a silylating agent) with an activated and optionally protected derivative 10 of formula XX to obtain, after deprotection, a compound corresponding to the formula : 0 15

ο ο Π JJ

Ν ^ -Ο-ΝΗ-ΝΗ-Ϊ-Α, Γ ^ Ν ^ XCVIII

2 6,

H

The nucleophile of formula 20 V in which R represents A can be prepared.

0 H JJ çh2x 25 -NH-A ^ -C-Ag '^^^ N and A ^ represents -N- in

H

reacting an optionally protected hydrazine derivative of formula: nh2-nh-ch2-x xcix 30 with an activated and optionally protected derivative of an acid of formula XX to obtain, after deprotection, a compound corresponding to the formula: 0 70

çh2x jfV

5 NH -N - C ^ \ n ^ C

2 It I

0 h

Alternatively, compounds of formula C in which X represents hydrogen can be prepared by reacting methylhydrazine with a derivative of an acid carboxylic ester of formula XX

(or an appropriately protected derivative thereof). The compounds of formula I in which R

represents 0 15 it ΓΤ ~ 0Η

l — I s 1 day

-A1-N N-A0-C-Ac * ^> 'n> s'N> i ^ are preferred.

1 2 6, Ύ 20 0

By far preferred are the compounds of formula I in which R represents.

0

not a word

25 _OH

i— | S J Γ -N N-NH-C. Also preferred are y 0 30 the compounds of formula I in which R ^ represents 0

II

-C- ^ N-O-R ^ and Rg represents a 2-amino-4-R group

g thiazolyl, while R ^ represents a methyl group, an ethyl group, a carboxymethyl group, a group 71

1-carboxy-1-methylethyl, a 1-carboxy-kethyl group ™ 2-> CH2> S

or a group - C - COOH where s represents 1, 2 or 3. The use of these preferred acyl groups gives an existing product in the form of the syn or anti isomer or in the form of a mixture of isomers.

„The syn isomer has a stronger activity than the anti isomer.

The following examples illustrate specific embodiments of the present invention.

Example 1

Acid £ -3S (Z) J-2-ΓΓΓΐ - (2-amino-4-thiazolyl) -2-C C1-ΓC CC 3- / 7 £ (1,4-dihydro-5-hydroxy-4-oxo- 2-pyridinyl) carbonylJ7amino J7-2-oxo-l-imidazolidinylJ -15 sulfonyl Jamino J7carbonyl J7-2-oxo-3-azetidinylJ - amino.jr-2-oxoethylidene ^ amino ^ 7oxy ^ -2-methylpropa- 'noique, salt disodium.

A) 2- (hydroxymethyl1) -5- (phenylmethoxy) -4H-pyran-4-one 69 g (3 moles) of sodium were dissolved in 5 l of methanol. Next, 425.3 g (3 moles) of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4-one was added and stirred at 30 ° C until a clear solution was obtained . Then, 595 g (3.5 moles) of benzyl bromide was added and the mixture was stirred for one hour at reflux. The hot, very dark solution was poured into 15 liters of ice water.

The product crystallized immediately. The crystals were collected and washed first with 8 L of water, then twice with 2.5 L of ether. The product was allowed to stand overnight and finally dried at 50 ° C for 16 hours. Yield: 646 g = 92.6%.

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

232 g (1 mole) of 2- (hydroxy-methyl) -5- (phenylmethoxy) -4H-pyran-4-one were poured into a 10 L shake flask containing 6.6 L acetone and 400 ml of water. By means of an ice bath, the clear solution was cooled to + 5 ° C. While maintaining the temperature between + 5 ° and 10 ° C, over a period of one hour, 10,640 ml of Jones reagent (202 g of Cr03, 600 ml of water, was added dropwise). 174 ml HgSO 4). Stirring was continued for 2 hours without cooling. The reaction mixture was filtered through a glass frit and the dark green residue was washed with 500 ml of acetone. The filtrate was then evaporated until all of the acetone was removed.

- To the partially crystalline aqueous product, 1.2 l of methanol were added, then this mixture was heated to its boiling point. The resulting dark green clear solution was placed in an ice bath and the product was allowed to crystallize. The crystalline product was filtered and washed with 500 ml of a cold solvent mixture consisting of 250 ml of methanol + 250 ml of water and finally it was dried.

25 Yield: 195 g = 79%. From the mother liquor, an additional 5% of the product could be isolated.

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

300 g (1.22 mol) of 4-oxo-30 5- (phenylmethoxy) -4H-pyran-2-carboxylic acid were poured into a flask and, while stirring, 5 l of NH 2 were added cautiously. OH at 33%. The reaction mixture was then stirred at reflux. After 3 hours, an additional 1 liter of 33% NH 4 OH was added slowly. Stirring was continued for an additional 2 hours at reflux. The reaction solution was then evaporated until the product crystallized. The product was transferred back to the reaction flask and water was added until a clear solution was obtained (about 5 L, pH 6.38). This solution was vigorously stirred while adding concentrated hydrochloric acid dropwise until a pH of 3 was obtained. By filtration, the precipitated white product was removed, washed with water. veniently with water and it was dried. Yield: 273 g (1.12 mole) = 91.8%.

D) 1,4-dihydro-4-oxo-N- (2-oxo-1-imidazolidinyl) -5- (phenylmethoxy) -2-pyridine-carboxamide

We put 12.26 g (0.05 mole) of 1,4-15 dihydro-4-oxo-5- (phenylmethoxy) -2-pyridine-carboxylic acid and 5.56 g (0.055 mole) of l-amino-2-imidazolidinone suspended in 120 ml of dimethylformamide. To this suspension was added 0.3 g of dimethylamino-pyridine and 0.4 g of N-hydroxybenzotriazole. After stirring for 30 minutes at room temperature, a solution of 11.35 g (0.055 mole) of dicyclohexylcarbodiimide in 50 ml of dimethylformamide was added dropwise and the mixture was stirred overnight at room temperature. The precipitate (dicyclohexylurea) was separated by filtration and the filtrate was evaporated in vacuo. The residual syrup crystallized during treatment with aqueous sodium bicarbonate to give 11.7 g of the title compound with a melting point of 158-160 ° C. An additional harvest of 0.8 g of the product at a melting point of 162-164 ° C crystallized from the aqueous filtrate.

E) 1,4-dihydro-5-hydroxy-4-oxo-N- (2-oxo-1-imidazolidinyl) -2-pyridine-carboxamide To a suspension of 12 g (0.0365 mole) of 35 1.4 -dihydro-4-oxo-N- (2-oxo-1-imidazolidinyl) -5- (phenyl- 74 methoxy) -2-pyridine-carboxamide in 150 ml of aceto-nitrile, 36.1 ml were added ( 0.146 mol) of bis- (trimethylsilyl) acetamide to form a slightly cloudy solution. After filtration, 566 g of 10% palladium on carbon were added and hydrogen was passed through the stirred reaction mixture.

After hydrogenation for 60 minutes, the catalyst was filtered off and 15 ml of methanol and 2 ml of acetic acid were added. Stirring was continued overnight; the title compound separated by crystallization to give 6.6 g of a product with a melting point of 270-275 ° C.

F) Acid (3S) - C! -CCCC 3-ΖΓ c (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl "Jamino J-2-oxo-l-imidazoli-15 dinylJ suifonylJamino £ 7 carbonyl j ^ -2-oxo-3-azetidinyl J-carbamic, phenylmethyl ester.

To a suspension of 13.8 g of (S) -3- Γ Γ (Phenylmethoxy) carbonyl amino ^ -2-azetidinone in 500 ml of ethyl acetate was added 5.63 ml (0, 0626 mol) of chlorosulfonyl isocyanate. The mixture was stirred for one hour at room temperature to form a solution of (S) -l- £ £ * (chlorosulfonyl) -amino Όcarbonyl J-3-ΓΖΓ (phenylmethoxy) carbonylJ-25 amino J7-2-azetidinone. The solution was cooled to 0 ° C, at which temperature a solution of 1,4-dihydro-5-hydroxy-4-oxo-N- (2-oxo-1-imidazolidinyl) -2-pyridine- was added slowly. silylated carboxamide (prepared from a suspension of 14.9 g (0.0626 mole) of 30 l, 4-dihydro-5-hydroxy-4-oxo-N- (2-oxo-l-imidazolidinyl) - 2 -pyridine-carboxamide in 500 ml of ethyl acetate by addition of 46.4 ml of N-methyl-N- (trimethylsilyl) -trifluoracetamide (0.25 mol) and by stirring for 30 minutes). Then 150 ml of dichloromethane was added and the mixture was stirred at room temperature overnight. To the clear solution was added 26.2 ml of triethylamine (0.188 mole), then 300 g of ice and 200 ml of water. The pH was 6.5. After stirring for an hour and a half, the two phases were separated and the aqueous phase was washed with three 200 ml portions of ethyl acetate.

After removing the residual ethyl acetate in vacuo, the pH of the aqueous phase was adjusted to 2 by slowly adding 47 ml of 2N hydrochloric acid 10 while cooling. The crystals were separated by filtration, suspended in 200 ml of ethyl acetate and stirred for one hour. Then, the crystals were separated by filtration, washed twice with 30 ml of ethyl acetate and twice with 50 ml of petroleum ether, then dried under vacuum to obtain 28.6 g of the compound under heading of a melting point of 190-200 ° C (decomposition).

G) (3S) -3-amino-N- CC3-CC (1,4-dihydro-5-hydroxy-20 4-oxo-2-pyridinyl) carbonylJamino J-2-oxo-l-imidazoli-dinyl I7sulfonyl J7- 2-oxo-1-azetidine-carboxamide, trifluoroacetate salt (1: 2) At room temperature, 4 g (0.00713 mol) of phenylmethyl ester of acid (3S) was added - ri-rrrcs-rr (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl, 7 amino_7-2-oxo-l-imidazolidinylJ-sulfonylJaminoJ7carbonyl ^ -S-oxo-S-azetidinylJ7carbamic to a mixture of 15 ml of trifluoroacetic acid and 3.5 ml of thioanisole at 10 ° C. The clear solution was stirred overnight at 10 ° C. After evaporation in vacuo at room temperature, the residual syrup was treated with ether to obtain the title compound as a yellow, 35 'solid. The yield was almost quantitative.

76 H) Acid £ * 3S (Z) ^ 7-2 - ^ - ^ £ “1- (2-amino-4-thiazolyl) - 2-ΓΓ1-ΓΓΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl J amino, 7-2-oxo-l-imidazolidinyl ~ f-sulfonyl J7amino ^ carbonyl J7-2-oxo-3-azetidinyl I- 5 amino 27-2-oxo-ethylidene ^ amino J7oxy ^ 7-2-methylpropanoic, diphenylmethyl ester To a solution of 3.08 g (0.007 mole) of (Z) -2-amino-0- acid - £ '£ 2- (diphenylmethoxy) -1,1 -10 dimethyl-2-oxo-ethoxy J7iniino J7-4-thiazole-acetic in 70 ml of dimethylformamide, 2.9 ml (0.021 mole) of triethylamine was added and then, after cooling to -30 ° C under an atmosphere of nitrogen, 1.55 ml (0.007 mole) of diphenyl chlorophosphate was added. The mixture was stirred for one hour at -30 ° C. Then, 1.95 ml of triethylamine (0.014 mole) was added, followed by 0.007 mole of the trifluoraceous-tate salt (1: 2) of (3S) -3-amino-N- CD-CC (1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonylJamino J-2-oxo-20 1-imidazolidinyl 17sulfonyl 27-2-oxo-1-azetidine-carbamide. The reaction mixture was stirred at -10 ° C for 2 hours and at 0 ° C for 1 hour. Then, the solvent was removed in vacuo. By treating the residue with water and ethyl acetate, an insoluble product was obtained which solidified upon treatment with ether to give 8 g of the crude compound.

I) Acid £ 3S (Z) Jz-CCC 1- (2-amino-4-thiazolyl) -z-bcc-crcrz-cc (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl aminoJ7-2-oxo-l-imidazolidinyl J7_ sulfonyl ”7amino ^ carbonyl ^ -2-oxo-3-azétidinyl" Jamino J1 -2-oxo-ethylidene 27amino ^ 7oxy jr-2-methylpropanoic, disodium salt_

8 g of diphenylmethyl ester of £ * 3S (Z) Γ £ l- (2-amino-4-thiazolyl) -2- 77 ca-cccca-rc (1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) carbonylCamino J7-2-oxo-l-imidazolidinylJ7-sulfonyl J / amino JcarbonylJf ^ -oxo-S-azetidinylJ-amino ^ -2-oxoethylidene ^ amino ^ 7oxy J7-2-methylpropa- 5 crude noique suspended in 15 ml of anisole.

After cooling to -10 ° C, 80 ml of trifluoroacetic acid was added dropwise and the mixture was stirred at -10 ° C for one hour. Addition of ether at 0 ° C caused precipitation of the free acid trifluoroacetate salt of the product (4.1 g of raw material). The raw material was suspended in water; the pH was adjusted to 5.5 by addition of a solution of sodium bicarbonate and the solution formed was lyophilized. The crude sodium salt was then purified by chromatography on "HP-20" (macroreticular resin of the styrene / divinylbenzene copolymer sold by "Mitsubishi Chemical Industries Ltd."). The product was eluted with water to obtain 0.52 g of the product.

Nuclear magnetic resonance spectrum (DMSOdg): é = 1.35 (s, 3H); 1.40 (s, 3H), 3.37 (dd, 1H); 3.47 (t, 2H); 3.81 (t, 2H + dd, 1H); 5.05 (m, 1H); 6.75 (s, 1H); 7.27 (s, 1H); 7.72 (s, 1H); 11.52 (br s, 1H).

25 Example 2

Acid £ 3S (Z) J7-2- ccu l- (2-amino-4-thiazolyl) -2-ΓΠ-ΓΓΓΓ2-Γ (1,4-dihydro-5-hydroxy-4-oxo-2-- pyridinyl) carbonyl .j ^ hydrazino J suifonylJamino Jcarbonyl, 7-2-oxo-3-azetidinylJ7amino .7-2-oxoethylidene J- 30 amino ^ oxyJ7-2-methylpropanoic acid, disodium salt_ A) 1,4-Dihydro-4- acid oxo-5- (phenylmethoxy) -2-pyridine-carboxylic, 2-C (1,1-dimethylethoxy) carbonyl J- hydrazide_

61.3 g (0.25 mole) of 1,4-35 dihydro-4-oxo-5- (phenylmethoxy) -2-pyridine-carboxylic acid 78 were suspended in 500 ml of dimethylformamide at at room temperature, then 39.65 g (0.3 mole) of N- (t-butoxycarbonyl) hydrazine, 1.5 g of dimethylaminopyridine and 2 g of 5-N-hydroxybenzo-triazole were added, then the mixture was stirred for 30 minutes at room temperature. Then, while stirring for 30 minutes, 57.7 g (0.28 mole) of dicyclohexylcarbodiimide dissolved in 100 ml of dimethylformamide was added dropwise and the mixture was stirred at room temperature overnight. The precipitate was separated (dicyclohexyl-urea) by filtration and the filtrate was evaporated in vacuo. The residual syrup crystallized during treatment with a dilute solution of sodium bicarbonate. The dried crude product was recrystallized from 2 liters of ethyl acetate to obtain 69.5 g of the title compound at a melting point of 173-175 ° C. A second harvest was obtained after evaporation of the mother liquor; 3.2 g of a product with a melting point of 160-165 ° C.

B) 1,4-Dihydro-5-hydroxy-4-oxo-2-pyridine-carboxylic acid, hydrazide At 0 ° C., 69 g (0.191 mole) of 2- {Z (1,1-dimethylethoxy) was added 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridine-carboxylic acid carbonyl J7 hydrazide to 370 ml of trifluoroacetic acid. The mixture was stirred for one hour at room temperature and then evaporated. The residual syrup was treated with ether to give 68.2 g of the trifluoroacetate (1: 2) salt of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2- acid hydrazide crude pyridine carboxyl as a solid.

The trifluoroacetate salt (1: 2) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -35 2-pyridine-carboxylic acid hydrazide was dissolved in 250 ml of acetonitrile 79 and stirred while cooling for one hour. The crystals were then separated by filtration and resuspended in 600 ml of acetonitrile. 135 ml of bis- (trimethyl-5 silyl) acetamide were added, followed by 28 g of 10% palladium on carbon.

Then, hydrogen was passed through the stirred solution. The hydrogenation was completed after 90 minutes. After filtration, 70 ml of methanol and 2 ml of acetic acid were added. After stirring overnight, by filtration, the crystals formed were separated to obtain 19.4 g of the title compound with a melting point of 290-340 ° C (decomposition).

C) (3S) -Z * t-CCCCCC l "4 -dihydro-4-oxo-5- (phenyl-15 methoxy) -2-pyridinyl„ 7car> konyl JJhydrazino J'sulfonyl J7-amino ^ carbonyl, 7- 2-oxo-3-azetidinyl ^ carbamic acid, phenylmethyl ester_ To a suspension of 5.19 g (0.0236 mole) of (S) - 3-Γ Γ (phenyImethoxy) carbonyl Jamino J-2-20 azetidinone in 160 ml d ethyl acetate, while stirring at room temperature, 2.05 g (0.0236 mole) of chlorosulfonyl isocyanate was added. The mixture was stirred for one hour at room temperature to form a solution of (S) -l- LU (chlo-25 rosulfonyl) amino 27carbonyl 17-3-iT £ T (phenylmethoxy) - carbonyl J7aniino J7-2-azetidinone . The solution was cooled to 0 ° C, 80 ml of dichloromethane was added, then 9.9 ml (0.0707 mol) of triethylamine and a solution of 1,4-dihydro-5-hydroxy acid hydrazide Silylated 4-oxo-2-pyridine-carboxylic acid (obtained from a suspension of 3.99 g (0.0236 mole) 1,4-dihydro-5-hydroxy acid hydrazide -4-oxo-2-pyridine-carboxylic acid in 50 ml of ethyl acetate and 8.75 ml of N-methyl-N- (trimethylsilyl) -35 trifluoroacetamide (8.75 ml = 0.0472 mol)). The mixture was stirred at room temperature overnight, then ice water was added and stirring continued for an additional 30 minutes. The aqueous layer was laminated with ethyl acetate and acidified to a pH of 2.5. The precipitate crystallized after stirring for one hour to give 6.6 g of the title compound.

By evaporation of the ethyl acetate phase and by treatment with petroleum ether, a second crop of 1.4 g of the title compound was obtained.

D) (3S) -3-amino-N- £ 7 ^ "2- £” (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl. Jhydrazino J suifonylJ-Z- 15 oxo- l-azetidine-carboxamide, trifluoroacetate salt (1: 2)

6.6 g (0.0133 mol) of phenylmethyl ester of acid (3S) - £ * 1 -JZZ ü Π UH dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl ^ carbonylZ7- were added. Hydrazino ZI sulfonyl-amino, 7carbonyl „7-2-oxo-3-azetidinyl 27carbamic to a stirred mixture of 22 ml of trifluoroacetic acid and 5.3 ml of thioanisole at room temperature and stirred for one overnight at room temperature. The trifluoroacetic acid was removed in vacuo and the residual syrup was treated with ether to obtain the title compound in quantitative yield.

E) Acid £ "3S (Z) 27-2- £ LL · 1“ (2-amino-4-thiazolyl) -2-ΓΓ1-ΓΓΓΓ2-Γ (1,4-dihydro-5-hydroxy-4-oxo- 2- 30 pyridinyl) carbonyl JJhydrazino 27 tallow onyl ZI amino Z - carbonylJ7-2-oxo-3-azetidinylJ7amino "7-2-oxoethyli-dene ^ amino270XYU-2-methylpropanoic acid, diphenyl-methyl ester __ To a solution of 5.84 g (0.0133 mole) 35 (Z) -2-amino-0 (- £ * £ 2- (diphenylmethoxy) -l, i- 81 dimethyl-2-oxoethoxy, 7imino ^ -4-thiazolacetic in 135 ml of dimethylformamide, 5.6 ml of triethylamine was added and (after cooling to -30 ° C), 3.57 g (0.0133 mole) of diphenyl chlorophosphate was added. The mixture was stirred for hour at -30 ° G, then 3.72 ml of triethylamine was added and then 0.0133 mole of (3S) -3-amino-N- £ * £ 2- £ "(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl 77hy <irazino <7sulfonylJ7 “2-oxo-1-azetidine-10 carboxamide, trifluoroacetate salt (1: 2).

The mixture was stirred at -10 ° C for 2 hours and at 0 ° G for one hour, the solvent was removed in vacuo and the residual syrup was treated with 150 ml of ethyl acetate and 70 ml of ice water 15 by adjusting the pH to 1.5-2 by adding 2N hydrochloric acid. The insoluble material was removed and triturated with ether to obtain 5.3 g of the crude product.

F) Acid £ * 3S (Z) J-2- ΓΖΓΓ1 - (2-amino-4-thiazoly1) -20 2- ΓΓi- ΓΓΓΓ2-Γ (1,4-dihydro-5-hydroxy-4-oxo- 2- pyridinyl) carbonyl Jhydrazino "J tallow onyl J amino J -carbonyl.7-2-oxo-3-azetidinyl ^ aminoJ7-2-oxoethylidene ^ 7- amino ^ 7oxy ^ -2-methylpropanoic acid, disodium salt.

5.3 g (0.0069 mole) of 3 "diphenyl methyl ester 3S (Z) J-2-Crn 1— (2-amino-4-thiazolyl) -2-C 01 -ΖΓ CCC 2- / d (1,4 -dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonylJ7hydrazino J suifonylJ -, aminç ^ carbonylJ7-2-oxo-3-azétidinylJ7amino ^ -2-oxo-ethylidene ^ amino ^ oxy J7-2-methylpropanoic acid in suspension in 10.6 ml of anisole The suspension was cooled to -10 ° C and, with stirring, 53 ml of trifluoroacetic acid were added. the mixture was stirred at this temperature for one hour, then 200 ml of ether was added at -10 ° C to precipitate the trifluoroacetate salt of the free acid of the compound under brick; the yield was 7.3 g.

The raw material was dissolved in a mixture of 100 ml of water and 50 ml of acetone. The pH was adjusted to 5-5.5 and the acetone was removed in vacuo. The residual aqueous solution was lyophilized to obtain 8.1 g of the crude product which was purified by chromatography on "HP-20" eluting with water.

Chromatography gave 1.05 g of the product.

Nuclear magnetic resonance spectrum (DMSOdg): 10 S = 1.40 (s, 3H); 1.42 (s, 3H); 3.25 (dd, 1H); 3.70 (dd, 1H); 5.10 (m, 1H); 6.75 (s, 1H); 7.40 (s, 1H); 7.80 (s, 1H); 11.32 (br s, 1H).

Example 3

Acid £ 3S (Z) J-2-ΓΓΓι - (2-amino-4-thiazolyl) -2-15 CCi-CCZrs-CC (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl , 7amino 7-2-oxo-l-imidazolidinyl Zl ~ sulfonyl ^ amino, 7 carbonyl J7-2-oxo-3-azetidinyl J-amino ^ -2-oxo-ethylidene JJamino Jox.y .7-2-acetic, salt disodium_ 20 A) Acid £ T3S (Z) ^ 7-2- £ * £ £ "l- (2-amino-4-thiazolyl) - 2-Γ C 1-Γ LC H 3-Γ Γ (1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl Zt amino J7 ~ 2-oxo-l-imidazol i dinyl J7 -sulfonyl .7amino Zlcarbonyl U-2-oxo-3-azetidinyl Zl ~ amino 77 ”2- oxo-ethylidene J7aminoJ7oxyJ7-2-acetic, 25 diphenylmethyl ester._ To a solution of 2.06 g (0.005 mol) of (Z) -2-amino-0 acid (- £ 7Π2- (diphenylmethoxy) -2-oxo -ethoxyJ7imino T '- ^ - thiazole-acetic in 100 ml of dimethylformamide, 2.1 ml (0.015 mol) of triethylamine was added, the mixture was cooled to -30 ° C and, with stirring, added 1.1 ml of diphenyl chlorophosphate (0.005 mole) After stirring for one hour at -30 ° C, an additional amount was added at -30 ° C containing 1.4 ml of triethylamine 35 (0.1 mol), then 2.7 g of (3S) -3-amino-N- ÜL 3- 83 in (1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) carbo-nyl J7amino ^ -2-oxo-l-imidazolidinyl „7sulfonyl 7-2-oxo-l-azetidine-carboxamide, trifluoroacetate salt (1: 2).

The reaction mixture was stirred at -10 ° C

for 2 hours and at 0 ° C for one hour. The solvent was removed by evaporation in vacuo, the oily residue was suspended in water and the pH of the suspension was adjusted to 2 by addition of 2N hydrochloric acid. The suspension was stirred for 30 minutes at room temperature, separated by filtration, the solid product was resuspended in water and again separated by filtration. After drying under vacuum over phosphorus pen-15, 5 g of the crude product were obtained.

The material was used in the next step * without further purification.

B) Π 3S (Z) acid J-2-Γ ΖΓΓι - (2-amino-4-thiazolyl) -2-ΓΖΓι-ΓΓ £ Γ3- £ Γ (1,4-dihydro-5-hydroxy-4-oxo- 20 2-pyridinyl) carbonyl J7 amino _7-2-oxo-l-imidazolidinyl J7 - sulfonyl J7 amino 7carbonyl 7-2-oxo-3-azetidinyl ^ amino J7-2-oxo-ethylidene7amino 7oxyJ7-2-acetic, disodium salt A -10 ° C, 5 g of diphenylmethylethyl ester ^ 3S (Z) 7-2-7 C Γ l- (2-amino-4-thia-25 zolyl) -2-7 7 1-7 CCI “3-7 ΖΓ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonylJamino J-2-oxo-1-imidazoli-dinyl J sulfonyl ^ amino J / carbonyl _ / - 2-oxo-3-azetidinyl .7-, aminoJ7-2-oxoethylideneJ7amino "7oxy7 ^ -2-acetic crude suspended in a mixture of 10 ml of anisole and 50 ml of trifluoroacetic acid. The reaction mixture was stirred at -10 ° C for 1 hour, then carefully added 100 ml of ether to precipitate the crude trifluoroacetate salt of the title compound. Yield: 3.7 g. The raw material was dissolved in a mixture of 30 ml of water and 60 ml of acetone 84 and the pH of the mixture was adjusted to 5-5.5 by addition of 0.1N sodium hydroxide. The acetone was evaporated and the aqueous phase was lyophilized to obtain 3.9 g of the crude product. The raw material 5 was purified by chromatography on HP-20. The product was eluted with water (fractions of 10 ml each). The product-containing fractions were lyophilized to give 0.6 g of material which was again subjected to HP-20 chromatography to give 0.25 g of the crude product.

Example 4

Acid C3S (Z) 7-2-CCC 1- (2-amino-4-thiazolyl) -2-ΓΠ-ΓΓΓΓΓ (1,4-dihydro-5-hydroxy-4-oxo-2-pyri-dinyl) methyl J7amino ^ sulfonyl J7amino ^ carbonyl j ^ -2-15 oxo-3-azetidinyl J7amino J7-2-oxoethylidene 7- oxy _7-2-methylpropanoic._ A) 2- (hydroxymethy1) -5- (phenylmethoxy) -4- (1H ) pyridinone

Overnight, a mixture of 9.65 g (41.59 moles) of 2- (hydroxymethyl) -20 5- (phenylmethoxy) -4H-pyran-4-one, 95 ml of ammonia was heated to reflux. concentrated and 20 ml of ethanol. An additional 75 ml of ammonium hydroxide was added, the mixture was heated to reflux for 2 hours and cooled. The brown solid obtained was filtered and washed with water until the detergents were neutral. The crude product was suspended in ethanol, filtered, washed with ethanol and hexane and dried in vacuo. The yield of the title compound was 7.61 g.

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

Under a argon atmosphere, a suspension of 3 g (12.99 millimoles) of 2- (hydroxy-methyl) -5- (phenylmethoxy) -4 (1H) -pyridinone was cooled to 0 °. ml 85 of chloroform and treated with 6.1 ml (83.62 millimoles) of thionyl chloride. In a few minutes, a homogeneous solution was obtained. After stirring for an additional 55 minutes, a cream-colored solid precipitated.

The cooling bath was removed and the mixture was heated to reflux for 45 minutes. The mixture was cooled to 0 ° C and the white precipitate was filtered, washed with chloroform and hexane and dried in vacuo. The yield of the title compound was 3.65 g.

C) 2- (azidomethyl) -5- (phenylmethoxy) -4 (1H) -pyridinone For 3.5 days, under an argon atmosphere and at room temperature, a mixture of 3.59 g was stirred ( 12.54 millimoles) of 2- (chloromethyl) -5- (phenylmethoxy) -4 (1H) -pyridinone hydrochloride, 4.08 g (62.7 millimoles) sodium azide and 2.19 ml ( 12.54 millimoles) of diisopropylethylamine in 70 ml of dimethylformamide. An additional 4.08 g of sodium azide was added and the mixture was heated to 45-50 ° C for 2 hours. After cooling, the reaction mixture was poured into 500 ml of water to obtain an insoluble white solid. The pH of the over-swimming liquid was lowered from 8.5 to 7.5 with dilute hydrochloric acid and the white solid was filtered. After washing with water, acetone and hexane, the solid was dried in vacuo. The yield of the title compound was 2.81 g.

D) 2- (aminomethyl) -4- (phenylmethoxy) -4 (1H) -pyridinone.

For 6 hours, at room temperature and under a hydrogen atmosphere, a mixture of 2.03 g (7.93 millimoles) of 2- (azidomethyl) - 5- (phenylmethoxy) -4 (1H) - was stirred. pyridinone and 200 mg of platinum oxide in 100 ml of dimethylformamide. The catalyst was removed by filtration and the solution was concentrated in vacuo to 1.5 g (yield: 82%) of the title compound as a gray powder.

„5 E) Acid (3S) - c ir nenne 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl ^ methylCamino ^ sulfonyl J-amino ^ carbonyl <J-2-oxo-3-azetidinyl ^ carbamic, phenylmethyl ester_ To a stirred suspension of 2.330 g (10.13 10 millimoles) of 2- (aminomethyl) -5- (phenylmethoxy) -4 (1H) -pyridinone in 60 ml of ethyl acetate, added 3.76 ml (20.26 millimoles) of N-methyl-N- (trimethyl-silyl) trifluoroacetamide. The resulting solution was stirred for 30 minutes at room temperature, then cooled to 0 ° C. At the same time, to a stirred suspension of 2.228 g (10.13 millimoles) of (S) -3-ΓΖΓ (phenylmethoxy) carbonyl ^ amino J7-2-azeti-dinone in 60 ml of ethyl acetate, added 882 µl (10.13 mmol) of 20-chlorosulfonyl isocyanate. The solution obtained was stirred for 30 minutes at room temperature, cooled to 0 ° C and finally, treated with 4.23 ml (30.39 millimoles) of triethylamine, then with the solution of 2- (aminome thy1) -5- (phenylmethoxy) -4 (1H) -pyridinone 25 silylated described above. The mixture was stirred for 2 days at room temperature. The mixture was concentrated in vacuo, the residue was dissolved in a 40:60 mixture of CH 4 CN / water and the pH was lowered to 2.9, after which a thick oil separated. Upon cooling to 5 ° C, the oil solidified. The solid was separated, washed four times with water and dried in vacuo to obtain 3.4 g of the crude product. The crude product was dissolved in a minimum volume of dimethylformamide 35 and loaded into a column (1 L) of HP-20 resin.

87

The column was eluted with a stepped acetone / water gradient. The desired material was eluted with about 65% acetone. The fractions concerned were combined and lyophilized to give 2.69 g of the title compound.

F) Acid £ 3S (z) J-2-ΓΓΓ 1 “(2-amino-4-thiazolyl) -2-CCI- HCC ce (1,4-dihydro-5-hydroxy-4-oxo-2-pyridiny1) me thy1 £ amino Jsulfony1Jamino £ c arbony1J -2-oxo-3-azetidinyl £ amino ^ 7-2-oxoethylidene J amino JJ-10 oxy .J-2-methylpropanoic, diphenylmethyl ester (as a mixture of monopotassium salts and monotriethylammonic) _

Under a hydrogen atmosphere, a mixture of 912 mg (1.64 millimole) of 15-phenyl methyl ester of acid (3S) was stirred - £ * 1- ££££££ 1,4-dihydro - 4-ΟΧΟ-5- (phenylmé thoxy) -2-pyridinyl ^ m thyl £ amino J -suif onÿl £ amino J7carbonyl I7-2-oxo-3-azétidinyl ^ carbamique, of 625 mg (3.28 millimoles) p-toluenesulfonic acid to one molecule of water and 190 mg of 10% palladium-on-carbon in 16 ml of dimethylformamide until consumption (about 3 hours) of 3.28 millimoles (73 ml) d 'hydrogen.

To a stirred solution of 846 mg (1.804 millimole) of (Z) -2-amino-0 (- £ £ 2- (diphenylmethoxy) -25 1,1-dimethyl-2-oxoethoxy J7iminoJ7-4-thiazole-acetic acid in 16 ml of dimethylformamide at -20 ° C., 374 yal (1.804 millimole) of diphenyl chlorophosphate were added, then 450yul (3.28 millimoles) of triethylamine.

The solution was stirred for one hour at -20 ° C, after which the above described mixture of (3S) acid phenylmethyl ester - £ 1-Γ £ CC £ C 1,4-dihydro was added -4-oxo-5- (phenylmethoxy) -2-pyridinyl £ methyl £ -amino £ suifony1_7 amino £ carbonyl _7-2-oxo-3-azetidinyl £ -carbonamic hydrogenolysed. The resulting mixture was stirred at -20 ° C for one hour, then at 5 ° C overnight.

88

The catalyst was removed by filtration, then the volatiles were removed in vacuo and the oil obtained was dissolved in a minimum volume of acetone / water (75-25, pH 5.2) and added dropwise 5 dropwise to a stirred suspension of 20 ml of "Dowex 50x2-400 (K +)" (Dowex 50x2-400: gel of styrene / divinylbenzene copolymer with SO 4 groups attached, sold by "Dow Chemical Co.") in a 35:65 mixture of acetone and water. After 40 minutes, the mixture was filtered and the filtrate was lyophilized to obtain 2.1 g of a solid. The solid was dissolved in a minimum amount of a 40:60 mixture of acetonitrile and water (pH 5.6) and loaded into a column (800 ml) of HP-20 resin, eluting with a stepped gradient of acetonitrile and water. The desired material was eluted with about 30% acetonitrile. The affected fractions were combined and lyophilized to obtain the impure title compound (254 mg).

20 G) Acid £ 3S (Z) J-2- £ £ £ l- (2-amino-4-thiazolyl) -2-ΖΓΓι-ΓΓΓΓΓ (ι, 4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) methyl ^ amino J ^ sulfonyl JJamino „Jcarbonyl J-2-oxo-3-azetidinyl ^ 7amino J7-2-oxoethylidene ^ Jarnino £} -oxy] 7-2-methylpropanoic_ 4.7 ml was added dropwise of trifluoroacetic acid to a stirred suspension of the £ 3S (Z) J7-2- ΓΓΙ1- (2-amino-4-thiazolyl) -2- ΓΓ1-ΓΓΓΓΓ (1,4-dihydro-) diphenylmethyl ester of £ 3S (Z) acid 5-hydroxy-4-oxo-2-pyridinyl) methyl J / aminoJ7sulfonylJ-30 amino ^ carbonyl J7-2-oxo-3-azetidinyl _7amino J-2-oxo-ethylideneJ7amino ^ 7oxy ^ 7-2-impure methylpropanoic (mixture of monopotassium and mono-triethylammonic salts) (131 mg) in 3 ml of dichloromethane and 0.3 ml of anisole at 0 ° C. After stirring for 45 minutes at 5 ° C, 2 ml of toluene 89 was added and the volatiles were removed in vacuo. The oil obtained was washed with hexane (3 x 4 ml) and triturated until a solid formed with 10 ml of ether. The solid product was washed 5 times with ether (10 ml) and dried in vacuo. The above reaction and treatment was repeated. above on 166 mg of diphenylmethyl ester of iT3S (Z) J-2-ΖΓ Π ü 1 - (2-amino-4-thiazolyl) -2- CL i-ΓΓΓΓ f (1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl) -10 methyl27 ^ 1 ^ 0.7sulfonyl 27amino 2 / carbonyl 27-2-oxo-3- azetidinyl "Jamino, 7-2-oxoethylidene Jaminooxy" J-2-methylpropanoic (mixture of monopotassium and monotriethylammonium salts). The crude products were combined, dissolved in 2 ml of a 40:60 mixture of CH 2 CN / water (pH 2.5) and subjected to chromatography in a column (200 ml) of HP-20 / resin using a gradient of acetonitrile and water.

The desired material was eluted with a 20:80 mixture of CH ^ CN / water. The fractions concerned were combined and lyophilized to obtain 103 mg of acid £ * 3S (Z) J-2-CC L l- (2-amino-4-thiazolyl) -2- ΓΠ-ΓΓΓΓΓ (1 , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl J amino ^ sulfonyl 27 amino. Jcarbonyl 27-2-oxo-3-azetidinyl 27amino, 7-2-oxoethylidene 27 amino 27oxy 27-2- 25 'methylpropanoic acid in the form of a white solid.

Example 5

Acid JT3S (Z) 27-2-2ΓCHl- (2-amino-4-thiazolyl) -2-ΓΓ1-ΓΓΓΓ2-ΓΓ2-Γ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridiny1) carbonyl2 / hydrazino 27carbonyl_7hydrazino J -30 sulfonyl J amino ^ carbonyl 27-2-oxo-3-aze tidinyl Z7 - amino 27-2-oxo-ethylidene. 7amino J oxy, 27-2-methylpropanoic acid, disodium salt_ A) 2 -iC * ΖΓ (4-methoxyphenyl) methoxy 27carbonyl J7hydrazide 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridine-35 carboxylic acid 90

A solution of 4.54 g (0.022 mole) of dicyclohexylcarbodiimide in 25 ml of dry dimethylformamide was added to a stirred suspension of 4.90 g (0.020 mole) of 1,4-dihydro-4-oxo-5- acid 5 (phenylmethoxy) -2-pyridine-carboxylic, 4.50 g (0.022 mole) 4-methoxybenzyl carbazate, 0.12 g (1 millimole) 4-dimethylamino-pyridine and 0.155 g (1 millimole) 1-hydroxybenzo-triazole hydrate in 25 ml of dry dimethylformamide at room temperature and stirring continued overnight. The precipitate was removed by filtration and the filtrate was evaporated in vacuo. The residue was solidified by stirring with ether and aqueous sodium bicarbonate, then the solid was collected, washed with water and finally dried in vacuo. The crude material (8.14 g) was extracted in a Soxhlet apparatus with 800 ml of CHClg (7 hours). 5.70 g (67%) of 2- Γ Γ (4-methoxy-phenyl) methoxy ^ 7carbonylJ7 acid hydrazide 1,4-20 dihydro-4-oxo-5- (phenylmethoxy) -2-pyridine-carboxylic acid pure crystallized directly from the cold CHClg extract and an additional impure amount (1.5 g, 18%) of the title compound was obtained by evaporation of the CHC1 solution

O

25 under vacuum; melting point: 174.5-178 ° C.

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

A solution at -10 ° C of 3.81 ml (35.04 millimoles) of anisole in 38 ml of tri-fluoracetic acid was added to an ice-cold suspension of 3.71 g (8.76 millimoles) of 2-ΓΓ (4-methoxyphenyl) methoxy J-carbonyl "Jhydrazide of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -l-pyridine-carboxylic acid in 15 ml of dry dichloromethane. After stirring at 0 ° C for 35 minutes, the solution was evaporated in vacuo to leave the title compound as a solid which was stirred with a few milliliters of dry ether, which was collected by wringing and that dried in vacuo Yield: 3.25 g (99%), melting point: 173-175 ° C (decomposition).

C) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyri-dine-carboxylic acid, hydrazide.

“R ..........— -” '““ ““ “

3.84 ml (19.64 millimoles) of N-methyl-N- (trimethylsilyl) trifluoracetamide was added to a suspension of 3.19 g (8.55 millimoles) of 1,4-dihydro-4- acid oxo-5- (phenylmethoxy) -2-pyridine-carboxyli-que, hydrazide, trifluoroacetate salt (1: 2) in 35 ml of dry acetonitrile and stirring was continued for 30 minutes at room temperature. After evaporation in vacuo, the residue was taken up in ether, then 1 ml of methanol was added dropwise. The precipitate was collected by wringing, washed with ether and petroleum ether and dried in vacuo to give 2.05 g (92%) of the title compound (dot melting point: 204-208 ° C, decomposition).

D) 1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridine-carboxylic acid, 2- / ΓC 2- (phenylmethoxy) carbonyl I7hydra-zino ^ carbonyl ^ hydrazide_ While cooling, we added 11.69 ml (0.060 mole) of N-methyl-N-trimethylsilyltrifluor-acetamide to a suspension of 5.19 g (0.020 mole) of 1,4-dihydro-4-oxo-5- (phenylmethoxy) acid hydrazide ) -2-pyridine-carboxylic acid in 20 ml of dry acetonitrile and stirring was continued for 30 minutes at room temperature. The clear solution was evaporated in vacuo and the residue was redissolved in 30 ml of dry dichloromethane. This solution was then added dropwise to a stirred solution of 4.57 g (0.020 mole) of 92 Ο

PhCHgOCNHNHCOCl (J. Gante, Chem. Ber. 97, 2551 (1964)) in 60 ml of dichloromethane at 0-5 ° C. After stirring at this temperature for 2.5 hours, the solution was evaporated in vacuo and the solid foam was redissolved in 20 ml of methanol. By evaporation in vacuo, the title compound was obtained as a solid foam which became crystalline upon stirring with dry ether. Yield: 10.87 g (98%); melting point: above 120 ° C (decomposition).

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

A solution of 4.02 g (8.9 15 millimoles) of hydrogenated 1,4-dihydro-4-oxo-5- (phenyl-methoxy) -2-pyridine-carboxylic acid, 2-ΓΓ2 - (phenyl) was hydrogenated. -methoxy) carbonyl ^ hydrazinoJ / carbonylJ7hydrazide in 50 ml of methanol containing 2.94 ml (35.6 millimoles) of concentrated hydrochloric acid in the presence of 0.4 20 g of palladium on carbon (10%) for 10 minutes. The catalyst was filtered off and the solvent was removed by vacuum distillation to obtain the title compound as a solid (2.58 g) which was stirred with a few milliliters of dry ether, then which was collected by wringing and dried under vacuum. Yield: 2.47 g (92%); melting point: 235-236 ° C (decomposition).

F) Acid (3S) -Γ1-ΓΖΓΓΖΓ2-ΓΖΓ2-Γ (1,4-dihydro-5 ~ hydroxy-4-oxo-2-pyridinyl) carbonyl_7hydrazino, 7carbo-nyl J7hydrazino ^ sulfonyl J7aminoJ7carbonyl I7-2-oxo-3 - azetidinyl.Jcarbamic, phenylmethyl ester_

4.86 ml (25 millimoles) of N-methyl-N-trimethyl-silyl-trifluoroacetamide was added to a suspension of 1.5 g (5 millimoles) of 1,4-dihydro-35 5-hydroxy-4 acid -oxo-2-pyridine-carboxylic, 2- (hydrazino-93 carbonyl) hydrazide, dihydrochloride in 20 ml of dry acetonitrile. After stirring for 45 minutes at room temperature, the clear solution was evaporated in vacuo and the residue was dissolved in 5 ml of dry ethyl acetate (solution A).

To a suspension of 1.10 g (5 millimoles) of (3) -3- / 7 ^ Ph®nylmethoxy) carbonyl ^ amino dinone in 40 ml of dry ethyl acetate, 0.45 ml was added (5 millimoles) of chlorosulfonyl isocyanate with stirring and the mixture was stirred for one hour at room temperature and then cooled to 0 ° C. After adding 10 ml of dry dichloromethane and 2.09 ml (15 millimoles) of triethylamine, solution A was poured dropwise while stirring at 0 ° C. After stirring overnight at 0 ° G, the reaction mixture was poured into ice water and the organic layer was separated. By acidification of the aqueous phase to a pH of 2 by adding 1N hydrochloric acid, the compound 20 was obtained under the heading in the form of a sticky precipitate which was collected by wringing, which was washed with water and dried under vacuum. Yield: 1.76 g (64%).

G) (3S) -3-amino-N- ΓΓ2-ce 2- £ “(1,4-dihydro-5-hydroxy-25 4-oxo-2-pyridiny1J7carbonylJ7hydrazino ^ carbonylJ- hydrazino J suifonylJ-2-oxo-l -azetidine-carboxamide, trifluoroacetate salt (1: 2) __ At 0 ° C, 1.73 g (3.1 millimoles) of phenylmethyl ester of acid (3S) was added - £ * \ - ΠΠC Π 2- 30 Γ Γ 2-C (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl ^ hydrazino ^ 7carbonyl J7hydrazino J7 tallow onyl 37 “amino ^ 7carbonyl | 7-2-oxo-3-azetidinyl ^ carbamic to a mixture of 5.13 ml of trifluoroacetic acid and 1.21 ml of thioanisole After stirring overnight at room temperature, the solution 94 was evaporated in vacuo and the residue was stirred with dry dichloromethane The precipitate was collected by wringing, washed with dichloromethane and dried in vacuo to give 1.78 g (88%) of the compound;

H) C 3S (Z) acid 7-2- £ * £ £ * 1- (2-amino-4-thiazolyl) -; 2-Γ C ^ -CC CC 2-ΖΓ Γ2-Γ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl J / hydrazino ^ carbonyl £ hydra-zino ^ sulfonyl "Jamino .Jcarbonyl J7 -2-oxo-3-azetidinyl "J-10 amino_7-2-oxoethylidene j [amino oxy J7-2-methylpropanoic, diphenylmethyl ester_

In a solution at -30 ° C of 1.10 g (2.5 millimoles) of (Z) -2-amino-0 (- £ * (2-diphenyl-methoxy) -1, l-dimethyl-2 acid -oxoethoxy 7imino 7-4-thiazole-15 acetic in 22 ml of dry dimethylformamide, 1.05 ml (7.5 millimoles) of triethylamine was added, then 0.53 ml (2.5 millimoles) of diphen chlorophosphate After stirring at -30 ° C for one hour, 1.05 ml (7.5 millimoles) of triethylamine was poured in, and 1.62 g (2.5 millimoles) of (3S) was added ) -3-amino-N- £ Γ2-ΓΓ2-Γ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl J7carbonylJ7hydrazino J7carbonyl j [-hydrazino £ sulfonylJ7-2-oxo-l-azetidine-carboxamide , trifluoroacetate salt (1: 2) The mixture was stirred for 2 hours at -10 ° C and an additional hour at 0 ° C. The solvent was removed in vacuo and the residue was taken up in a few milliliters of ethyl acetate and ice water. The pH of the mixture was adjusted to 2 by the addition of dilute hydrochloric acid. The insoluble material was collected by spin drying. t it was stirred with a few milliliters of ethyl acetate until it became crystalline to obtain, after drying under vacuum, 1.72 g (82%) of the title compound.

95 I) Acid £ * 3S (Z) J7-2- £ '£ “£' l- (2-amino-4-thiazolyl) -z-Cni-nCCLz-CCz-t: (1,4-dihydro-5 -hydroxy ~ 4-oxo-2-pyridinyl) carbonyl ^ 7hydrazino J7carb ° nyl "IZ ^ ydra-zino_7 suif onyl J amino JJcarbonyl .J-2-oxo-3-azétidi-5 nyl] | 7 aminoZ7-2-oxoethylidene amino Joxy ^ J-2-methylpropanoic acid, disodium salt_ To a suspension of 1.68 g (2 millimoles) of diphenylmethyl acid ester, £ * 3S (Z) J-2-rrri- (2-amino-4- thiazolyl) -2-ΖΓ ΣΓ1 — ΖΓ OC Π. 2- £ * ΖΓ 2- Ç (1,4-10 dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl ^ 7hydra- z ino J c arbony 1J7 hydr az ino “/ sul f ony 1J amino J7 c arbo-nyl J7-2-oxo-3-azetidinyl “7 amino^7-2-oxoethylidene" J-amino 37oxyJ7-2-crude methylpropanoic in 3 ml of dry dichloromethane, 2 ml of anisole were added, then 15 ml trifluoroacetic acid at -10 ° C. After stirring at 0 ° C for 10 minutes, the solvent was removed in vacuo at 0-5 ° C. The residue was taken up in ice water and ether and the pH was adjusted to 6 by addition of dilute sodium hydroxide (1%).

The organic phase and the insoluble material were separated (0.38 g) and the aqueous phase was lyophilized (2.66 g). The lyophilization residue was purified on the "XAD-2" (styrene-divinylbenzene macroreticular) resin (eluting with water) to obtain, during lyophilization, 0.25 g (17%) of the compound under section in the form of a colorless powder (melting point above 213 ° C, decomposition).

Example 6

Acid ΖΓ3S- £ 3 C ((Z), 4ß J7 J-2- £ "ΓΖΓΜ 2-amino-4-thia-30 zolyl) -2- £ f £ 71-Z" L · Π Π 2-ΖΓ (1 , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl ^, hydrazinoJ7sulf'onyl-7aminoJ7-carbonylJ7 ~ 4-methyl-2-oxo-3-azetidinylJ7amjLno ^ -2-oxo-ethylidene ^? AminoJ7oxy ^ 7-2-methylpropionic acid, disodium salt_ 96 A) (3S-trans) -Ç1-Z * £ acid. CH 2- £ "Π1» 4-dihydro-4- oxo-5-hydroxy-2-pyridinyl J ^ carbonyl ^ hydrazino J-sulfonyljjamino ^ carbonyl ^ 7-4-methyl-2-oxo-3-azéti-dinylJ7carbamic, ester phenylmethyl_ 5 A suspension of 2.34 g of (3S-trans) - (4-methyl-2-oxo-3-azetidinyl) carbamic phenyl- methyl ester in 50 ml of dry ethyl acetate , 1.41 g of chlorosulfonyl isocyanate was added. After stirring for one hour at room temperature, a clear solution was formed (solution A).

To a suspension of 1.70 g of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridine-carbo-xylic acid hydrazide in 50 ml of dry ethyl acetate was added 15 6 g of N-methyl-N- (trimethylsilyl) trifluoroacetamide.

After stirring at 50 ° C for one hour, a clear solution was formed (solution B).

After cooling to -10 ° C, solution B was added to solution A and the mixture was stirred overnight at room temperature. While cooling to -15 °, 3 g of triethylamine were added, then 150 ml of ice water. After stirring for one hour at 0 °, the organic phase was washed with 50 ml of water. The combined aqueous phases were adjusted to pH 2 with IN HCl and extracted three times with 100 ml of ethyl acetate. The combined organic phases were dried and the solvent was evaporated to give 3.64 g of the title compound.

B) (3S-trans) -3-amino-NZ "ΖΓ 2-27 (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonylJ7hydrazino ^ 7 sulfonyl.7-4- methyl-2 -oxo-l-azetidine-carboxamide, trifluoraceous-tate salt (1: 2) _

A 3.5 g of phenylmethyl ester of acid (3S-trans) - £ * 1- Γ 2Γ ΓΓ2-ΓΓ 1,4-dihydro-4-oxo-5-35 hydroxy-2-pyridinylJcarbonyl j ^ hydrazino JsulfonylJ

97 amino ^ carbonyl 3f-4-methyl-2-oxo-3-azetidinyl carbonic acid in 20 ml of thioanisole, 50 ml of trifluoroacetic acid was added at room temperature, then the reaction mixture was stirred for 13. 5 hours. After adding 100 ml of ether, 3.2 g of a crude precipitate were obtained. This precipitate was then stirred for one hour in 50 ml of a 1: 1 mixture of isopropanol and methylene chloride to obtain 2.21 g of the title compound.

10 C) Acid ^ S- ^ 73 0 ((Z), 4ßJ JCΠ'Li 2-amino-4-thiazolyl) -2- £ * Γ ^ -CCC C 2-ΖΓ (1,4-dihydro-5-hydroxy - 4-oxo-2-pyridinyl) carbonyl J ^ hydrazino ^ sulfonylJ-amino ^ 7carbonyl 27-4-methyl-2-oxo-3-azetidinylJamino J-2-oxoethylidene. 7 amino 7 oxy 7-2-methylprop ionic, 15 diphenylmethyl ester_ To a solution of 1.8 g of (Z) -2-amino acid - "- ΓΓ 2-diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy" J-imino „7-4-thiazole-acetic and 1.2 g of triethylamine in 30 ml of dimethylformamide, at -30 °, 2.1 g of diphenyl chlorophosphate were added. After stirring at -30 ° for 45 minutes, 1.95 g were added of (3S-trans) -3-amino-N- ΠΓ 2-Γ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl ^ hydrazino "Jsuifonyl" J-4 ~ methyl-2- oxo-1-azetidine-carboxamide, trifluoraceous salt-25 (1: 2) in 10 ml of dimethylformamide, then 0.8 g of triethylamine After stirring at -10 ° C for 2 hours and at 0 ° C for one hour , the dimethylformamide was removed in vacuo, then the residue was stirred with 250 ml ethyl acetate and 400 ml of ice water.

The aqueous phase was adjusted to pH 1.5 with 2N HCl and extracted twice with 200 ml portions of ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to give 1.3 g of the title compound in the raw state.

98 D) Acid 73S-73 0 ((Z), 4ß 7 7-2-777 l- (2 — amino-4— thiazolyl) -2- ΓΓ1-ΓΓΓΓ2-Γ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl7hydrazino7 tallow onylJ-c amino Jcarbonyl7 “4-methyl-2-oxo-3-azetidinyl J- = 5 amino 7-2-oxoethylidene _7amino_7oxy 7-2-methylpropionic, disodium salt_ To a solution of 1.2 g of diphenyl- v "methyl ester 73S-73 OC (Z), 4ß 7 7-2-7 7 71- (2-amino-4-thiazolyl) -2-7 7 1 -7 7 7 72 “7 (1,4-dihydro-10 5-hydroxy-4-oxo-2-pyridinyl) carbonyl7hydrazino 7- sulf onyl J amino 7c3-rt) onyl7” 4 “m®'fchyl-2-oxo -3-azetidinyl 7 amino7-2-oxoethylidene 7amino7oxy 7-2-methylpropionic in a mixture of 10 ml of methylene chloride and 15 ml of anisole, 30 ml of trifluoroacetic acid was added to -5 ° C. After stirring for 30 minutes, 100 ml of ether were added to obtain 0.8 g of a precipitate, this precipitate was suspended in 20 ml of water and the pH was adjusted to 6 , 5 with sodium bicarbonate. The clear solution was then subjected to a chr omatography on the resin "XAD-2" with water as eluent to obtain 0.28 g of the title compound in the pure state.

Example 7

Acid 73S (Z) Jl-77 7 1 ~ (2-amino-4-thiazolyl) -2-25 77 i-7 77 7 3-7 7 (1,4-dihydro-5-hydroxy-4-oxo-2 - pyridinyl) carbonyl 7 aminol7-2-oxo-l-imidazolidinyl7-sulfonyl ^ aniino "JearbonylJ7-2-oxo-3-azetidinyl" J-amino 7-2-oxoethylidene 7amino 7oxy 7cyclo Pentane-carboxylic, disodium salt_ 30 A) Acid 73S (Z) 7-1-7 7 7l- (2-amino-4-thiazolyl) -: 2-771-77773-77 (1,4-dihydro-5-hydroxy-4-oxo 2-pyridinyl) carbonyl7amino J-2-oxo-l-imidazolidinyl7-suif onyl 7amino Jcarbonyl 7-2-oxo-3-azetidinyl J-amino 7 “2-oxo-ethylidene 7amin0 70Xy 7cycl ° Pen'tane“ 35 carboxylic, diphenyl methyl ester_ 99 To one suspension of 3.9 g (8.3 millimoles) of (Z) -2-amino- <x-rrr 1- (diphenylmethoxy) carbonyl Jcyclopentyl J oxy Jimino 'JA-thiazole-acetic acid in 100 ml of dry acetonitrile , 3.5 ml (25 millimoles) of triethylamine was added to form a clear solution. After cooling to -30 ° C, 1.8 ml (8.3 millimoles) of diphenyl chlorophosphate was added and the mixture was stirred at -30 ° C for one hour (solution A).

At the same time, 4.5 g (8.3 milli moles) of (3S) -3-amino-N- ^ T ^ 3- £ * £ (1,4-dihydro-5-hydroxy-4) -oxo-2-pyridinyl) carbonylJamino J-2-oxo- 1- imidazolidinyl ^ sulfonyl J7-2-oxo-1-azetidine-carbo-xamide, trifluoroacetate salt (1: 2) suspended in 15 100 ml of acetate d 'dry ethyl. Then, 7.2 ml of bis- (trimethylsilyl) acetamide was added at room temperature to obtain a clear solution after 5 minutes. After stirring for one hour, the solution was cooled to 0 ° (solution B).

While stirring, solution B was added dropwise to solution A at -30 ° for 10 minutes. The mixture was stirred for one hour at -10 ° C and for 1.5 hours at 0 °. The volatiles were evaporated and the residue was triturated with water.

The residue solidified and the solids were collected, then resuspended in water to a pH of about 2. After stirring for 30 minutes, the solid was collected and dried to obtain 12 g of the compound under heading in the raw state.

B) Acid “3S (Z) 7-i-LLC 1- (2-amino-4-thiazolyl) -; 2-ΓΓ1-7 7 77 3-ΓΖΓ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl ^ amino J7-2-oxo-l-imidazolidinyl ^ -sulfonyl J1 amino "7carbonyl J7- 2-oxo-3-azetidinyl - amino ^ -2-oxo-ethylideneJ | 7aniino 7 ° XY 7 ° ycloPea'fcane- carboxylic, disodium salt • 100

We put 12 g of diphenylmethyl ester of Z73S (Z) J-1-ΓΓΓ 1- (2-amino-4-thiazolyl) -2-ΓΓ1-ΓΓΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl) carbonyl JJ3 ™! 110 ^ -2-oxo-l-imidazolidi-5 nyl ^ / rsulfonyl127aminoJ7carbonyl] 7-2-oxo-3-azetidinyl-7-aminoJ7 ~ 2-oxoethylidene ^ amino J7oxy ^ crude cyclopentane-carboxylic suspension in 20 ml of anisole and, while cooling to -10 ° C, 100 ml of trifluoroacetic acid was added. The mixture was stirred 10 at -10 ° C for one hour and 300 ml of ether was added at -10 ° to obtain a precipitate. After stirring for one hour, the precipitate was separated by filtration to obtain 5.7 g of material. This material was dissolved in a mixture of 30 ml of water and 60 ml of acetone and the pH of the solution was adjusted to 5.5 by adding 0.1N NaOH at 0 ° while stirring. The acetone was evaporated in vacuo and the aqueous solution was lyophilized to obtain 5.7 g; a solid residue. This residue was subjected to "HP-20" chromatography (eluting with water) to obtain 1.69 g (27%) of the title compound in pure form.

Nuclear magnetic resonance spectrum H (DMSO-d6 + CFgCOOH): 6 = 1.67 (s, 4H); 2.07 (2.4H); 3.65 (t, 2H); 3.75 (dd, 1H); 3.97 (dd, 1H); 4.07 (t, 2H); 5.07 (dd, 1H); 7.00 (s, 1H); 7.67 (s, 1H); 8.07 (s, 1H); parts per million.

Example 8

Acid £ “3S (Z) J7-2-Z" Z "£ ~ 1- (2-amino-4-thiazolyl) -2-30 ΓΓι- ££ ΓΓ 3-Γ (1,4-dihydro-5-hydroxy -4-oxo-2- pyridinyl) methyl J7-2-oxo-l-imidazolidinyl ^ sulfonylJ- t "amino Z7 carbonylO-2-oxo-3-azetidinyl" 7 amino ^ -2-oxo-ethylideneZ7cmiino Z7oxy I7-2-methylpropanoic acid , disodium salt 35 _ 101 A) 2- (azidomethyl) -5- (phenylmethoxy) -l- (phenylmethyl) - 4 (1H) pyridinone_ To a suspension of 2 g (6 millimoles) of 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -5 4 (1H) -pyridinone in -20 ml of acetonitrile, 3.9 g (60 millimoles) of sodium azide and 0.1 g of 18- were added crown-6 and the mixture was heated to reflux for 4 hours. The salts were filtered by suction and the filtrate was evaporated in vacuo.

The residue was purified by column chromatography on silica gel (ethyl acetate / methanol, 8: 2) to obtain 1.86 g of the title compound under a melting point of 120 ° C.

B) 2- (aminomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) - 15 4 (1H) -pyridinone_

1 g (2.89 millimoles) of 2- (azidomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4 (1H) -pyridinone was dissolved in 50 ml of methanol and 0.10 g of d 'platinum oxide. Hydrogen was bubbled through the mixture for 30 minutes and the catalyst was filtered by spinning on "Hyflo". The filtrate was evaporated in vacuo and the oily residue was triturated with ether to obtain the title compound in crystalline form (0.89 g) having a melting point of 207 ° C.

C) 2- £££] £ (2-chlorethyl) amino 7carbonyl Jamino J- methyl J-5- (phenylmethoxy) -2- (phenylmethyl) -4 (1H) -pyridinone_

M

To a suspension of 48 g (0.15 mol) of 2- (aininomethyl) -5- (phenylmethoxy) -l- (phenylmethyl) - 4 (1H) -pyridinone in 1.5 l of ethyl acetate, 12.8 ml (0.15 mole) of 2-chloro-methyl isocyanate was added. The mixture was stirred overnight at room temperature, the product was filtered by suction, washed with ethyl acetate and dried in vacuo to give 59, 6 g of the compound under the heading of a melting point of 130 ° C.

D) 2- / I (2-oxo ~ l-imidazolidinyl) methyl, 7-5- (phenyl-, methoxy) -l- (phenylmethyl) -4 (1H) -pyridinone_ 5 A solution of 7.29 g (0.13 mole) of potassium hydroxide in 500 ml of ethanol to a mixture of 60.8 g (0.13 mole) of 2- £ C (2-chlorethyl) amino. ^ Carbonyl Camino J-me thylJ7-5- (phenylmethoxy) -2- (phenylmethyl) -4 (1H) -10 pyridinone and 1.3 l of ethanol. The reaction mixture was heated to reflux for 3 hours and the solvent was evaporated in vacuo. The residue was purified by column chromatography on silica gel using a 7: 3 mixture of ethyl acetate and methanol as eluent to give 23.1 g of a product which was further purified by recrystallization from acetonitrile to obtain 17 g of the title compound having a melting point of 190 ° C (decomposition).

E) 5-hydroxy-2-ZT (2-oxo-1-imidazolidinyl) methyl J7-4 (1H) -pyridinone, p-toluene sulfonate salt_ To a solution of 4.98 g (12.8 millimoles) of 2 - £ * (2-oxo-1-imidazolidinyl) methyl J ^ -5- (phenyl-methoxy) -1- (phenylmethyl) -4 (1H) -pyridinone in 90 25 ml of dimethylformamide, 4.86 g were added (25.6 millimoles) of p-toluene sulfonic acid to one molecule of water and 1 g of palladium on carbon, then hydrogen was bubbled through the mixture for 30 minutes. The catalyst was filtered by wringing and the filtrate was evaporated in vacuo. The residue was triturated with dichloromethane and ether and the product was filtered by wringing to give 4.12 g of the title compound having a melting point of 195 ° C.

103 F) 5-hydroxy-2- £ “(2-oxo-1-imidazolidinyl) methylJ- 4 (1H) pyridinone_

4 g (10.5 millimoles) of 5-hydroxy-2- £ (2-oxo-1-imidazolidinyl) methyl J7-4 (1H) -5 pyridinone, p-toluene sulfonate salt, were dissolved in 50 ml of water and the pH was adjusted to 6.5 by addition of 2N sodium hydroxide. The precipitate was filtered by wringing, washed with water and dried in vacuo to give 1.5 g of the title compound 10 having a melting point of 280 ° C (decomposition).

G) Acid (S) (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl ^ 7-2-oxo-l-imidazolidinyl j [-sulfonyl ^ amino J7carbonyl ^ -2-oxo-3 7carbamic azetidinyl, phenylmethyl ester. 1.10 g (5 millimoles) of (S) -3- r ”^ * (phenylmethoxy) carbonyl. 7amino.7-2-azetidinone was added. suspended in 20 ml of dry ethyl acetate and 0.44 ml (5 millimoles) of isocyanate was added; chlorosulfonyl. The mixture was stirred at room temperature for one hour (solution a).

To a suspension of 1.04 g (5 millimoles) of 5-hydroxy-2- £ * (2-oxo-1-imidazolidinyl) methyl J7-4 (1H) -pyridinone in 10 ml of dry ethyl acetate, added 3.70 ml (20 millimoles) of N-methyl-N-25 (trimethylsilyl) -trifluoroacetamide and the mixture was heated to 60 ° C. The clear solution obtained was evaporated in vacuo at 60 ° C and the residue was dissolved in 10 ml of dry ethyl acetate (solution b).

Solution (b) was added to solution (a) and the reaction mixture was stirred overnight at room temperature. The solvent was removed in vacuo and the residue was triturated with ether to obtain 2.91 g of the title compound having a melting point of 180 ° C (decomposition).

104 H) (S) -3-amino-N- ^ '£ * 3- £ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl J7-2-oxo-l-imidazolidinyl j / ~ sulfonyle7-2-oxo-l-azetidine-carboxamlde, tri-fluoracetate salt _ 5 0.50 g (0.93 millimole) of phenylmethyl ester of acid (3) was added - ^ 1- ^ 7 ^ ^^ 3 - ^ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl J-2-oxo- 1- imidazolidinyl ^ sulfonyl J ^ amino. Jcarbonyl J-2-oxo- 3-azetidinylJ7carbamic , to a mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid. The solution was stirred overnight at room temperature and evaporated in vacuo "The residue was triturated with ether, filtered by wringing and dried in vacuo to obtain 0 , 49 g of the title compound having a melting point of 155 ° C.

I) £ * 3S (Z) - (2-amino-4-thiazolyl) - 2- £ Γι-ΓΓΓΓ3-Γ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl77-2 acid -oxo-l-imidazolidinylJJsulfonylJ7_ 20 amino I7carbonyl ^ -2-oxo-3-azetidinyl ^ / amino, 7-2-oxo-ethylidene I amino Toxy J7-2-methylpropanoic ester diphenylmethyl_ To a suspension of 0.41 g (0, 93 millimoles) (Z) -2-amino- ¢ C- £ "£ ,, 2- (diphenylmethoxy) -1, 1- 25 dimethyl-2-oxoethoxy J7lmino ^ 7-4-thiazole-acetic in 20 ml dry acetonitrile, 0.39 ml (2.8 millimoles) of triethylamine was added, the mixture was cooled to -30 ° C and 0.19 ml (0.93 millimoles) was added dropwise. diphenyl chlorophosphate The reaction mixture was stirred for 1 hour at -30 ° C (solution a).

0.48 g (0.93 millimole) of the trifluoroacetate salt of (S) -3-amino-N- ΓΓ 3- £ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) was added methyl .7-2-oxo-l-imidazo-35 lidinyl J7sulfonyl ^ -2-oxo-l-azetidine-carboxamide 105 suspended in 20 ml of dry acetonitrile and 0.78 ml (3.2 millimoles) was added bis-trimethyl-silylacetamide. The suspension was stirred for 30 minutes at room temperature, then it was; 5 added to solution (a).

The reaction mixture was stirred for one hour at -10 ° C, then for 1.5 hours at 0 ° C. The clear solution obtained was evaporated in vacuo and 50 ml of water was added to the oily residue. The mixture was adjusted to a pH of 2 by addition of 2N hydrochloric acid and the disodium salt of the acid £ ~ 3S (Z) J-2-CC C l- (2-amino-4-thiazolyl) - 2- £ "£ l- £ * ζ £ £ 3- £" (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl J-2-oxo-l-imidazolidinyl, 7sulfonyl ^ amino Jcarbonyl. 7-15 2-oxo-3-azetidinyl J7amino ^ -2-oxo-ethylidene ^ amino jf-oxy J7-2-methylpropanoic crystallized out of the solution. The product was filtered by wringing, washed with water and dried in vacuo to obtain 0.7 g of the title compound.

20 J) Acid £ "3S (Z) 7-2-ΓΓΓι - (2-amino-4-thiazolyl) - 2-Γ L ι-Γ Γ Π Π 3- £ * (1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl) methyl 7-2-oxo-1-imidazolidinyl. JsulfonylJ-amino ^ carbonyl ^ -2-oxo-3-azetidinyl. 7amino J-2-oxo-ethylidene JJa ^ ino ^ oxy 7- 2-methylpropanoic acid, disodium salt

0.7 g (0.85 mmol) of the diphenylmethyl ester £ 3S (Z) 7-2-Z "£ C 1— (2-amino-4-thiazolyl) -2-J ££ 1 -Γ £ LH 3- £ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methylJ7-2-oxo-l-imida-30 zolidinylJ / sulfonyl7amino7carbonyl7-2-oxo-3- azétidinyl _Jamino J7-2-oxo-ethylidene ^ 73111 ^ 110 Joxy J-

V

2-methylpropanoic suspended in 1.4 ml of ani-sole and cooled to -10 ° C. Trifluoroacetic acid was added and the solution was stirred for one hour at -10 ° C. 100 ml of ether was added and the precipitate was filtered by wringing, washed with ether and dried in vacuo.

The trifluoroacetic acid salt was dissolved in a mixture of methanol and water and the pH was adjusted to 6.5 by addition of 2N sodium hydroxide. The methanol was removed in vacuo and the aqueous solution lyophilized to obtain 0.5 g of the title compound. The latter was purified by MPLC; melting point: 250 ° C (decomposition).

10 Example 9

Acid _ £ “3S (Z) £ -2- £ £ £ l- (2-amino-4-thiazolyl) -2-rc ir crc ^ -r (1,4-dihydro-5-hydroxy-4-oxo- 2-pyridinyl) methyl J-2,3-dioxo-1-piperazinyl J ^ sulfonyl J-amino J7carbonyl ^ -2-oxo-3-azetidinyl ^ amino J-2-oxo-15 ethylidene J7amino "7oxy ^ 7-2-methylpropanoic , disodium salt_ A) 2- (chloromethyl) -5- (phenylmethoxy) -l- (phenylmethyl) -4 (1H) -pyridinone, hydrochloride_

A suspension of 3.21 g (10 millimoles) of 2- (hydroxymethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4 (1H) -pyridinone was cooled to 0 ° C. ml of chloroform and 4.65 ml (64 millimoles) of thionyl chloride was added dropwise. The mixture was stirred for 10 minutes at 0 ° C, then heated to reflux for one hour. The solvent was evaporated in vacuo, the residue was washed with petroleum ether and dried in vacuo to give 3.66 g of the title compound with a melting point of 85 ° C ( decomposition).

B) 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) - \ 4 (1H) -pyridinone j * 1 1 'T "" 1

3.5 g (9.3 millimoles) of 2- (chloromethyl) -5- (phenylmethoxy) -l- (phe-nylmethyl) -4 (1H) -pyridinone hydrochloride were dissolved in a mixture of water and 35 ethyl acetate and the layers were separated. The organic phase was washed twice with water, dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with petroleum ether, filtered by suction and dried in vacuo to give 2.27 g of the title compound with a melting point of 115-120 ° C (decomposition).

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

For one hour, a mixture of 11.4 g (100 millimoles) of 2,3-piperazin-dione, 55.7 g (270 millimoles) of bis-trimethylsilylacetamide and 150 was heated to reflux. ml of acetonitrile. For 30 minutes, 22.2 g (80 millimoles) of triphenylmethyl chloride was added dropwise and the mixture was again heated at reflux for 2 hours. After stirring overnight at room temperature, 21.6 ml of water was added to the clear solution. The precipitate obtained (3.13 g) was separated by filtration and the filtrate was concentrated in vacuo. The residue was triturated with water and dried to obtain 25.5 g of the title compound in the raw state which was crystallized from ethanol. Yield of pure product: 12.19 g, melting point: 230-235 ° C.

25 D) 1- ΓΠ.4 -dihydro-4-oxo-5- (phenylmethoxy) -1- (phe-nylmethyl) -2-pyridinyl ^ 7methylJ7-4- (triphenylmethyl) - 2,3-piperazine-dione_ solution of 4.19 g (11.77 millimoles) of N- (triphenylmethyl) piperazine-2,3-dione in 95 30 ml of dry dimethylformamide, 0.35 g (11.77 millimoles) of hydride was added sodium (80% oil). When the evolution of hydrogen ceased, a solution of 4 g (11.77 millimoles) of 2- (chloro-methyl) -5- (phenylmethoxy) -l- (phenylmethyl) -4 (1H) was added. pyridinone in 25 ml of dry thick suspension dimethylformamide 108 which then turned into a clear solution. After stirring for one hour at room temperature, precipitation began. After 2 hours, the calls were separated by filtration, washed and dried in vacuo to give 5.13 g of the title compound, mp 165-168 ° C.

E) 1-ΓΓ1.4 -dihydro-4-oxo-5- (phenylmethoxy) -1- (phe-nylmethyl) -2-pyridinyl Jmethyl J-2,3-piperazine-dione 10 To a solution of 8.77 g (13.23 millimoles) of 1- ΓΖΓ1.4 -dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmé thyl) -2-pyridiny1J7 methyl-4- (triphenylmethyl) - 2.3- piperazine-dione in 65 ml of dichloromethane, at room temperature, 65 ml of formic acid were added dropwise. After stirring for 3 days, the volatiles were separated by vacuum distillation and the residue was triturated twice with ether to give 5.24 g of 1-ΓΓ1.4-dihydro-4-oxo-5- (phenylme thoxy) -1- (phenylme thyl) -2-20 pyridinylJ / methylJ7 ~ 2,3-piperazine-dione with a melting point of 260-265 ° C.

F) Acid (S) - ^ l- £ * Zr £ * £ * 4- ^ 7 £ l, 4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinylJ7methyl J7-2.3 - dioxo-1-piperazinylJ suifonylJamino .JcarbonylJ - 25 2-oxo-3-azetidinylI7carbamic, phenylmethyl ester To a solution of 0.44 g (2 millimoles) of (S) -3-ΓΓ (phenylmethoxy) carbonylJaminoJ-2-azéti- dinone in 25 ml of dry ethyl acetate, 0.28 g (2 millimoles) of chlorosulfonyl isocyanate was added and the solution was stirred for 30 minutes at room temperature. 12 ml of dichlo romethane, 0.61 g (6 millimoles) of triethylamine and a pre-stirred mixture (3 hours) of 0.83 g (2 millimoles) of 1-ΓΓ1.4 -dihydro-4- were added thereto. oxo-5- (phenylmethoxy) -35 l- (phenylmethyl) -2-pyridinylJ7methylJ7-2,3-piperazine-109 dione and 1.59 g (8 millimoles) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in 25 ml dry ethyl acetate. After stirring for 3 days at room temperature, ice water was added and the pH was adjusted to 1 with hydrochloric acid. The insoluble residue was separated by filtration and dried under vacuum to obtain 1.15 g of the title compound of 72% purity.

G) (S) -3-amino-N -ΓΓ4-Γ (1,4-dihydro-5-hydroxy-4- 10 oxo-2-pyridinyl) methyl „7-2,3-dioxo-1-piperazinyl ^ 7 - sulfonyl ^ 7-2-oxo-l-azetidine-carboxamide, 4-methylbenzene-sulfonic acid salt_ To a solution of 0.98 g (1.32 millimole) of phenylmethyl ester of acid (S) - £ "l- £ * £ £ * £ 4-15 ΓΠ, 4 -dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinyl _7methyly-2,3-dioxo-l-piperazinyl _ sulfonyl J7amino J7carbonyl J7-2-oxo-3-azetidinyl ^ 7carbamic- in 20 ml of dimethylformamide was added; 0.5 g (2.64 millimoles) of p-toluene sulfonic acid 20 and 0.5 g of palladium on carbon (10%). For one hour, hydrogen was bubbled through the mixture. The catalyst was filtered off, the solvent was distilled off in vacuo and the residue was triturated with dichloromethane to obtain, after drying, 0.82 g of the title compound with a melting point of 160-185 ° C (decomposition).

H) Acid “3S (Z) L 1- (2-amino-4-thiazolyl) - 2-ΓΠ-ΓΓΓΓ 4-f (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl ^ -2,3-dioxo-1-piperazinyl 17suifonyl 30 aminoJ7carbonyl J7-2-oxo-3-azetidinyl ^ aminoJ7-2-oxoethylidene ^ amino ^ oxy, 7-2-methylpropanoic, diphenylmethyl ester_ At 30 ° C, at a solution of 0.57 g (1.3 millimole) of (Z) -2-amino acid - << -, £ * £ * 2- (diphenylmethoxy) -35 l, l-dimethyl-2-oxoethoxy ^ 7imino ^ -4-thiazole-acetic 110 in 30 ml of dimethylformamide, 0.39 g (3.9 millimoles) of triethylamine and 0.31 g (1.3 millimole) of triphenyl chlorophosphate were added. After stirring for one hour, 0.39 g (3.9 millimoles) of triethylamine and 0.98 g (1.3 millimoles) of the 4-methylbenzene sulfonic acid salt of (S) -3- were added. amino-N- ΓΓ4-Γ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl ^ 7-2,3-dioxo-l-pipérazinylJ7-sulfonylJ7 ~ 2-oxo-l-azetidine- carboxamide. The mixture was stirred for two hours at -10 ° C and for 1.5 hours at 0 ° C. Water and ethyl acetate were added and the pH was brought to 1 with 3N hydrochloric acid. The precipitate was separated by filtration, washed with ethyl acetate and dried in vacuo to obtain 0.86 g of the title compound with a melting point of 130-190 ° C (decomposition).

I) Acid £ * 3S (Z) ^ -2- ^ 1 £ l-ÎZ-amino ^ -thiazolylJ- Sr Γ 1-Γ CC Γ 4-2Γ (1,4-dihydro-5-hydroxy-4-oxo- 2-20 pyridinyl) methyl J7 ~ 2,3-dioxo-l-piperazinylJsulfonylJ7- aminoj ^ carbonyl ^ -2-oxo-3-azetidinyl J7amino J-2-oxo-ethylidene _7amino.7oxy ^ -2-methylpropanoic, salt disodium_ At -10 ° C, to a suspension of 0.8 g (0.94 25 millimole) of diphenylmethyl ester of £ 3S (Z) ^ 2 ~ 2— £ J2 1— (2 — amino — 4— thiazolyl) - 2— CC 1-ΓΓΓΖΗ &. , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -methyl J7 “2,3-dioxo-l-pipérazinyly suifonyl Jamino ^ -carbonyl J7-2-oxo-3-azetidinyl amino J7-2-oxo -ethyli-30 dene I7aminoJ7oxyJ7-2-methylpropanoic acid in 1.4 ml * of anisole, 7 ml of trifluoroacetic acid were added.

After stirring for one hour, 30 ml of ether were added, the precipitate obtained was filtered off and dried in vacuo. This trifluoroacetic acid salt was suspended in water and the pH was adjusted to 6.5 with 2N sodium hydroxide. By subjecting the solution to lyophilization, 0.66 g of the crude product was obtained, which was chromographed with a second sample prepared in the same way (total: 1.55 g) on a macro-reticular copolymer of styrene / divinylbenzene under MPLC conditions to obtain 0.34 g of the title compound. A second column chromatography on a macroreticular copolymer of styrene / divinyl-10-benzene gave 0.18 g of the compound under the heading of a melting point of 242-270 ° C.

Example 10

Acid £ T3S (Z) J-2-ΓΓΠ - (2-amino-4-thiazolyl) -2.-ΓΖΓ1-ΓΓΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy-4-oxo-2-15 pyridinyl) methylene .Jamino ^ -2-oxo-l-imidazolidinyl J- sulfonyl "7 aminoJ7carbonylJ7-2-oxo-3-azétidinylJ-amino.,7-2-oxo-ethylidene ^ amino J7oxy J? -2-methylpropanoic acid, disodium salt_ i A) 4,5-bis- (phenylmethoxy) -2-pyridine-carboxylic acid, phenylmethyl ester

21.5 g (156 millimoles) of potassium carbonate was added to a suspension of 29.4 g (120 millimoles) of 0-benzylcomenamic acid in 350 ml of dimethylformamide and stirred for 1 hour at room temperature . 31 ml (264 millimoles) of benzyl bromide was added and the mixture was heated to 100 ° C while stirring for 25 hours. After cooling to room temperature, the dimethylformamide was distilled off in vacuo and the residue was triturated with ethyl acetate while heating for a short time at 60 ° C. By filtration, 40 g of inorganic salts were separated, the filtrate was concentrated to about 75 ml and subjected to chromatography on silica gel with a 90:10 mixture of ethyl acetate 112 and petroleum ether as eluent to obtain 35.5 g of the compound under a melting point of 116.7 ° C, B) 4,5-bis- (phenylmethoxy) -2-pyridine-methanol 5 A suspension of 95 mg (25 millimoles) of lithium aluminum hydride in 10 ml of ether and 10 ml of tetrahydrofuran, 1.06 g (25 millimoles) of phenylmethyl ester of 4,5-bis was added - (phenylmethoxy) -2-pyridine-carboxylic in three portions at 0 ° C. After stirring for 20 minutes at 0 ° C, 0.2 ml of a saturated sodium bicarbonate solution, 0.2 ml of a 10% potassium hydroxide solution and an additional amount of saturated solution were added sodium bicarbonate until the inorganic precipitate flocculates. The clear organic phase was decanted and evaporated in vacuo to obtain an oil which slowly crystallized. Yield: 0.6 g; melting point: 96.6 ° C.

C) 4,5-bis- (phenylmethoxy) -2-pyridine-carboxaldehyde To a solution of 0.54 g (1.7 millimole) of 4,5-bis- (phenylmethoxy) -2-pyridine-methanol in 15 ml of acetone, 1.5 mg (17 millimoles) of manganese dioxide was added and the mixture was stirred overnight at room temperature. The mixture was then filtered through a column of silica gel (70-250 mesh) and the aldehyde was eluted with acetone. By evaporating the eluent and triturating the residue with petroleum ether, 0.3 g of the title compound was obtained with a melting point of 104.3 ° C.

D) 1,4-dihydro-5-hydroxy-4-oxo-2-pyridine-carboxaldehyde_ To a solution of 1.9 g (6 millimoles) of 4,5-bis- (phenylmethoxy) -2-pyridine -carboxaldehyde 113 in 25 ml of dry dimethylformamide, 0.2 g of a palladium-on-carbon catalyst was added and hydrogen was bubbled through the mixture for 3 hours. The catalyst was removed by filtration, the solvent was distilled off in vacuo and the residue was triturated with ether to obtain 0.64 g of the title compound with a melting point of 174-177 ° C (decomposition).

E) Acid £ * 3S (Z) Ώ ü l- (2-amino-4-thiazolyl) - 10 2- rni-CCCüs-rr (1,4-dihydro-5 ~ hydroxy-4-oxo 2-pyridinyl) methylene „7amino _7-2-oxo-l-imidazolidi-nyi ^ sulfonyl ^ amino Jcarbonyl J'-2-oxo-3-azétidinyl J-aminoJ7-2-oxo-ethylidene ^ amino JoxyJ7-2-methylpropanoic acid, disodium salt_ 15 To a solution of 0.64 g (1.1 millimole) of the monosodium salt of £ ”3S acid (Z) ^ -2- ΓΓΓ2-ΓΓ1-cra 3-amino-2-oxo-1-imidazolidinyl) sulfonyl ^ amino J-carbonyl ^ -2-oxo-3-azetidinyl Jamino. 7-1- (2-amino-4-thiazolyl) -2-oxoethylidene J7aMino J7oxy 7-2-propanoic 20 in 15 ml of dry dimethylformamide, 0 was added , 18 g (1.3 millimole) of 1,4-dihydro-5-hydroxy-4-r oxo-2-pyridine-carboxaldehyde and, after stirring for 4.5 hours, an additional amount of 0.02 was added g (0.14 millimole) of 4. After stirring overnight at room temperature, the solvent was evaporated in vacuo, the residue was taken up in 30 ml of water, filtered and lyophilized the solution. 0.82 g of raw material was dissolved in 5 ml of water and subjected to chromotography on a macroreticular resin of a styrene / divinylbenzene copolymer with water as eluent to obtain 0.22 g of a pure product with a melting point of 248 ° C (decomposition).

114

Example 11

Acid ÜT3S (Z) Π-2-Π CL l- (2-amino-4-thiazolyl) -2-C C1-Γ C CL 4-Γ Γ (1,4-dihydro-5-hydroxy-4-oxo- 2-pyridinyl) carbonylJamino J-2,3-dioxo-1-piperazi- k 5 nyl J7sulfonyl Jamino ^ Jcarbonyl J7-2-oxo-3-azetidinyl J7- amino „7-2-oxoethylidene amino J7 ° XY thylpropanoic, disodium salt_ A) 4,5-bis- (phenylmethoxy) -2-pyridine-carboxylic acid_ 10 To a solution of 11.8 g (28 millimoles) of phenylmethyl ester of 4,5-bis- (phenyl -methoxy) -2-pyridine-carboxylic acid in 115 ml of tetrahydrofuran, 16 ml of water and 35 ml of IN potassium hydroxide were added. After stirring overnight at room temperature, 115 ml of water was added and the pH was adjusted to 2.5 with 1N hydrochloric acid. The acid was filtered off, washed with water and dried in vacuo to give 8.6 g of the title compound at 203.6 ° C .

B) N- (2,3-dioxo-1-piperazinyl) -4,5-bis- (phenyl-methoxy) -2-pyridine-carboxamide_ To a suspension of 7.1 g (21.17 millimoles) of acid 4,5-bis- (phenylmethoxy) -2-pyridine-carboxy-liquefy, 0.29 g (2.12 mmol) of hydroxybenzo-triazole and 2.73 g (21.17 mmol) of N- amino-piperazine-2,3-dione in 140 ml of dry dimethylformamide, after stirring for 15 minutes, 4.80 g (23.3 millimoles) of dicyclohexylcarbodiimide was added. After stirring for 21 hours at room temperature, by filtration, the dicyclohexylurea (4g) was separated and the solvent was evaporated in vacuo.

The solid residue was triturated for 40 minutes with 240 ml of tetrahydrofuran, filtered, washed with tetrahydrofuran and dried in vacuo to give 7.76 g of the title compound d '' a melting point of 231.1 ° C.

C) Acid (S) -Cl-C C CC4- ΓΓΓ4.5 -bis- (phenyl-methoxy) -2-pyridinyl ^ carbonyl Camino J-2,3-dioxo- „5 1-pipérazinylJ7sulfonyl ^ amino ^ carbonylJ7“ 2 -oxo-3- azetidinyl ^ / carbamic, phenylmethyl ester_ To a suspension of 2.02 g (9.18 millimoles) of (S) -3- rc (phenylmethoxy) carbonyl. 7amino ^ 7-2-azetidinone in 130 ml of ethyl acetate, 1.43 g (10 millimoles) of chlorosulfonyl isocyanate was added and, after stirring for one hour, 2.79 g (27.54) was added at 0 ° C millimoles) of tri-thylamine. To this mixture was added a pre-stirred solution (1.5 hours) of 4.10 g (9.18 millimoles) of N- (2,3-dioxo-1-piperazinyl) -4,5-bis - (phenylmethoxy) -2-pyridine-carboxamide and 5.4 g (27.54 millimoles) of N-methyl-N- (trimethylsilyl) trifluoroacetamide in 150 ml of ethyl acetate. After stirring overnight at room temperature, 220 ml of ice water was added and the pH was adjusted to 2 (from 10.3) with 3N hydrochloric acid. When the separated organic phase was treated with brine, the title compound precipitated, then filtered, washed with water and dried in vacuo to give 5 , 35 g. When 2.5 g of this material was triturated for one hour with a mixture of 25 ml of water and 37.5 ml of acetone at a pH of 6.3, 2.12 g of the compound were obtained under heading.

D) (S) -N- £ "4-r Γ Z (3-amino-2-oxo-1-azetidinyl) carbo-30 nyl .7amino .Jsulfonyl, 7-2,3-dioxo-1-piperazinyl .7 -1.4 dihydro-5-hydroxy-4-oxo-2-pyridine-carboxamide_ To a solution of 1.54 g (2 millimoles) of phenylmethyl ester of (S) acid - [1— [[[[4 - [[[4,5-bis- (phenylmethoxy)> 2-pyridinyl] carbonyl] amino] -2,3-dioxo-1-piperazinyl] -suifonyl] amino] -35 carhonyl] -2-oxo-3-azetidinyl ] carbamic in 30 116 ml of dimethylformamide, 0.77 g of palladium on carbon was added and the mixture was subjected to hydrogenolysis for 45 minutes, the catalyst was removed by filtration on "Hyflo" and the solution was used. obtained for the next step without isolation of the compound under heading.

E) Acid £ "3S (Z) J-2-ΓΓΖΓι - (2-amino-4-thiazolyl) -2-ca-LC l (1,4-dihydro-5-hydroxy-4-oxo 2-pyridinyl) carbonylJaminoJ-2,3-dioxo-1-piperazinylJ -10 sulfonyl ^ amino ^ carbonyl J7-2-oxo-3-azetidinyl Camino J-2-oxo-ethylidene Jamino j ^ oxy, 7-2-methylpropanoic, diphenylmethyl ester_ Has a solution of 0.88 g (2 millimoles) of (Z) -2-amino- JT 2- (diphenylmethoxy) -1, 1-dimethyl-2-oxoethoxy ^ imino jf-4-thiazole-acetic acid in 20 ml of dimethylformamide, 0.60 g (6 millimoles) of triethylamine was added and, at -30 ° C. and under a nitrogen atmosphere, 0.54 g (2 millimoles) of triphenyl chlorophosphate was added. stirring for 20 hours at -30 ° C, 0.20 g (2 millimoles) of triethylamine and the solution of (3) were added dropwise. Ν- £ · 4-ΓΓΓ (3-amino-2-oxo -l-Azetidinyl) carbonyl Zl-amino J7suifonyl ^ 7-2,3-dioxo-1-piperazinyl1,4-dihy-dro-5-hydroxy-4-oxo-2-pyridine-carboxamide in dimethylformamide. mixing for 2 hours at -10 ° C and for 17 hours at 0 ° C. The solvent was removed by vacuum distillation and the residue was partitioned between 40 ml of ethyl acetate and 20 ml of ice water. When the pH was adjusted to 1.5 with dilute hydrochloric acid, an oil separated which was separated from the solvent and which was dried under vacuum to give 1.35 g of the compound under heading.

117 F) Acid £ “3S (Z) J-2- £ £ * l- (2-amino-4-thiazolyl) -2-ΓΓ1-ΓΓΓΓ4-ΓΓ (1,4-dihydro-5-hydroxy-4-oxo -2-pyridinyl) carbonyl J? amino J-2,3-dioxo-l-pipérazi-nyl J7 tallow onyl amino i Orbonyl J7-2-oxo-3-azé t idinyl 7? - „5 amin ^ -2-oxo-ethylidene amino ^ oxy 7-2_m®'t:; hy1Pr0Pa" · noic, disodium salt_ To a mixture of 2.6 ml of anisole and 13 ml of trifluoroacetic acid, -10 ° C, 1.3 g (1.48 millimole) of diphenylmethyl ester 10 £ "3S (Z) J-2-ΓΓΓ 1- (2-amino-4-thiazolyl) -2 was added -ΓΓ1-Γ ΓΓΓ4-ΓΓ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl J ^ amino .7-2,3-dioxo-l-pipérazinyl J-sulfonyl Z7amino ^ carbonyl ^ - 2-oxo-3-azetidinyl "Jamino J-2-oxoethylidene ^ amino Ioxy, 7-2-methylpropanoic and the mixture was stirred for 2 hours at 0 ° C. The volatiles were separated by distillation under - vacuum and the residue was triturated with ether to give 1.06 g of the trifluoroacetic acid salt after drying. This trifluoroacetic acid salt was put

20 suspended in 20 ml of water and the pH was adjusted

to 6.5 with IN sodium hydroxide. The lyophilized solution gave 1.10 g of a crude product which was chromatographed on a macroreticular copolymer of styrene / divinylbenzene under MPLC conditions with water as eluent. Yield: 0.48 g.

This material was again subjected to chromatography twice with other samples prepared in the same manner. The second column chromatography was carried out on a macroretic acid copolymer of styrene / divinylbenzene and the third on "Organogen", each time with water as eluent. Final yield: 0.10 g; melting point: above 300 ° C.

118

Example 12 Γ3δ (Ζ) J-3- £ “C (2-amino-4-thiazolyl) - <£ '(2-fluorethoxy) -imino ^ acetyl' JaminoJ ^ -NZ * £ 3 — ZT C (1,4 -dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl Jamino | 7-2-oxo-1 "5 imidazolidinyl ^ sulfonyl, ^ - 2-oxo-1-azetidine-carboxamide, ethyl salt diisopropylamine_ To a solution of 0.33 g (1.4 millimole) of (Z) -2-amino-0 (- £ * (2-f luorethoxy) iminoJ7-4-thiazole-acetic acid in 5 ml of dry dimethylformamide 0.19 g (1.4 millimole) of N-hydroxybenzo-triazole and 0.18 g (1.4 millimole) of N-ethyl-diisopropylamine were added. At 0 ° C., 0 was added. , 29 g (1.4 millimole) of dicyclohexylcarbodiimide and the mixture was stirred for one hour, to which was added a solution of 0.87 g (1.6 millimole; see example IG) of the trifluoroacetate salt (1: 2) of (3S) -3-amino-N- £ Τ3-ΓΓ (1,4-i dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl amino J7-2-oxo-l-imidazolidinyl J7sulfonylJ-2- oxo-1-, azetidine-carboxamide and 0.41 g (3.2 millimoles) of N-ethyldiisopropylamine in 3 ml of dimethylformamid dry and, after stirring for 2 hours at 0 ° C, the mixture was stirred for an additional 16 hours at room temperature. The dicyclohexylurea was removed by filtration and the solvent was removed by vacuum distillation. The residual oil was triturated with water until the end of crystallization. The solid (0.82 g) was collected by filtration, the filtrate was brought to a pH of 6.1 and lyophilized. The solid was suspended in 40 ml of water and the pH was brought to 6 with 0.25N sodium hydroxide. By filtration, the undissolved material was separated and the filtrate was lyophilized. Two portions of the lyophilized material (about 0.6 g) were combined and subjected to chromatography on a macroreticular copolymer 119 of styrene / divinylbenzene with water and a 95: 5 mixture of water and d acetonitrile as eluent. After lyophilization, the appropriate fractions gave 0.22 g of the title compound with a melting point of 163-165 ° C.

k *

Example 13

Acid £ 3S (Z) Jz-LCLi-iz -amino-4-thiazolyl) -2- £ ΓEL1-ΓΓΓΓ 2- (carboxymethyl) -2- / 7 (1,4-dihydro-5-hydroxy- 4-oxo- 2-pyridinyl) carbonyl. Jhydrazino J tallow onyl "J -10 amino J7carbonyl / 7” 2-oxo-3-azétidinyl77amino L7-2-oxo-ethylidene / 7 amino,7oxy // - 2-methylpropanoic, trisodium salt_ A) N, O-dibenzyl-comenamyl, hydrochloride

In a suspension of 16.77 g (50 milli-15 moles) of Ν, Ο-dibenzyl-comenamic acid in 360 ml of dry dichloromethane, 11.45 g (55 milli- »moles) of phosphorus pentachloride was added in portions at 0-5 ° C. Stirring was continued for one hour at room temperature and the preci-20 was collected by wringing, washed with 20 ml of dry dichloromethane and dried in vacuo to give 15.02 g of the compound under heading with a melting point of 126-127 ° C (decomposition).

B) "" 2- / 7 (phenylmethoxy) carbonyl J7hydrazino J- acetic acid, 1,1-dimethylethyl ester

In a stirred solution of 6.65 g (0.040 mole) of Ν- / Γ (phenylmethoxy) carbonylJ7 hydrazine in 40 ml of dimethylformamide, a solution of 8.58 g (0.044 mole) of t bromacetate was poured dropwise -butyl in 20 ml of dimethylformamide, then a solution of 8.2 ml (0.048 mole) of NN-diisopropyl-ethylamine in 8 ml of dimethylformamide. After the mixture was stirred at room temperature for 1 day, the solvent was distilled off in vacuo and the residue was taken up in ether and water. The organic layer was washed three times with water, dried (magnesium sulfate) and evaporated in vacuo to obtain an oil (10.6 g) which was purified by chromatography in column „5 on silica gel, eluting with a 1: 1 mixture of ethyl acetate and toluene. The appropriate fractions were evaporated in vacuo and the residue was stirred with petroleum ether to obtain 6 g of the title compound of mp 61-10 62 ° C.

C) Γ 1-ΓΠ.4 -dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl JJcarbonyl ^ 7-2 - ^ (phenylmethoxy) carbonyl hydrazino ^ acetic, 1,1-dimethylethyl ester_

15.6 ml (80 millimoles) of N-15 methyl-N-trimethyl-silyltrifluoracetamide was added to a solution of 11.2 g (40 millimoles) of 1,1-dimethyl-1-ethyl ester of ΖΓ acid 2- £ (phenylmethoxy) carbonyl J7-hydrazino Jacétique in 60 ml of dry acetonitrile.

^ After stirring for 30 minutes at room temperature, the clear solution was evaporated in vacuo and the residue was dissolved in 45 ml of dry dichlorome-thane. This solution was poured dropwise into a suspension of 15.61 g of N, O-dibenzyl-comenamyl chloride (hydrochloride) in 60 ml of dry dichloromethane at room temperature. After stirring overnight, the reaction mixture was evaporated in vacuo to obtain a residue which was stirred with 10 ml of methanol, which was again evaporated in vacuo and then subjected to chromatography on silica gel, eluting with ethyl acetate and a 10: 1 mixture of ethyl acetate and methanol. After evaporation in vacuo, the appropriate fractions gave a solid foam which became crystalline upon stirring with ether. Yield: 12.7 g; melting point: 121 177-178 ° C (decomposition).

D) Γ1-Γ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonylJ7hydrazino ^ acetic acid, 1,1-dimethyl-ethyl ester 5 A suspension of 7.17 g was hydrogenated (12 millimoles) of 1,1-dimethylethyl ester £ l- £ £ l, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyri-dinyl ^ / carbonyl £ -2- £ ( phenylmethoxy) carbonylJ-hydrazino "Jacetic in 400 ml of methanol in the presence of 1.6 g of palladium on charcoal (10%) for 40 minutes.

By filtration, the catalyst and the precipitated product were separated and washed well with 300 ml of dry dimethylformamide to dissolve the precipitated product. From the combined filtrates, the solvents were removed in vacuo to obtain a residue which crystallized upon stirring with ether (1.68 g; melting point: 221 ° C, decomposition). By recrystallization from methanol, the compound was obtained in the pure state. Yield: 1.26 g; melting point: 20,225 ° C; sintering: 229 ° C (decomposition).

E) (3S) -j ^ l- £ * (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonylJ - 2-Γ C Zt 2-ΟΧΟ-3-Ζ * £ (phenyl -methoxy) carbonyl J7amino J7-1-azetidinyl J7carbonyl J-amino JsulfonylJJhydrazino £ acetic, 1,1-dimethylethyl ester

9 ml (46.2 millimoles) of N-methyl-N-trimethyl-silyltrifluoracetamide were added to a suspension of 3.2 g (11 millimoles) of £ 1- £ 1,1-dimethylethyl ester (1 , 4-dihydro-5-hydroxy-4-oxo-

'W

2-pyridinyl) carbonyl. Acid hydrazino in 120 ml of dry ethyl acetate. At room temperature, stirring was continued for one hour to obtain a clear solution (solution A).

To a suspension of 2.42 g (11 millimoles) of (S) -3- £ “£ * (phenylmethoxy) carbonyl.Jamino J-2-azé.ti- 122 dinone in 80 ml of dry ethyl acetate while stirring, 0.99 ml (11 millimoles) of chlorosulfonyl isocyanate was added. The mixture was stirred for one hour at room temperature, then cooled to 0 ° C, Solution A was poured in dropwise at 0 ° C and continued stirring overnight at ambient temperature. After adding 4 ml of triethylamine, the mixture was evaporated in vacuo. The residue was dissolved in 10 ml of a 4: 1 mixture of methanol and water. This solution was poured dropwise into a mixture of 30 ml of methano] / water, the pH of which was kept at 2 to obtain a residue (10.25 g) which became crystalline by stirring with a few milliliters of water and methanol.

The precipitate was purified by successive washings (with stirring) with a 4: 1 mixture of isopropanol and water, methanol, a 1: 1 mixture of methanol and ether and ether. Yield after vacuum drying: 2.39 g.

20 F) (S) -3-amino-1 - ^^ ££ “2- (carboxymethyl) -2-ZT (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl, 7hydra- zino £ 7 sulfonylj / anri-no J / carbonyl j'-2-azetidinone, trifluoroacetate salt_ At 0 ° C, 2.39 g (3.9 millimoles) was added

25 of 1,1-dimethylethyl ester (3S) - £ 1- £ T (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonylJ-2-CCUC 2-ΟΧΟ-3 -Γ * C (phenymethoxy) carbonylJamino J

1-Azetidinyl Zl carbonyl ^ amino j ^ sulfonyl ^ hydrazino acetic to a mixture of 7 ml of trifluoroacetic acid and 1.66 ml of thioanisole. After stirring overnight at room temperature, the solution was evaporated in vacuo. The residue was washed successively (with stirring) with ethyl acetate, a 1: 1 mixture of ethyl acetate and petroleum ether, petroleum ether and dichloromethane, then dried it 123 under vacuum. This crude salt was used in the next step without any further purification. Yield: 2.15 g.

G) Acid £ 3S (Z) J-2-ΓΓΓΐ - (2-amino-4-thiazolyl) -s 2-Γ £ ι- £ Γ £ Γ2 - (carboxymethyl) -Z- £ (1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonyl Jhydrazino J- sulfonyl £ amino £ carbonyl 27-2-oxo-3-azetidinyl <JaminoJ7- 2- oxo-thylidene JT'aniino £ oxy ^ -2-me thylpropanoic , diphenylmethyl ester. 0.70 ml (3.24 millimoles) of diphenyl chlorophosphate was poured dropwise into a mixture cooled to -30 ° C. and consisting of 1.42 g (3.24 millimoles) of acid ( Z) -2-amino- 0 (- ££ 2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy J7 imino J -15 4-thiazole-acetic and 1.81 ml (12.96 millimoles) of triethylamine in 30 ml of dry acetonitrile (solution A).

3.27 ml (12.96 millimoles) of bis-trimethylsilylacetamide was added to a suspension of 2.13 g (<V3.3 millimoles) of the trifluoroacetate salt of (S) - 3-amino-1-rr cri - (carboxymethyl) -2- £ * (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl J hydrazino J-sulfonyl J7amino, 7carbonyl J7-2-azetidinone in 30 ml of acetate d dry ethyl at room temperature. After stirring for one hour, the clear solution was cooled and poured dropwise into solution A at -30 ° C. The mixture was stirred for one hour at -10 ° C, then for an additional 1.5 hours at 0 ° C and then evaporated in vacuo. The residue was stirred with a few milliliters of water, the pH of which was adjusted to 2 by addition of dilute hydrochloric acid. The precipitate was separated by filtration, washed with water, redissolved in a mixture of water and acetone at a pH of 5.5-6 (addition of hydroxide diluted sodium) and 124 was purified by MPLC on a macro-styrene / divinylbenzene copolymer, eluting with a water / methanol gradient (0-100%). By lyophilization of the appropriate fractions, 270 mg of the purified products were obtained. A suspension of this salt was acidified in a few milliliters of cold water / with hydrochloric acid diluted to a pH of 2 to precipitate the free acid which was collected by wringing and dried under vacuum to obtain 0.19 g; 10 melting point: above 180 ° C (decomposition).

H) Acid £ "3S (Z) J-2-ΖΓΓΓι - (2-amino-4-.thiazolyl) -2-Γ Γ Γ ΓΓ 2 - (carboxymethyl) -2- £ * (1,4-dihydro- 5 -hydroxy-4-oxo-2-pyridinyl) carbonyl. Jhydrazino J-sulf onyl 7amino J7carbonyl TJ-2-oxo-3-azétidinyl73 -15 amino J7-2 - oxoethylidene ^ 7amino Joxy .7-2-methylpropanoic, trifluoroacetic acid salt_

0.17 g (0.2 millimole) of diphenylmethyl ester £ * 3S (Z) J7-2 - ^ * ^ * ^ l- (2-amino-4-thiazolyl) -2- was added slowly Π Π i-CCCCz - (carboxymethyl) -20 2-Γ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl j ^ hydrazinoJJsalfonyl J7amino JJcarbonyl ^ -2-oxo-3-azetidinyl 7amino, 7-2-oxo-ethylidene 7amino J oxy 7-2-methylpropanoxque in a stirred solution, cooled to -10 ° C and consisting of 0.62 ml (8 millimoles) of trifluoroacetic acid and 0.087 ml (0 , 8 millimole) of thioanisole. Stirring was continued for 15 minutes at 0 ° C. The suspension was evaporated in vacuo at 0-5 ° C and the residue was stirred with dry ether, collected by wringing, washed with dry ether and washed. dried under vacuum to obtain 0.14 g; melting point: above 230 ° C (decomposition).

125 I) Acid £ * 3S (Z) J -? - ££ £ l- (2-amino-4-thiazolyl) -2-ΓΓ1-ΓΓΓΓ2 - (carboxymethyl) -2- £ "(1,4-dihydro - 5-hydroxy-4-oxo-2-pyridinyl) carbonyl ^ hydrazino "J -sulfonyl, ^ aminoJ7carbonyl (i> 2-2-oxo-3-azétidinyl ^ - 5 amino, 7-2-oxo-ethylidene J7ainino ^ oxy 7-2-raethylpro-panoic, trisodium salt_

115 mg (0.146 millimole) of the trifluoroacetate salt of LCC acid i-C2-amino-4-thiazolyl) -2- £ £ l- £ CC Π2- (carboxymethyl) -10 2- £ * (1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl ^ hydrazino ^ sulfonyl ^ 7amino J ^ carbonyl ^ -2-oxo-3-az é tidi ny1] amino] -2-oxo-ethylidene] amino] oxy] -2-methyl-propanoic suspended in 1.5 ml of water and the pH was adjusted to 5.5 by adding dilute sodium hydroxide dropwise. The solution was passed through two successive columns of a macroreticular copolymer of styrene / divinylbenzene (0.05-0.1 mm) and a crosslinked dextran gel (25-100 µm) eluting with water . The appropriate fractions were combined and lyophilized to obtain 100 mg of the title compound.

Example 14

Acid £ * 3S (Z) J7-2-T üO - (2-amino-4-thiazolyl) -2-rrwrrr 3-æt (1,4-dihydro-5-hydroxy-4-oxo-2-25 pyridinyl ) acetylJ7amino ^ '- 2-oxo-l-imidazolidinyl7-sulfonyl ^ 7aminoI7carbonyl 7-2-oxo-3-azétidinylJ-amino ^ -S-oxoethylidene J7amiho Joxy 7-2-methylpropanoic acid, disodium salt_ A) 2- (cyanomethyl ) -5- (phenylmethoxy) -1- (phenylmethyl) - 30 4 (1H) -pyridinone ______ To a suspension of 2 g (6 millimoles) of 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) - 4 (1H) -pyridinone in 20 ml of acetonitrile, 3.9 g (60 millimoles) of potassium cyanide and 0.1 g of 18-crown-6 were added; the mixture was heated to reflux 126 for 2.5 hours. The salts were filtered by suction and the filtrate was evaporated in vacuo. The residue obtained was purified by column chromatography on silica gel using an 8: 2 mixture of ethyl acetate * 5 and methanol as eluent to obtain 0.55 g of the compound under a point 175-180 ° C.

B) 1,4-Dihydro-5-hydroxy-4-oxo-1- (phenylmethyl) - 2-pyridine-acetic acid 10 A mixture of 2.45 g (7.16 milligrams) was stirred

moles) of 2- (cyanomethyl) -5- (phenylmethoxy) -1- (phenyl-methyl) -4 (1H) -pyridinone and 40 ml of concentrated hydrochloric acid (37%) for 4 hours at 70 ° C, then it was evaporated in vacuo. The residue was added to the board in 15 ml of ice water and the pH was adjusted.

to 2 by addition of 5N sodium hydroxide. The precipitate was separated by filtration, washed with ice water and ether and dried in vacuo (1.71 g). The crude acid was dissolved in 20 ml 0.5N sodium hydroxide, reprecipitated by acidification (pH: 1.8) with 2N hydrochloric acid, collected by wringing and it was washed with ice water. Yield: 1.52 g; melting point: 231-235 ° C.

C) 1,4-dihydro-5-hydroxy-4-oxo-N- (2-oxo-1-imidazolidinyl) - l- (phenylmethyl) -2-pyridine-acetamide_

4.99 ml (35.83 millimoles) of triethylamine was added to a suspension of 9.29 g (35.83 millimoles) of 1,4-dihydro-5-hydroxy-4-oxo-1- (phenyl) acid -30 methyl) -2-pyridine-acetic, 0.28 g (1.79 millimole) of N-hydroxybenzotriazole, 0.22 g (1.79 millimole) of N-dimethylaminopyridine, 3.62 g (35 , 83 millimoles) of N-aminoimidazolidinone and 8.13 g (39.41 millimoles) of dicyclohexylcarbodiimide in 115 ml of dry dimethylformamide. The agitation t * k 127 • was continued overnight at room temperature. By filtration, the precipitated dicyclohexylurea was separated, washed with dimethylformamide and the filtrate was evaporated in vacuo to give a residue which became crystalline upon stirring with 110 ml of dichloroethane. The precipitate was collected by wringing and dried in vacuo. To a suspension of this raw material in 65 ml of dry acetonitrile was added 14 ml (71.6 millimoles) of N-methyl-N-trimethyl-10 silyl-trifluoroacetamide. After stirring for 30 minutes at room temperature, by filtration, the undissolved dicyclohexylurea was separated and the filtrate was evaporated in vacuo. The oily residue was boiled in 70 ml of methanol for 15 minutes and cooled. The precipitate was collected by wringing, washed successively with methanol, a 1: 1 mixture of methanol and ether, as well as with ether, then dried in vacuo. Yield: 8.7 g; sintering: 242 ° C; melting point: 20 260-265 ° C (decomposition).

D) Acid (S) - ri-rrzrzrs-rrr 1,4-dihydro-5-hydroxy- 4-oxo-l- (phenylmethyl) -2-pyridinyl ^ 7acétylJ7amino J7-2-oxo-l-imidazolidinyl sxalfonyl ^ amino ^ 7carbonyl J-2-oxo-3-azetidinyl ^ / carbamic, phenylmethyl ester, monosodium salt_

5.86 ml (30 millimoles) of N-methyl-N-trimethylsilyltrifluoracetamide was added to a suspension of 3.42 g (10 millimoles) of 1,4-dihydro-5-hydroxy-4-oxo-N- (2 -oxo-1-imidazolidinyl) -1- (phenylmethyl) -2-30 pyridine-acetamide in 50 ml of dry ethyl acetate and stirring was continued for one hour at room temperature (solution A).

To a solution of 2.20 g (10 millimoles) of (S) -3- £ Z (phenylmethoxy) carbonyl ^ amino] 7-2-azéti-35 dinone in 50 ml of dry ethyl acetate was added 128 0.90 ml (10 millimoles) of chlorosulfonyl isocyanate with stirring and the mixture was stirred for one hour at room temperature, then cooled to 0 ° C. While stirring, it was poured drop by drop. 5 solution A at 0 ° C. After stirring overnight at room temperature, the mixture was evaporated in vacuo and the residue was taken up in a few milliliters of methanol and water. The pH was adjusted to 5.5 by addition of dilute sodium hydroxide and the filtered solution was freeze-dried. By MPLC on a macroreticular copolymer of styrene / divinylbenzene, eluting with an 8: 1 mixture of water and acetone and by lyophilization of the pure fractions concerned, 0.40 g of the compound under heading was obtained. The impure fractions were purified by performing a second MPLC using the same conditions. Yield: 0.60 g.

E) (3) -Ν-Γ3-Γ £ Γ (3-amino-2-oxo-l-azetidinyl) carbo-nyl ^ amino ^ sulfonyl J7-2-oxo-l-imidazolidinyl J-1,4-20 dihydro -5-hydroxy-4-oxo-2-pyridine-acetamide, trifluoroacetate salt_

For 20 minutes, a solution of 0.90 g (1.3 millimole) of the monosodium salt of the phenylmethyl ester of acid (S) -π-γγ £ γ 3-25 CCIΓ 1,4-dihydro- was hydrogenated. 5-hydroxy-4-oxo-l- (phenylmethyl) - 2-pyridinyl, 7acetyl J7amino <7-2-oxo-l-imidazolidinyl J7- sulfonyl ^ amino J7carb ° ny1 J7_2 “Oxo-3-azetidinyl .Jcarba-mique in 13 ml of dry dimethylformamide containing 0.50 ml (6.5 millimoles) of trifluoroacetic acid in the presence of 0.15 g of palladium on charcoal (10%). The catalyst was filtered off and washed with a few milliliters of dimethylformamide. Evaporation of the filtrate in vacuo gave an oily residue which became crystalline upon stirring with some 35 milliliters of ethyl acetate. Yield: 0.675 g; 129 melting point: above 150 ° C (decomposition).

By simple stirring of this title compound in the crude state in dry ethyl acetate for one hour, then by filtration, washing with ethyl acetate and drying in vacuo, I I. Ml · «i Il III II 'improved the purity; yield: 80%; melting point: above 165 ° C (decomposition).

F) Acid £ * 3S (Z) ^ 7-2- ECC 1- (2-amino-4-thiazolyl) - 2-ΓΓ1-ΓΓΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy-4-oxo-10 2-pyridinyl) acetyl.7amino J7-2-oxo-l-imidazolidinylC ~ sulfonyl ^ amino. ^ CarbonylI7-2-oxo-3-azétidinyl J-amino J7-2-oxo-ethylidene j ^ amino, 7oxy .J-2 -methylpropanoic, diphenylmethyl ester_

1.1 ml (4.45 millimoles) of bis-15 trimethylsilylacetamide was added to a suspension of 0.75 g (1.35 millimoles) of the trifluoroacetate salt of (S) -N- £ 3-ΓΓΓΟ -amino-2 -oxo-l-azetidinyl) carbonylJamino J -sulfonyl J7-2-oxo-l-imidazolidinyl "J-1,4-dihydro-5-hydroxy-4-oxo-2-pyridine ~ acetamide in 12 ml of acetate 20 d dry ethyl After stirring for 1 hour at room temperature, the clear solution was evaporated in vacuo and the oily residue was dissolved in 12 ml of dry ethyl acetate (solution A).

In a suspension cooled to -30 ° C and made up of 0.60 g (1.35 mmol) of (Z) -2-amino-Of- ^ "2- (diphenylmethoxy) -1, l-dimethyl- acid 2-oxo-ethoxy ^ imino J7-4-thiazole-acetic in 12 ml of dry acetonitrile, 0.57 ml (5.4 millimoles) of triethylamine was added dropwise, then 0.29 ml ( 1.35 millimole) of diphenyl chlorophosphate.

Stirring was continued for one hour at -30 ° C and for an additional hour at 0 ° C. The solvent was removed in vacuo and the residue was precipitated by stirring with a few milliliters of water (0 ° C).

The precipitate was collected by wringing, washed 130 with cold water, suspended in water at pH 2 (addition of a few drops of dilute hydrochloric acid) , it was filtered off, washed successively with water, methanol and ether, then dried in vacuo.

Yield: 1.07 g; melting point: above 180 ° C (decomposition). This raw material was used in the next step without any further purification.

10 G) Acid £ 3S (Z) 7-2-ΓΖΓΖΓ1 - (2-amino — 4-thiazolyl) -2- ££ i- ££££ 3— £ £ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) acetyl £ amino £ -2-oxo-l-imidazolidinyl £ -sulfonyl £ amino £ carbonyl £ -2-oxo-3-azetidinyl £ amino 7-2-oxoethylidene £ amino £ oxy I7-2 -methylpropanoic, disodium salt_

1.01 g (1.17 mmol) of £ 3S (Z) j-2-rrn- (2-amino-4-thiazolyl) -2- £ £ 1 diphenylmethyl ester was added £ 3- £ £ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) acetyl £ amino £ -2-oxo-l-20 imidazolidinyl £ sulfonyl £ amino £ carbonyl £ -2-oxo-3 - azét idiny1 £ amino £ -2-oxoé thy1i dene £ amino £ oxy £ -2-methylpropanoic crude in a solution at -10 ° C consisting of 2 ml of anisole in 10 ml of trifluoracetic acid. After stirring for 20 minutes at -10 ° C, the solvent was removed in vacuo at + 10 ° C. The residue was stirred with a few milliliters of dichloromethane, separated by filtration, again stirred with a few milliliters of dichloromethane, collected by wringing, and washed with hexane and dried in vacuo. This crude product (1.06 g) was suspended in a few milliliters of a water / acetonitrile mixture, then dissolved by adjusting the pH to 6 by adding 1N sodium hydroxide. After concentration in vacuo, the aqueous solution was subjected to chromatography 131 (MPLC) on a macroreticular copolymer of styrene / divinylbenzene eluting with water. The appropriate fractions were combined and lyophilized. Yield: 0.10 g; melting point: greater than 5,255 ° C.

Example 15

Acid £ “3S (z) 7-2-ΓΓΓ1 - (2-amino-4-thiazolyl) -2-CC ^ -CCCCZ-CC 3- (1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) -l-oxo-2-propenyl Jamino '"] -2-oxo-l-imida-10 zolidinyl J7sulfonyl J amino ^ / carbonyl ^ -2-oxo-3-azetidinyl] 7aminoI7” 2-oxoethylidene ^ 7aminoJ ^ oxy] 7-2-methyl-propanoic, disodium salt_ A) 2 - ((1-hydroxy-1-methoxy) methyl) -5- (phenylmethoxy) - 4 (1H) -pyridinone_ 15 Overnight at temperature ambient, 9 g of 2- (hydroxymethyl) -5- (phenylmethoxy) -4 (1H) -pyridinone and 26 g of manganese dioxide (activated) in 100 ml of methanol were stirred. After boiling the reaction mixture for 10 minutes, then by hot filtration through "Hyflo" and after washing the filter cake twice with 50 ml of boiling methanol, the combined filtrates were evaporated and the residue was stirred with 50 ml of ethyl acetate White crystals of the product were formed Yield: 9.7 g, melting point: 156 ° C (decomposition).

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-methoxy-methyl) -5- (phenylmethoxy) -4 (1H) were stirred for 3 hours -pyridinone and 8.35 g of carbethoxymethylene-triphenylphosphorane in 100 ml of dioxane at 70 ° C. A clear, dark-colored solution has formed. By evaporation of the solvent in vacuo, an oily residue of the title compound 132 and triphenylphosphine oxide was obtained. The residue was dissolved in 30 ml of isopropanol and the product crystals began to separate. After allowing them to stand in a refrigerator overnight, the crystals were filtered out, washed with ether and recrystallized from isopropanol. Yield: 5.72 g; melting point: 188 ° C.

C) 3- / Γ1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2- 10 pyridinyl J-2-propenoic acid_

1.5 g of 3-Cl54-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinylJ7-2-propenoic acid and 0.29 g of hydroxide were stirred for 2 hours at 50 ° C. of potassium in 30 ml of ethanol. After evaporation of the solvent, the residue was dissolved in 100 ml of water and filtered. To the filtrate, 2N hydrochloric acid was added until a pH of 5 was reached. The crystals of the title compound were separated from the solution. They were filtered, washed with water and dried in vacuo. Yield: 1.14 g; melting point: 236 ° C.

D) 3-C1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinylJ- N- (2-oxo-l-imidazolidinyl) -2-propenamide_

For 30 minutes, 10.85 g of 3- £ * 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinylJ7-2-Propenoic acid, 1 g of N-hydroxybenzotria- were stirred. zole, 0.01 g of Ν, Ν-dimethylaminopyridine and 8.24 g of dicyclohexylcarbodiimide in 100 ml of dimethylformamide. After cooling to 0 ° C, 4 g of N-amino-imidazolidinone was added and stirring was continued for one hour at 0 ° C and for 10 hours at room temperature. Then, the suspension obtained was heated to 60 ° C and filtered.

It was resuspended in 50 ml of dimethylformamide, heated to 60 ° C and filtered again. The combined filtrates were evaporated at 40 ° C (oil vacuum). The oily residue was stirred with 50 ml of water containing 2 g of sodium bicarbonate. After filtration, the solid was washed with water, acetone and ether. After drying, 12.3 g of a solid were obtained naked. It was stirred with 8 g of p-toluene sulfonic acid in 100 ml of dichloromethane for one hour. By filtration, 12.98 g of a white solid were obtained. We put this material in 10-board in water. By recrystallization from a mixture of water and dimethylformamide, 8.49 g of the compound were obtained under the heading of a melting point of 271 ° C.

E) Acid (3S) - Π1-Γ £ Γ Γ3-Γ Γ3-Γ 1,4-dihydro-4-oxo-15 5- (phenylmethoxy) -2-pyridinyl J'-l-oxo-2-propenyl J- amino I7-2-oxo-1-imidazolidinyl J7sulfonyl. ^ amino £ f-carbonyl, ^ - 2-oxo-3-azetidinyl J7carbamic, phenylmethyl ester ^ We put 3.55 g of, 4-dihydro-4- oxo 5- (phenylmethoxy) -2-pyridinyl J7-N- (2-oxo-1-imidazolinidyl) -2-propenamide suspended in 100 ml of ethyl acetate and 6.3 g were added of N-methyl-N- (trimethylsilyl) trifluoroacetamide. After stirring for one hour, a clear solution was obtained.

The solution was then added for 10 minutes to a cooled (0 ° C) solution of 3.3 g of (S) -l-CC (chlorosulfonyl) amino ^ carbonylJ-3-f “£ (phenyl-methoxy) carbonyl , 7amino J, -2-azetidinone in 50 ml of ethyl acetate. After stirring overnight, the solvent was evaporated and the oily residue was stirred for one hour with 50 ml of isopropanol. The precipitate obtained was isolated by filtration and washed with isopropanol and ether. Yield: 5.91 g.

134 F) (3S) -3-amino-N- ΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyrldinyl J7 ~ l “oxo-2“ ProPényl J'amino J-2- oxo- 1- imidazolidinylJ7sulfonyl ^ 7-1-azetidine-carboxamide, trlfluoroacetate salt; 5 Overnight, at room temperature, 6.8 g of phenylmethyl ester of (3Β) acid were stirred - £ ΐ-ΓΓΓΓ3- ΓΓ3-Γΐ.4 -dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl, | 7 “l-oxo-2-ProP®nyl ^ amino J- 2- oxo-l-imidazolidinylJ suifonylJamino J7carbonylJ - 2-oxo-3-azetidinylJ7carbamic acid in 60 ml of a 3: 1 mixture of trifluoroacetic acid and thioanisole After evaporation of the solution obtained to one third of its volume, 50 ml of isopropanol and 10 ml were added ether. The trifluoroacetate salt of (3S) -15 3-amino-N- Γ L 3-Γ L (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl ^ 7-l was obtained. -oxo-2-propenyl _7amino, 7-2-oxo-l-imida-zolidinyl J tallow onyl ^ 7-1-azetidine-carboxamide in the form of a white precipitate. It was washed several times with ether and dried, Yield: 4.30 g.

G) Acid £ * 3S (Z) Π-2 - ΠΠ Π l- (2-amino-4-thiazolyl) -2-γπ-γζ: γγ3-γγ 3- (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) -1-oxo-2-propenyl J7amino] 7-2-oxo-l-imida-zolidinyl. ^ Sulfonyl J7amino J7carbonyl "7-2-oxo-3-azeti- dinylii7amino ^ ?, "2-oxoethylidene Jamino ^ Joxy ^ -2-methyl-propanoic, disodium salt_

2.2 g of (Z) -2-amino- <X-ΠC2- (diphenylmethoxy) -l, l-dimethyl-2-oxoethoxy "J-imino] 7“ 4-thiazole-acetic and 1 , 5 g of triethylamine 30 in 150 ml of acetonitrile At -30 ° C., 1.4 g of diphenyl chlorophosphate were added dropwise and the mixture was stirred for one hour.

3.3 g of the 2,0-trifluoroacetate salt of (3S) -3-amino-N- ΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy-35 4-oxo-2-pyridinyl ^ -l were treated -oxo-SP ^ openylJ7aminoJ7-2-oxo- 135 1-imidazolidinyl Jsulfonyl Jl-azetidine-carboxamide suspended in 100 ml of ethyl acetate with 6 ml of N-methyl-N- (trimethylsilyl) trifluoroacetamide and stirred for one hour at room temperature. The solution with activated acid was added dropwise at -30 ° C (15 minutes). Then stirred for one hour at -10 ° C and for 30 minutes. at 0 ° C. The solvent was evaporated in vacuo and the residual oil was stirred with ice water at pH 2 (2N phosphoric acid). The ice water was removed and washed with water. the residue again with ice water, then dissolved in 100 ml of tetrahydro-furan. The solution was dried over sodium sulfate and the filtrate was evaporated. The diphenylmethyl ester was isolated from compound under heading as a solid foam (1.81 g).

1.5 g of the material was stirred in 30 ml of trifluoroacetic acid / anisole at 0 ° C for 30 minutes and, after addition of 100 ml of ether, by filtration, 1.7 g of the salt were isolated trifluoracetic acid of the compound under heading. It was dissolved in 10 ml of water and sodium bicarbonate was added until a pH of 5.5 was reached. The filtered solution was subjected to chromatography on a macroreticular styrene / divinyl-benzene copolymer (400 g) using water as the eluent.

The appropriate fractions contained 0.64 g of product. The bio-autography revealed a minor bioactive side product. The material was subjected to a second column chromatography on "Merck Lobar C" using water as the eluent. The appropriate fractions contained 0.17 g of the title compound.

136

Example 16

Acid £ * 3S (Z) J-2- £ £ £ * l- (2-amino-4-thiazolyl) -2-ΓΓι-ΓΓΖΓΓ2-Γ3- (1,4-dihydro-5-hydroxy-4-oxo- 2-pyridinyl) -1-oxo-2-propenyl 7hydrazino 7sulfonyl 7-5 amino 7cart> onyl 7-2-oxo-3-azetidinyl 7amino 7-2-oxo-ethylidene J7amino ^ oxy 7-2-methylpropanoic acid, disodium salt_ A) 3-7 * 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl7-2-propenoic acid, 2-7 (1,1-dimethylethoxy) - 10 carbonyl 7hydrazide_ At 0 ° C, for 20 minutes, 1.36 g of 3-71> 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl7-2-propenoic acid, 0.75 g of N-hydroxy-benzotriazole, were stirred , 01 g of N, N-dimethylaminopyridine 15 and 1.06 g of dicyclohexylcarbodiimide in 20 ml of dimethylformamide. 0.66 g of N- (t-butoxy-carbonyl) hydrazine was added. After stirring overnight, by filtration, the dicyclohexylurea formed was separated and the filtrate was washed with 10 ml of dimethylformamide. The filtrate was evaporated to dryness and the residue was suspended in 30 ml of water, 1 g of sodium bicarbonate was added and, after stirring, the title compound was filtered off. Recrystallization from a mixture of dimethylformamide 25 and water gave white crystals. Yield: 1.47 g; melting point: 141 ° C.

B) 3-7l, 4-dihydro-4-oxo-5- (phenylmethoxy) -2- pyridinyl 7-2-propenoic acid, hydrazide_

3.86 g of 2-7 (1,1-dimethyl-ethoxy) carbonyl7hydrazide of acid 3-7l> 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl 7-2- were stirred. propenoic acid for half an hour in 30 ml of trifluoroacetic acid at 0-5 ° C. The trifluoroacetic acid salt of the title compound precipitated after addition of 50 ml of diethyl ether. The salt was suspended in 30 ml of water, stirred with 2 g of sodium bicarbonate for 20 minutes, and the title compound was filtered, washed with water. water and dried to obtain a beige powder. Yield: 2.75 g.

C) (3S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -2- pyridine-carboxylic acid, 2- cccc 2-OXO-3ζ (phenyl-methoxy) carbonyl ^ amino 7-1-azetidinyl Jcarbonyl J-amino J7 sulfonyl 7hydrazide_ For one hour, 2.86 g of 3-ZTl, 4-dihydro-4-oxo-5- (phenyl-methoxy) -2-pyridinyl acid hydrazide were stirred. “2-propenoic. And 8.1 g of N-methyl-N- (trimethylsilyl) trifluoroacetamide in 50 ml of ethyl acetate. To the clear solution obtained was added a solution of 3.27 g of (S) -l- £ "£“ (chloro-sulfonyl) amino7carbonyl 7-3-Π ΖΓ (phenylmethoxy) -carbonyl 7aniino 72-azetidinone in 30 ml of ethyl acetate (addition within 10 minutes) at 0 ° C. After stirring overnight, the solvent was evaporated and the residue was stirred with 50 ml of isopropanol and a drop of acid The title compound was filtered off and washed with isopropanol and ether Yield: 5.42 g.

D) (3S) -3-iT 1,4-dihydro-5-hydroxy-4-oxo-2-pyri-dinyl7-2-propenoic acid, 2-ΠΠΠ (3-amino-2-oxo-1-azeti - dinyl) carbonyl 7hydrazide> tri-fluoracetate_ salt

5.2 g of 2-ΓΓΓΓ 2-OXO-3- rc (phenyl-30 methoxy) carbonyl J7aniino 7-l-azetidinyl_7carbonyl J- amino7sulfonyl 7hydrazide acid (3S) were stirred overnight at room temperature. -1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridine-carboxylic in 50 ml of a 3: 1 mixture of trifluoroacetic acid and thioanisole. To the clear solution was added 100 ml of an 8: 2 mixture of ether and isopropanol.

138

By filtration, the precipitate obtained was separated and washed with ether. Yield: 4.01 g after drying.

E) Acid Æs (z) Cz-CCCi - (2-amino-4-thiazolyl) -2-:: 5 Γ Γ1-Γ CCC 2-Γ 3- (1,4-dihydro-5-hydroxy-4-oxo -2-pyridinyl) -1-oxo-2-propenyl, 7hydrazino ^ sulfonyl Jamino J-carbonyl ^ -2-oxo-3-azetidinyl ^ amino ^ 7-2-oxoethyli-deneCaminoJ7oxy J-2-methylpropanoic, disodium salt On a dissolved 1.5 g of (Z) -2-amino-0 (-10 ΓΓ2 - (diphenylmethoxy) -l, l-dimethyl-2-oxoethoxy Π- iminoe7-4 “'thiazole-acetic acid and 1 g of triethylamine in 100 ml of acetonitrile, at -30 ° C., 1 g of diphenyl chlorophosphate was added dropwise and the mixture was stirred for one hour.

2 g of 2-ΓΓΖΓ (3-amino-2-oxo-1-azetidinyl) carbonylJ -amino ^ sulfonyl ^ acid hydrazide (3S) -3- ^ 7 1,4-dihydro- were stirred 2 g 5-hydroxy-4-oxo-2-pyridinyl ^ 7 "2" Penoic Pr ° and 5.5 ml of N-methyl-N- (trimethylsilyl) trifluoraceous-20 tamide in 50 ml of ethyl acetate at temperature room for one hour. A clear solution was formed and, after cooling, was added dropwise to the activated acid at -30 ° C. The mixture was stirred for 1 hour at -30 ° C, for 30 minutes at -10 ° C and for one hour at 0 ° C. The solvents were then evaporated in vacuo and the residue was stirred with 50 ml of isopropanol. A solid has formed.

It was isolated by filtration and stirred with

St 100 ml of ice water for 20 minutes at a pH of 2 30 (phosphoric acid). Filtration gave the diphenylmethyl ester of the title compound which was washed three times with 50 ml portions of ice water and dried (1.78 g). 1.5 g of the ester was stirred with 50 ml of a 4: 1 mixture of trifluoroacetic acid and anisole for 30 minutes at 1390 ° C. After the addition of 150 ml of ether, by filtration, the trifluoroacetate salt of the free acid of the title compound (1.65 g) was isolated.

1 g of this material was suspended in 5 ml of water and the pH was adjusted to 6.0 (sodium bicarbonate). The clear solution was then subjected to chromatography on 400 g of macroreticular copolymer of styrene / divinylbenzene using water as eluent to obtain 413 g of the com-10 put under heading. 400 mg of this material was again subjected to chromatography on "Merck Lobar C" using water as the eluent; yield: 160 mg.

Example 17

Acid £ -3S (Z) J-2- rrr l- (2-amino-4-thiazolyl) -2-15 ΖΓΓ 1-JT £ CCC 2_ £ "ü (1, 4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) carbonyl JJ amino JJ thyl amino J tallow onyl 17-amino J7carbonyl Z7 "'2-oxo-3-azetidinyl JJamino JJ-2-oxo-ethylidene J7 amino J7 oxy J7-2-methylpropanoic, disodium salt_ 20 A) N- (4-methoxybenzyl) -O-benzylcomenamic acid

For 4 hours, 10 g of O-benzylcomenic acid and 10 ml of 4-methoxy-benzylamine in 60 ml of water were heated to reflux. Acidification of the reaction mixture at room temperature with 2N hydrochloric acid to a pH of 2a gave 15 g of crystals. By recrystallization from dioxane, 12 ^ 3 g of the compound was obtained under the heading of a melting point of 175 ° C.

B) 1,4-dihydro-1- £ J (4-methoxyphenyl) methyl J7-4-OXO- 5- (phenylmethoxy) -N- £ "2- £ * (phenylmethyl) amino JJé thyl" J- 2-pyridine -carboxamide_

For one hour at room temperature, 3.69 g of N- £ * (4-methoxyphenyl) -methylJJ-O-behzyl-comenamic acid, 1.50 g of N-hydroxy-benzotriazole and 2 were stirred. 0.05 g of dicyclohexylcarbodiimide 140 in 50 ml of dioxane. A solution of 1.35 g of N-benzyl-ethylenediamine in 5 ml of dioxane was then added dropwise. After stirring for one. overnight, by filtration, the 5-dicyclo hexylurea formed was separated and the dioxane was evaporated from the filtrate.

The residue (oil) was dissolved in 50 ml of dichloromethane and extracted with two 50 ml portions of 10% sodium bicarbonate, then washed with water. After drying the solution of dichloromethane over sodium sulfate and after evaporation, the residual solid was recrystallized from ethanol to obtain crystals (4.2 g) of the compound under a melting point 112 ° C.

C) N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2-15 pyridine-carboxamide, p-toluene sulfonate salt.

9.95 g of 1,4-dihydro-1- £ (4-methoxypheny1) mé thy1 J-4-oxo-5- (phenylmethoxy) -N- £ T (phenylmethyl) aminoj ^ ethyl ^ -2- were treated. pyridine-carbo-xamide and 7.7 g of p-toluene sulfonic acid in 100 20 ml of methanol with 3 g of palladium carbon (10%) and hydrogen was bubbled through the reaction mixture at 45 -50 ° C for 6 hours. A stream of argon was then bubbled through the reaction mixture for 10 minutes. By filtration and evaporation of the filtrate, beige crystals of the title compound were obtained which were washed first with 20 ml of cold methanol, then with 50 ml of ether. Yield: 10.5 g; melting point: 271 ° C.

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

5.42 g of the p-toluene sulfonate salt of N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2-pyridine-carboxamide were dissolved in 50 ml of acid formic 35 and 7.5 ml formic acid / hydrochloric acid gas (2.2 equivalents hydrochloric acid) was added, followed by 150 ml ether; white crystals were obtained.

By isolation by filtration and washing with 200 ml of ether, 2.60 g of the title compound was obtained with a melting point of 287 ° C.

E) Acid (3S) - £ l-ζ CCLC 2- £ Γ (1 »4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonylJamino JéthylJ -amino J7sulfonyl Jamino ^ carbonyl ^ -2-oxo-3 -azetidinyl J- carbamic, phenylmethyl ester 10 ′ To 4.38 g of (S) -3- £ * C (phenylmethoxy) - carbonyl ^ 7amino jr-2-azetidinone suspended in 50 ml of ethyl acetate, added 2.83 g of chlorosulfonyl isocyanate at room temperature. After stirring for 30 minutes, a clear solution was obtained.

5.40 g of N- (2-aminoethyl) -1,4-dihydro-5 ~ hydroxy-4-oxo-2-pyridine-carboxamide hydrochloride were stirred in 50 ml of acetonitrile with 24 g (6 equivalents) of N-methyl-N- (trimethylsilyl) tri-fluoracetamide at 50 ° C for one hour. The volatile products were then evaporated in vacuo. To the remaining oily residue was added 50 ml of ethyl acetate.

The solutions prepared above were cooled to 0 ° C and the second solution was added to the first while stirring. After stirring overnight, 200 ml of isopropanol was added with stirring at 0 ° C to obtain the compound under the form of beige crystals. Yield: 8.77 g; melting point: 145 ° C.

30 F) ^ (3-amino-2-oxo-1-azetidinyl) carbonyl. 7amino Jamino J ^ ethyl J7-1,4-dihydro-5-hydroxy-4-oxo-2-pyridine-carboxamide, salt 2.0 -tri- fluoracetate_

2 g of phenylmethyl ester of acid (3S) -Γ 1 -CC CL C 2-Γ £ (1,4-dihydro-5,142 hydroxy-4-oxo-2-pyridiny1) c arbony1Jamino J7 were stirred. ethy1 J - amino j ^ sulfonyl J7 & mino J ^ carbonyl ^ -2-oxo-3-azetidinylJ7- carbamic in 20 ml of thioanisole / 40 ml of trifluoroacetic acid at 0 ° C for 12 hours. After addition of 100 ml of ether, by filtration, white (fine) crystals of the title compound were isolated.

By washing with 50 ml of isopropanol and 100 ml of ether, 2.12 g of the compound was obtained under the heading of a melting point of 36 ° C (decomposition).

10 G) Acid £ ”3S (Z) J-2- £ Γ Γ 1 - (2-amino-4 ~ thiazolyl) - 2-ΓΕι-ΓΓΓ Γ £ · 2-ΓΓ (ι, 4 -dihydro-5-hydroxy -4-oxo-2-pyridinyl) carbonyl amino J thyl J amino J tallow onyl J-amino .7carbonyl j ^ -2-oxo-3-azétidinyl "Jamino J-2-oxo-ethylidene aminoJ7oxy ^ -2-methylpropanoic, ester 15 diphenylmethyl_

4.40 g of (Z) -2-amino-0 (-ΓΓ 2 - (diphenylmethoxy) -1, l-dimethyl-2-oxoethoxy J-imino 17-4-thiazole-acetic acid and 3 g were dissolved. of triethylamine in 150 ml of acetonitrile, at -30 ° C, 2.8 g of diphenyl chlorophosphate were added dropwise and the mixture was stirred for one hour.

6.13 g of the 2, O-trifluoroacetate of (3S) -N- united (3-amino-2-oxo-1-azé t idiny 1) carbonyl) 1 ^ amino J7 tallow onyl were stirred for 2 hours amino j [-25 ethyl J-1,4-dihydro-5-hydroxy-4-oxo-2-pyridine-carboxamide and 17 g of N-methyl-N- (trimethylsilyl) trifluor-acetamide in 100 ml of acetate ethyl. The solvent was separated from the clear solution by vacuum distillation and the residual oil was evaporated for 2 hours at 30 ° C (oil vacuum <0.01 mm). The residue was dissolved again in 100 ml of ethyl acetate and added dropwise to the activated acid at -30 ° C (30 minutes). The mixture was stirred for one hour at -10 ° C and for one hour at 0 ° C. The solvent was evaporated and the remaining oily residue 143 was stirred with ice water at pH 3 (2N phosphoric acid). The ice water was removed and the residue was washed with ice water, then dried. Yield: 7.8 g of beige crystals.

5 H) Acid / Z3S (Z) Jz-CETî - (Ξ-amino — 4-thiazolyl) - z-rci-rccccz-ct (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl7amino JTethyl Jamino J ^ ulfonyl J-amino ^ carbonyl _7-2-oxo-3-azetidinyl J ^ amino J7-2-oxo-ethylidene .Jamino.7oxy ^ -2-methylpropanoic acid, disodium salt_

For 3 minutes, 3 g of diphenylmethyl ester of ^ 3S (Z) J-2.-CCL · l- (2-amino-4-thiazolyl) -2- ΓΖΓ1-dip2-ΓΖΓ (1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl JaminoJ7ethyl J-15 amino J7sulfonyl, 7-2-oxo-3-azetidinyl J- amino J-2-oxoethylidene ^ amino JJoxy J-2-methylpropa- noic in 30 ml of trifluoroacetic acid / anisole.

The trifluoroacetate salt of the free acid was isolated after precipitation with ether. 7.9 g of this material was suspended in 20 ml of water and the pH was adjusted to 6.0 with sodium bicarbonate. After stirring for half an hour, the suspension was filtered and the solution was subjected to chromatography on a macroreticular copolymer of styrene / divinylbenzene with water as eluent to obtain 0.24 g. This material was again subjected to chromatography in a column of "Merck Lobar C"; yield: 0.078 g; melting point: 275 ° C (decomposition).

144

Example 18

Acid £ T2S £ * 2 OC, 3ß (Z) J 7-2-ΓΓΓ 1- (2-amino-4-thiazolyl) -2- ΓΠ-ΓΓΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) carbonyl7anûno 7 “2-oxo-,; 1-imidazolidinyl J7 onyl follow 17amino | 7carbonyl ^ -2- 5 methyl-4-oxo-3-azetidinyl 7amino 7-2-oxoethylidene 7 “amino 7oxy7-2-methylpropanoic acid, disodium salt_ A) (2S-trans) -Ç1- acid 7 ΖΓ7 Π 3-7 771,4-dihydro- 4-oxo-5- (phenylmethoxy) -2-pyridinyl7cartOnyl 7amino 7- 2-oxo-l-imidazolidinyl7sulfonyl7amin ° 7carbonyl 7- t 10 2-methyl-4-oxo-3 -azetidinyl7carbamic, phenylmethyl ester_

For one hour, at 0-5 ° C., 2.35 g of phenylmethyl ester of (3S-trans) - (4-methyl-2-oxo-3-azetidinyl) carbamic acid and 1.41 g were stirred. of chlorosulfonyl iso-cyanate in 50 ml of ethyl acetate. A clear solution was obtained (solution A). 3.28 g of 1,4-dihydro-4-oxo-N- (2-oxo-1-imidazolidinyl) -5- (phenylmethoxy) -2-pyridine-carbo-xamide and 6 g of N-methyl were stirred -N- (trimethylsilyl) trifluor-20 acetamide in 50 ml of ethyl acetate for one hour at 40 ° C (solution B).

To solution A cooled (0 ° C), solution B was added with stirring for 30 minutes. After continuous stirring overnight, the solvent was evaporated and the residue (oily) was stirred with 50 ml of isopropanol and 1 drop of acetic acid. The title compound formed as a beige precipitate; melting point: 163 ° C (decomposition); 4.3 g.

30 B) (2S-trans) -N-r3-rT Π (3-amino-2-methyl-4-oxo-l-azé tidinyl) carbonyl7 amino 7 tallow onyl 7-2-oxo-l-imida-zolidinyl7 “ 1> 4-dihydro-5-hydroxy-4-oxo-2-pyridine-carboxamide, di-p-toluene-sulfonate_

For one hour at room temperature, hydrogenated 5.9 g of phenylmethyl ester of 145 (2S-trans) acid Γ1-phén3-ΓΓΓ 1,4-dihydro-4-oxo-5- (phenylmethoxy ) -2-pyridinyl ^ Jcarbonyl Camino "J-2-oxo-1-imidazolldinyl ^ sulfonyl J7amino ^ carbonyl J-2-methyl-4-oxo-3-azetidlnyl ^ 'carbamic in 50 ml of dimethylformamide and 3.8 g hydrated p-toluene sulfonic acid, as well as 2.5 g of palladium on carbon (10%). After filtration on "Hyflo", the dimethylformamide was separated by vacuum distillation. The oily residue was stirred with 100 ml of dichlorome-10 thane. The title compound (5.8 g) formed immediately as a white crystalline material.

C) Acid ZT2S- £ “20 <, 3ß (Z) J J-2- £ T £" £ “l- (2-amino-4-thiazolyl) -2- CC ^ ~ CCCL 3-CC (1,4 -dihydro-5-15 hydroxy-4-oxo-2-pyridinyl) carbonyl J7amino, 7-2-oxo-l-imidazolidinyljjsulfonyl ^ amino ^ carbonyl J-2-methyl-4-oxo-3-azetidinyl J7amino J7-2- oxoethylidene "J- aminoJ7pxy _ / - 2-methylpropanoic acid, salt ~ disodium_

4.40 g of (Z) -2-amino-0 <-20 l-dimethyl-2-oxoethoxy J-imino ^ 7-4-thiazole-acetic acid and 3 g of triethylamine were dissolved in 150 ml of acetonitrile. At -30 ° C, 2.8 g of diphenyl chlorophosphate was added dropwise and stirred for 1 hour.

For 5 minutes, at -20 ° C., 7.90 g of (2S-trans) -N-iT3-ΓΠΠ (3-amino-2-methyl-4-oxo) di-p-toluene sulfonate were stirred -l-azetidinyl) carbonyl ^ - amino J7shlfonyl j7-2-oxo-l-imidazolidinyl .7-1 »4-dihydro-5-hydroxy-4-oxo-2-pyridine-carboxamide and 30 2.02 g of triethylamine in 50 ml of dimethylforma mide.

The solution and suspension prepared above were combined at -30 ° G and stirred for one hour at -30 ° C, for 1 hour at -10 ° C and overnight at 0-10 ° C. The solvents 146 were then separated by vacuum distillation and the residue was stirred with 100 ml of ice water at pH 3 (phos-phoric acid). The diphenylmethyl ester was separated from the title compound by filtration and washed with water. Yield: 6.13 g of a beige powder.

2 g of the ester was stirred in 30 ml of a 4: 4 mixture of trifluoroacetic acid and anisole for 30 minutes at 0 ° C. By adding 100 ml of ether, the trifluoroacetate salt of the free acid precipitated.

It was suspended in 10 ml of water and the pH was adjusted to 6. After filtration, the filtrate was passed through a column of styrene / divinylbenzene macro-reticular copolymer (with water 15 as eluent). Yield: 0.48 g.

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

Example 19 20 ^ 3S (Z) J-2-amino-N- ^ l- ^ ΓΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl „7a-miho J7-2 -OXO-1-imidazolidinyl ^ sulfonyl J7amino J7carbonyl J7-2-OXO- 3-azetidinylJ-0 (- (methoxyimino) -4-thiazole-acetamide, monopotassium salt_ To a suspension of 0.6 g (0.003 mole) of (Z) -2-amino-0 <- (methoxyiniino) -4-thiazole-acetic acid, 2.14 ml (0.009 mole) of tributylamine was added at room temperature. The suspension was cooled to -30 ° C, temperature at which 0.66 ml (0.003 mole) of diphenyl chlorophosphate was added The reaction mixture was stirred at -30 ° C for one hour (mixture A).

To a suspension of 1.62 g (0.003 mole) of (3S) -3-amino-N- ΓΓ3-ΓΖΓ (1,4-dihydro-5-hydroxy-35 4-oxo-2-pyridinyl) carbonylJ7amino I7-2 -oxo-l-imidazo- 147 lidinylJ7sulfonyl J7-2-oxo-l-azetidine-carboxamide in 20 ml of ethyl acetate, 2.6 ml of bis-trimethylsilyl-acetamide was added at room temperature to to form a light brownish solution which was stirred for one hour at room temperature, then cooled to 0 ° C (solution. B)

While stirring, solution B was added dropwise to mixture A, while maintaining the temperature at -30 ° C (about 10 minutes). The mixture was stirred at -10 ° C for one hour and at 0 ° C for an additional hour and a half, then evaporated in vacuo. The residual syrup was dissolved in 50 ml of acetone. To this solution, 6 ml of 1M potassium ethylhexanoate was added to precipitate 3 g of the crude product. By adding ether to the filtrate, an additional 0.2 g of raw material was obtained. Chromatography of the raw material on a macroreticular copolymer of styrene / divinylbenzene gave 1.85 g of the title compound.

Example 20

C3S (Z) J-2-ΓΓΓ l- (2-amino-4-thiazolyl) -2-ΓΓ1-ΓΓΓΓ3-ΖΓΓ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl J acid / aminoJ7-2-oxo-1-imidazolidinylJ7 ~ 25 sulfonyl ^ amino ^ JcarbonylJ7-2-oxo-3-azetidinyl J- amino ^ 7_2-oxoethylidene J / amino J7oxy J7-2-methylpropanoic _________

2.2 g (see Example 1) of the disodium salt of / 73S (Z) acid were dissolved. J-2-JZ ÜC l- (2-amino — 4— thiazolyl) -2- £ · Cl- Ç Π Π L 3- £ * Æ'd ^ -dihydro-S- hydroxy-4-oxo-2-pyridinyl) carbonyl J ^ amino ^ -2-oxo-l-imidazolidinylUsulfonylJ7amino carbonyl J7-2-oxo-3-azetidinyl ^ aminoJ ^ -2-oxoethylidene. 7amino Joxy J-2-methylpropanoic acid in 20 ml of a 1: 1 mixture of ac-35 tone and water and the pH was adjusted to 2 with hydrochloric acid 148 2N. By chromatography using a macroreticular copolymer of styrene / divinyl-benzene, 0.7 g of the title compound was obtained.

Example 21: 5 ij3S (Z) U-2-C12 £ Tl- (2-amino-4-thiazolyl) -2-ϋΓ ΖΓ 1- Γ / ΓΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy-4- oxo-2-pyridi-nyl) carbonyl ^ 7amino ^ -2-oxo-l-imidazolidinyl 3 ~ sulfonyl amino. ^ carbonyl "7-2-oxo-3-azétidinyl J7-amino ^ 7-2-oxoéthylidène Jamino J7oxy JN- Yiy & royy-Z- 10 methylpropanamide, sodium salt_

4.72 g of (Z) -2-amino- <X -CC 1,1-dimethyl-2-oxo-2- £ (triphenylmethoxy) amino J7ethoxy imino. 7-4-thiazole-acetic acid were added suspended in 65 ml of acetonitrile and, at -30 ° C, 3.72 ml of triethylamine was added. After stirring for 10 minutes, 1.97 ml of diphenyl chlorophosphate was poured in dropwise. Stirring was then continued for 90 minutes (solution A).

We put 8.9 ml of (3S) -3-amino-N- ΓΓ3-20 rr d, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonylJ7amino3r-2-oxo-l- imidazolidinyl ^ sulfonyl J7-2-oxo-1-azetidine-carboxamide suspended in 70 ml of acetonitrile and 7.7 ml of bis-trimethyl-silylacetamide was added. A clear solution was obtained after stirring for one hour at -10 ° C and for one and a half hours at 0 ° C. The solvent and the trimethylsilyl ester of tri-fluoracetic acid formed were evaporated in vacuo, then the residual oil was dissolved in 70 ml of ethyl acetate (solution B).

The solution A was then poured dropwise into the stirred solution B at -20 ° C for 30 minutes. Stirring continued at -10 ° C for one and a half hours and at 0 ° C for one hour terminated the reaction.

149

The solvents were then separated by vacuum distillation and the oily residue was stirred with 300 ml of ice water, the pH of which was adjusted to 4 with phosphoric acid (10%). Then we have; The solid formed was filtered off, washed with water and dried in vacuo overnight. Yield: 9 g of crude product.

4.5 g of the crude product were stirred with 45 ml of formic acid (98%) and 4.5 ml of dichloromethane 10 at 0 ° C for one hour. 2.3 g of the title compound were obtained by precipitation with diethyl ether.

Example 22

Acid £ * 3S (z) j-2-rrri - (2-amino-4-thiazolyl) -2-i5 rci-c π ε c 2-c C3-c c (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl) carbonyl ZIamino, 7-2-oxo-l-imidazoli-dinyl ^ carbonyl 7hydrazinoZ7sulfonyl J amino J7carbo-nyl Z7-2-oxo-3-azetidinyl U amino j ^ -2-oxoethylidene J- amino 7oxy Z7-2-methylpropanoic acid, disodium salt_ 20 A) 2 - ^^ (phenylmethoxy) carbonyl ^ amino ^ -2-imidazoli-dinone_

26 g (0.257 mol) of 1-amino-2-imidazolidinone was dissolved in 200 ml of water. The solution was laminated with 200 ml of ethyl acetate and 43.8 g (0.257 mol) of chloroformic acid benzyl ester was added dropwise to the mixture while stirring and maintaining the pH to 8.5-9 by addition of a saturated sodium bicarbonate solution. After stirring overnight at room temperature, by filtration, the title compound was separated, washed first with water, then with ethyl acetate. Yield: 46.7 g; melting point: 140-144 ° C.

150 B) 1-ΕΠ (phenylmethoxy) carbonyl ^ amino. JS-tchloro-carbonyl) -2-imidazolidinone_ To a suspension of 69.9 g (0.297 mole) of 2- £ "£" (phenylmethoxy) carbonyl Jamino, 7- 2-imidazoli-5 dinone in 1 l of dichloromethane, a solution of 35 g of phosgene in 200 ml of dichloromethane was added. The mixture was stirred overnight at room temperature to form a clear solution. The solvent was removed in vacuo and the residual syrup was triturated with ether. Yield: 76 g; melting point: 102-105 ° C.

C) 3- CC acid (phenylme thoxy) c arbony 1 j [amino j [- 2-oxo-1-imidazolidine-carboxylic, 2- £ (1,1-dimethylethoxy) -carbony1Z7hydrazide_ 15 At room temperature, 76 g (0.255 mol) of 1-7 * (phenylmethoxy) carbonyl ^ 7-amino. 7-3- (chlorocarbonyl) -2-imidazolidinone added to 1.5 l of ethyl acetate. After cooling to 0-5 ° C for 30 minutes, a solution of 39.6 g (0.9 mole) of N- (t-butoxycarbonyl) -hydrazide and 41.8 ml of triethylamine (0.3 mole) in 150 ml of ethyl acetate. The mixture was stirred overnight. The precipitate was separated by filtration, dried, stirred with 800 ml of water to remove the triethylamine hydrochloride, filtered, washed with water and dried it. Yield: 71.2 g; melting point: 195-198 ° C.

D) 2- ΓΓ3-ΓΖΓΖΓ1.4 -dihydro-4-oxo-5- (phenyl- * methoxy) -2-pyridinyl ^ carbonyl.7amino, 7-2-oxo-l-imida-30 zolidinyl Jcarbonyl .Jhydrazine- acid carboxylic, 1,1-dimethylethyl ester_

31.5 g (0.08 mole) of 2- £ (1,1-dimethylethoxy) carbonylI7hydrazide of acid 3 ~ Γ £ (phe-nylmethoxy) carbony1 ^ amino ^ 7-2-oxo-l-imidazolidine were dissolved -35 carboxylic acid in 400 ml of dimethylformamide, 151 g of palladium on carbon (10%) were added and hydrogen was passed through the stirred reaction mixture. After one hour, the catalyst was filtered off. To the filtrate was added 19.62 g. 5 (0.08 mole) O-benzyl-comenamic acid, 0.48 g of dimethylaminopyridine and 0.64 g of N-hydroxybenzo-triazole. The mixture was stirred for one hour at room temperature. At room temperature, a solution of 18.13 g (0.088 mole) of dicyclohexylcarbodiimide was added and the mixture was stirred overnight. By filtration, the precipitate was separated (dicyclohexylurea), the filtrate was evaporated in vacuo and the residue was triturated with water to which sodium bicarbonate was added to adjust the pH to 7.5. The precipitate was separated by filtration to obtain 36 g of the title compound.

E) 3- ΓΓΓ1,4 -dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl J ^ carbonyl ^ amino J7-2-oxo-l-imidazolidine-carboxylic, hydrazide_ 20 While stirring at - 10 ° C, 36 g of 1,1-dimethylethyl ester of 2- £ Γ3-ΓΓ £ ι, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinylJ7carbonylJ-amino J7- were added 2-oxo-1-imidazolidinyl J'carbonyl. Jhydrazine-carboxylic to 300 ml of trifluoroacetic acid. The mixture was stirred at 0 ° C for one hour, the trifluoroacetic acid was removed in vacuo and the residue was triturated with ether to obtain 41 g of the trifluoroacetate salt of the title compound. While cooling, the trifluoroacetate salt was suspended in water and the pH was adjusted to 7 by addition of 2N sodium hydroxide. The precipitate was separated by filtration to obtain 21.9 g of the title compound.

152 F) Acid 3- £ “£" (1,4-dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) carbonyl amino J ^ -2-oxo-l-imidazolidine-carboxylic, hydrazide_

21.9 g of hydrazide of acid 3- ΓΓ - 5 £ “1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl J1- carbonyl ^ amino J7“ 2-oxo- l-imidazolidine-carboxylic suspension in 250 ml of acetonitrile. To the suspension, 75 ml of bis-trimethylsilylacetamide was added and the mixture was stirred to form a solution.

To this solution, 10 g of palladium on carbon (10%) was added and hydrogen was passed through. the mixture stirred vigorously. Debenzylation was complete after one hour. After filtration, 15 ml of methanol and 10 drops of acetic acid were added to precipitate the title compound. Yield: 10.8 g. This raw material was stirred with 150 ml of ethanol to obtain 8.8 g of the title compound with a melting point below 205 ° C (decomposition).

20 G) Acid (S) - £ l- £ CC C 2-Γ £ 3-C £ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl 'Jamino J7-2-oxo- 1-imidazolidinyl J7carhonyl. Jhydrazino ^ sulfonyl ^ amino carbonyl ^ -2-oxo-3-azetidinyl J7carbamic, phenylmethyl ester 25 suspension of 5.9 g (0.02 mole) of 3- ce acid drazide ( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonylOamino 0-2-oxo-1-imidazolidine-carboxylic, 14.9 ml (0.08 mol) of N-methyl was added N- (trimethylsilyl) trifluoroacetamide and the mixture was stirred at 50 ° C to form a solution (solution A).

To a suspension of 4.4 g (0.02 mole) of (S) -ZT yC (phenylmethoxy) carbonyl Jamino jr-2-azetidinone in 160 ml of ethyl acetate was added 1.76 ml 35 d chlorosulfonyl isocyanate at room temperature.

153

The mixture was stirred for 1 hour (solution B).

Solution A (with ice cooling) was added to solution B. After stirring for one hour, 2.8 ml (0.02 mole) of - triethylamine was added to the mixture which was then stirred overnight at room temperature. An additional 2.8 ml (0.02 mole) of triethylamine was added, followed by ice water. The mixture was vigorously stirred for one hour and the layers were separated. The aqueous phase was acidified to a pH of 3 and the precipitate was isolated by filtration. Yield: 5.3 g of the title compound in the raw state.

The raw material was dissolved in a mixture of acetone and water and the pH of the solution was adjusted to 6.5 by addition of 2N sodium hydroxide. After removing the acetone in vacuo, the aqueous solution was filtered and lyophilized to obtain 5.5 g of the crude sodium salt of the title compound. Chromatography of the crude sodium salt on a macroreticular copolymer of styrene / divinylbenzene gave 0.64 g of purified material. The latter was dissolved in water and acidified with 2N hydrochloric acid to precipitate the compound under brick. Yield: 0.5 g.

H) (S) -N-r3-rC2-rrr (3-amino-2-oxo-l-azetidinyl) -carbonyl j ^ amino J7sulfonyl .Jhydrazino .7carbonyl J-2-oxo-l-imidazolidinyl 7-1,4 -dihydro-5-hydroxy-4-oxo-2-pyridine-carboxamide_ 0.5 g of phenylmethyl ester of (S) -Γι-Γ £ ΓΓ2-ΓΓ3-ΓΖ acid was added: (1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl Camino j ^ -oxo-l-imidazolidinyl J7 carbonyl jhydrazino "J suif onyl J-amino 7 ° arbonyl ^ -2-oxo-3-azetidinyl" / carbamic to A mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid 154. The mixture was stirred overnight at room temperature and evaporated in vacuo. The residue was triturated with ethyl acetate to obtain the title compound in quantitative yield.

I) Acid £ "3S (Z) ^ -2- £ £ £ 2-amino-4-thiazolyl 'Jz-CCi-CCCCs-rCs-CC (1,4-dihydro-5-hydroxy- 4-oxo-2- pyridinyl) carbonylJamino J7 “2-oxo-l-imidazoli-dinyl JjJcarbonyl .Jhydrazino, 7sulfonyl J amino J7carbo-10 nyl ^ -2-oxo-3-azetidinyl ^ 7 aminoI7-2-oxoethylidene amino j ^ oxyJ7-2-methylpropanoic acid, ester diphenyl-methyl_ To a solution of 0.35 g (0.0008 mole) of (Z) -2-amino-0 acid <- £ 7Zr2- (diphenylmethoxy) -1,15-dimethyl-2-oxoethoxyI7imino17-4 -thiazole-acetic in 10 ml of acetonitrile, 0.34 ml of triethylamine was added, the mixture was cooled to -30 ° C. and 0.17 ml of diphenyl chlorophosphate was added.

The reaction mixture was stirred at -30 ° C for one hour (solution A).

To a suspension of 0.008 mole of (S) -N-Γ3-ΓΓ2-ΓΓΓ (3-amino-2-oxo-l-azetidinyl) carbo-nyl J amino J tallow onyl j ^ hydrazino j ^ carbonyl, 7-2- oxo-1-imidazolidinyl I? -1,4-dihydro-5-hydroxy-4-oxo-2-pyri-dine-carboxamide in 6 ml of ethyl acetate, 0.7 ml of bis- was added trimethylsilylacetamide (solution B).

Solution B was added to solution A at -30 ° C. The mixture was stirred at -10 ° C for 2 hours and at 0 ° C for one hour, then evaporated in vacuo. After treating the residue with water, 0.7 g of the title compound in the raw state was obtained having a melting point of 155 ° C (decomposition).

155 J) Acid ü 3s (z) 7-2-1 * Γ Ci - (2-amino-4-thiazolyl) -2-ΓΓι-ΓΓ ££ 2- £ Γ3-ΓΓ (1,4-dihydro-5- hydroxy- 4-oxo-2-pyridinyl) carbonylJ7 amino7-2-oxo-l-imidazo-lidinyl 7carbonyl 7hydrazinoe7sulfonyl ^ amino 7carbo-5 nyl 7-2- ° x ° -3-azetidinyl ^ amino 7 “2“ ox ° ethylidene7 “Amino7oxy7-2-methylpropanoic acid, disodium salt_ To a suspension of 0.7 g (0.00077 mol) of diphenylmethyl ester of T3S (Z) J-2-C UC i- £ T2 -amino-4-thiazolyl iz-rn- ΠΠΙΠ2-10 ΓΓ3-ΓΓ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl J7amino7-2-oxo-l-imidazolidinyl7carbonyl7-hydrazino ^ 7sulfonyl 7 ^ 1 ^ 0 7carbonyl 7-2-oxo-3-azeti-dinyl 7 amino. 7-2-oxoethylidene 7 amino 7oxy 7 -2-methyl-propanoic in 1 ml of anisole, 6 ml of trifluoroacetic acid was added at -10 ° vs. The mixture was kept at -10 ° C for one hour. At -10 ° C, ether was added to precipitate the free acid trifluoroacetate from the starting material; yield: 0.5 g.

The precipitate was suspended in water while cooling and the pH was adjusted to 5.5 by addition of 2N sodium hydroxide. Lyophilization gave 0.55 g of raw material. The raw material was purified by chromatography on a macroreticular copolymer of styrene / divinylbenzene to obtain 0.1 g of the purified title compound.

Example 23

73S (Z) j-2-rrn - (2-amino-4-thiazolyl) -2-CCl- £ * C Π £ 2 ~ C (1,4-dihydro-5-hydroxy-4-oxo-2- pyri-30 dinyl) carbonyl 7-2-methylhydrazino7sulf onyl 7 - amino 7carbonyl 7-2-oxo-3-azetidinyl 7amino 7-2-oxo-ethylidene 7amino7oxy 7-2-methylpropanoic acid, disodium salt______ A) Acid 1,4-dihydro -4-oxo-5- (phenylmethoxy) -1- (phenyl-methyl) -2-pyridine-carboxylic, 1-methylhydrazide_ 156

0.15 mole of N, 0-dibenzylcomenamyl chloride was suspended in 150 ml of dichloromethane while cooling with ice.

To the suspension was added 26.2 ml (0.5 mole) of methylhydrazine, then 150 ml of acetonitrile. The mixture was stirred overnight at room temperature. The cloudy solution was evaporated in vacuo and triturated with 300 ml of water. The solid material obtained was filtered and dried to obtain 26.3 g of crude material. By recrystallizing the raw material from water, 12.7 g of the pure title compound was obtained having a melting point of 138-142 ° C.

B) (S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -1-15 (phenylmethyl) -2-pyridine-carboxylic acid, l-methyl-2- ΓΓΖΓΓ 2-oxo-3-j / 7 £ * (phenylmethoxy) carbonyl ^ amino ^ - * 1-azétidinyljjcarbonyl ^ amino 7sulfonyl Jhydrazide

1.82 g (0.005 mol) of 1-methyl-hydrazide of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -20 l- (phenylmethyl) -2-pyridine-carboxylic acid was suspended in 20 ml of ethyl acetate. At room temperature, a total amount of 1.85 ml of N-methyl-N- (trimethylsilyl) trifluoroacetamide (0.01 mole) was added. The mixture was stirred for 4 hours at 60 ° C (suspension A).

1.1 g (0.005 mole) of (S) -3- ce (phenylmethoxy) carbonyl ^ amino J ^ -2-azetidinone were suspended in 40 ml of ethyl acetate at room temperature and 0.5 ml of chlorosulfonyl isocyanate was added. The mixture was stirred at room temperature for one hour to form a solution (solution B).

To solution B was added 1.2 ml of triethylamine (with ice cooling), then 35 ml of dichloromethane and suspension A. The suspension was stirred overnight at room temperature . To the slightly cloudy solution was added 30 ml of dichloromethane and 20 ml of water and the mixture was stirred for one hour at room temperature. The pH of the aqueous solution was 6.5-7. 60 ml of ethyl acetate was added, the organic layer was separated and the aqueous phase was washed twice with a 1: 3 mixture of dichloromethane and ethyl acetate. The combined organic phases were dried (magnesium sulfate) and evaporated to give 4.5 g of a syrup which crystallized when left to stand for a weekend. After treatment with ether, 2.6 g of the title compound in the raw state were obtained.

C) 1,4-Dihydro-5-hydroxy-4-oxo-2-pyridine-carboxylic acid, 2- LZLi 3-amino-2-oxo-1-azetidinyl) carbonyl "2 ~ amino ^ sulfonyl J7- l-methylhydrazide, trifluoroacetate salt To a solution of 2 g of l-methyl-2- ΓΓΓΓ 2-oxo-3- £ Q (phenylmethoxy) carbonyl ^ aminoJ ^ -l-azéti-20 dinyl JcarbonylCamino ^ sulfonyl ^ hydrazide (S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenyl-methyl) -2-pyridine-carboxylic in 60 ml of dimethylformamide, 1.1 ml of trifluoroacetic acid, then 1 g of palladium on carbon (10%). After flushing with nitrogen, hydrogen was passed through the solution for 60 minutes while stirring, the catalyst was removed by filtration, the filtrate was evaporated in vacuo and the residue was triturated with ether to obtain 1.1 g of the title compound 30 in a crude state Yield: 86.6%.

D) Acid £ 73S (z) ^ 7-2 “Zr ^ £ '1- (2-amino-4-thiazolyl) -2- £ ΓΓι-ΓΓΓΓ2-Γ (ι, 4 -dihydro-5-hydroxy-4- oxo-2-pyridinyl) carbonylJ-2-methylhydrazino J7 suifonyl 17 -aminoJ7carbonyl I7-2-oxo-3-azetidinyl ^ amino ^ 7-2-oxo-35 ethylidene ^ aminoJ7oxyJ ^ -2-methylpropanoic, ester 158 diphenylmethyligue_ To a suspension 0.88 g (0.002 mole) (Z) -2-amino-0 (-ir '£ "2- (diphenylmethoxy) -1,1-dimethyl-2-oxoethoxy ^ imino, 7-4-thiazole acid -acetic 5 in 30 ml of acetonitrile, 0.7 ml (0.005 mole) of triethylamine was added and then, at -30 ° C., 0.44 ml (0.002 mole) of diphenyl chlorophosphate. The mixture was stirred at -30 ° C for one hour (solution A).

To a suspension of 1.2 g (0.002 mole) of 10 2- £ * £ * £ * (3-amino-2-oxo-1-azetidinyl) carbonyl J-aminoJJsulfonyl Jf-1-methylhydrazide of 1,4 acid -dihy-dro-5-hydroxy-4-oxo-2-pyridine-carboxylic acid (trifluoroacetate salt) in 30 ml of ethyl acetate, 2 ml (approximately 0.008 mol) of bis-trimethyl-15 silylacetamide were added to room temperature to form, after 30 minutes, a clear solution (solution B).

: At -30 ° C, solution B was added dropwise to solution A (about 10 minutes). The temperature was maintained at -10 ° C for one hour and at 0 ° C for an additional hour.

The solvent was evaporated and the residue was treated with water to obtain, after filtration and drying, 2.4 g of the title compound in the raw state.

E) Acid £ 3S (z) J-2-ΓΓΓΐ - (2-amino-4-thiazolyl) -25 2- ΓΓ 1-Γ CC Γ 2-f (1,4-dihydro-5-hydroxy-4-oxo -2-pyridinyl) carbonyl ^ -2-methylhydrazino ^ sulfonylJ-amino Jcarbonyl 7-2-oxo-3-azetidinyl J ^ aminoJ-2-oxo-ethylidene j ^ amino Joxy J-2-methylpropanoic acid, disodium salt_ 30 A - 10 ° C, 2.4 g of diphenylmethyl ester £ * 3S (Z) was added. 7-2-ΖΓ L £ l- (2-amino-4-thiazolyl) -2- £ " Zr 1- £ CFC 2 (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl, 7-2-methylhydrazino 'J-sulfonyl J7amino Z7carbonyl Z7-2-oxo-3-azetidinyl J-35 amino, 7-2-oxoethylidene J7aminotjroxy, 7 ~ 2-methylpropanoic crude 159 to a mixture of 20 ml of trifluoroacetic acid and 4 ml of anisole. The mixture was stirred at -10 ° C for hour and the reaction product was precipitated by addition of ether at -10 ° C, yield: 1.12 g of the crude trifluoroacetate of the compound under rubric.

The raw material was converted to the sodium salt by addition of 2N sodium hydroxide to a suspension in a mixture of acetone and water and by lyophilization. The sodium salt was purified by chromatography on a macroreticular copolymer of styrene / divinylbenzene (elution with water). Yield: 0.25 g.

Example 24 15 (3S) Acid -2- £ “£" £ "1- (2-amino-4-thiazolyl) -2- £ * £" 1- cccoc (1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) -methyl J'amino J / sulfonyl „Ja-mino ^ carbonyl 2 ~ 2-oxo-3-azétidinyl J7amino“ 7-2-oxoethylidene j ^ amino I7oxy.J-2-methylpropanoic_ 20 A) 2 - (hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one

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

The mixture was heated to reflux for 3.5 hours, cooled and poured into 1 L of water. The solid obtained was filtered and washed with about 1.5 l of water, 200 ml of ethanol and 400 ml of hexane.

After drying under a high vacuum, the product obtained weighed 55.7 g.

B) 1,4-dihydro-2- (hydroxymethyl) -5- (phenylmethoxy) - 4-pyridinone_

Overnight, a mixture of 9.65 g (41.59 millimoles) of 2-hydroxy-160 methyl-5- (phenylmethoxy) -4H-pyran-4-one, 95 ml of, was refluxed. concentrated ammonia and 20 ml of ethanol. An additional 75 ml of ammonium hydroxide was added, the mixture was heated to reflux for 2 hours and cooled. The brown solid obtained was filtered and washed with water until the detergents were neutral.

The crude product was suspended in ethanol, filtered, washed with ethanol and hexane and dried in vacuo. The yield of the title compound was 7.61 g.

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

Under a argon atmosphere, a suspension of 3 g (12.99 millimoles) of 1,4-dihydro-2- (hydroxymethyl) -5-phenylmethoxy) -4-pyridinone was cooled to 15 ° to 0 ° C. 15 ml of chloroform and treated with 6.1 ml (83.62 millimoles) of thionyl chloride.

- In a few minutes, a homogeneous solution was obtained.

After stirring for an additional 5 minutes, a cream-colored solid precipitated. The cooling bath was removed and the mixture was refluxed for 45 minutes. The mixture was cooled to 0 ° C and the suspended white matter was filtered, washed with chloroform and hexane and dried in vacuo. The yield of the title compound was 3.65 g.

D) 2- (azidomethyl) -1,4-dihydro-5- (phenoxymethyl) -4- pyridinone_ For a period of 3.5 days, under an atmosphere of argon and at room temperature, a mixture of 3 was stirred, 59 g (12.54 millimoles) of 1- (chloromethyl) -1,4-dihydro-5- (phenylmethoxy) -4-pyridinone hydrochloride, 4.08 g (62.7 millimoles) of sodium azide and 2.19 ml (12.54 millimoles) of diisopropyl pylethylamine in 70 ml of dimethylformamide. An additional 4.08 g of sodium azide was added and the mixture was heated to 45-50 ° C for 2 hours. After cooling, the reaction mixture was poured into 500 ml of water to obtain an insoluble white solid. The pH of the supernatant liquid was lowered from 8.5 to 7.5 with dilute hydrochloric acid and the white solid was filtered. After washing with water, acetone and hexane, the solid was dried in vacuo. The yield of the title compound was 2.81 g.

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

For 6 hours, at room temperature and under a hydrogen atmosphere, a suspension of 2.030 g (7.93 mmol) of 2- (azido-methyl) -1,4-dihydro-5- (phenoxymethyl) was stirred ) -4-pyridinone and 200 mg of platinum oxide in 100 ml of dimethylf ormamide. The catalyst was removed by filtration and the solution was concentrated in vacuo to give 1.5 g of the title compound as a gray powder.

F) (3S) -l ~ C Π CC C (lj4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methylJ7amino_7sulfonyl 7amino 7carbonyl J-2-οχο-3- £ * Z (phenylmethoxy) carbonyl 7amino Jazetidine 25 To a stirred suspension of 2.330 g (10.13 millimoles) of 2- (aminomethyl) -4-oxo-5- (phenylmethoxy) -pyridine in 60 ml of ethyl acetate was added 3.76 ml (20 , 26 millimoles) of N-methyl-N- (trimethyl- "silyl) trifluoroacetamide. The naked solution was stirred for 30 minutes at room temperature, then cooled to 0 ° C. At the same time, to a stirred suspension of 2.228 g (10.13 millimoles) of (S) -3-ff (phenylmethoxy) carbonyl J7-2-azetidinone in 60 ml of ethyl acetate was added 882 yul 35 (10.13 millimoles) of chlorosulfonyl isocyanate.

162

The solution obtained was stirred for 30 minutes at room temperature, then cooled to 0 ° C and treated with 4.23 ml (30.39 millimoles) of triethylamine, then with the solution of 2 - (aminomé-e 5 thyl) -4-oxo-5- (phenylmethoxy) silylated pyridine described above. The mixture was stirred for 2 days at room temperature.

The mixture was concentrated in vacuo, the residue was dissolved in a 40:60 mixture of acetonitrile and water and the pH was lowered to 2.9, after which a thick oil separated. Upon cooling to 5 ° C, the oil solidified. The solid was separated, washed four times with water and dried in vacuo to give 3.4 g of the crude title compound 15. The crude product was dissolved in a minimum volume of dimethylformamide and the solution obtained was charged to a column (1 l) of macroreticular copoly mother of styrene / divinylbenzene. The column was eluted with a stepped gradient of acetone and water. The desired material was eluted with about 65% acetone. The affected fractions were combined and lyophilized to obtain 2.69 g of the title compound.

G) (3S) acid -2- £ * £ '£ * l- (2-amino-4-thiazolyl) -2-CCl-25 ccccc (1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl) - methyl j7amino Jsulfonyl] 7amino 7cark ° nyl i7 “2-oxo-3-azetidinyl, 7amino, 7-2-oxoethylidene„ 7amino J oxy J-2- methylpropanoic acid, diphenyl methyl ester_

30 912 mg (1.64 millimole) of (3S) -1-ΓΓ HC Π (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methylCamino J was stirred under an atmosphere of hydrogen -sulfonyl J7amino J7carbonyl.7-2-oxo-3- rz: (phenyl-methoxy) carbonyl J7amino J7azetidine, 625 mg (3.28 millimoles) of p-toluene sulfonic acid to one molecule of water and 190 mg of 10% palladium-on-carbon in 16 ml 163 of dimethylformamide until the consumption of 3.28 millimoles (73 ml) of hydrogen (approximately 3 hours).

To a stirred solution of 846 mg (1.804 millimole) of (Z) -2-amino-0 <- £ '^ 2- (diphenylmethoxy) -5 1,1-dimethyl-2-oxoethoxy J7iroino J7-4-thiazole -acetic acid in 16 ml of dimethylformamide at -20 ° C., 374 μl (1.804 millimole) of diphenyl chlorophosphate were added, followed by 450 yal (3.28 millimoles) of triethylamine.

The solution was stirred for one hour at -20 ° C, after which the above described mixture of the hydrogenolysed compound was added. Then 921yul (6.6 millimoles) of triethylamine was added. The resulting mixture was stirred at -20 ° C for one hour, then at 5 ° C overnight. The catalyst was removed by filtration, the volatiles were removed in vacuo and the oil obtained was dissolved in a minimum volume of a 75:25 mixture of acetone and water (pH: 5.2 ) and the solution obtained was added dropwise to a stirred suspension of 20 ml of "Dowex 50x2-20 400 (K +)" in a 35:65 mixture of acetone and water.

After 40 minutes, the mixture was filtered and the filtrate was lyophilized to obtain 2.1 g of a solid.

This solid was dissolved in a minimum amount of a 40:60 mixture of acetonitrile and water (pH: 5.6) and the solution obtained was loaded into a column (800 ml) of a macroreticular copolymer styrene / divinylbenzene, eluting with a stepped gradient of acetonitrile and water. The desired material * was eluted with about 30% acetonitrile. The affected fractions were combined and lyophilized to obtain the title compound.

H) (3S) - 2-CFΠl- (2-amino-4-thiazolyl) -2-ΠΠ1-Γ ΠΓϋ Π (1,4-dihydro-5-hydroxy-4-oxo-2-pyri-dinyl) acid thyl amino J tallow onyl ^ amino. ^ canbonyl J-2-35 oxo-3-azetidinylJ7amino ^ -2-oxoethylidene ^ 7amino, 7oxy 164 2-methylpropanoic_

4.7 ml of trifluoroacetic acid were added dropwise to a stirred suspension of 131 mg (0.113 millimole) of 5 (3S) -2-£ * £ * ^ 7l- diphenylmethyl ester (2- amino-4-thiazolyl) -2- rci-ccc cc (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl J-amino ^ sulfonyl ^ amino j ^ carbonyl] 7-2-oxo- 3-Azetidinyl * J-amino J7-2-oxo-ethylidene. Jamino Ioxy 17-2-methylpropanoic in 3 ml of dichloromethane and 0.3 ml of ani-10 sole at 0 ° C. After stirring for 45 minutes at 5 ° C, 2 ml of toluene was added and the volatiles were removed in vacuo. The oil obtained was washed with hexane (3 x 4 ml) and triturated into a solid with 10 ml of ether. The solid was washed once with ether (10 ml) and dried in vacuo. The above reaction and treatment was repeated above on 0.166 millimole of diphenylmethyl ester of (3S) -2-iT £ "Zri- (2-amino-4-thiazolyl) -2-ΠΠ 1-ccccc ( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -20 methyl J7 & mino] 7sulfonyl, 7amino J'carbonyl] 7-2-oxo-3-azétidinyl _7amino, 7-2-oxoéthylidène J7amino j ^ oxy ^ -2-methylpropanoic acid The crude solids were combined, dissolved in 2 ml of a 40:60 mixture of acetonitrile and water (pH 2.5) and subjected to column chromatography (200 ml) of a macroreticular copolymer of styrene / divinylbenzene using a gradient of acetonitrile and water The desired material was eluted with a 20:80 mixture of acetonitrile and The combined fractions were combined and lyophilized to obtain 103 mg of the title compound as a white solid with a melting point of 180 ° C (decomposition).

Claims (27)

165 1. Compound corresponding to the formula: • 2 Rl “NH '^ R3 2. A compound according to claim 1 in which R represents r 0 Λ OH. 1. i T 0 3. A compound according to claim 1 in which R represents 0 Ù / -V s Xr 4. Compound according to claim 1, in which R represents 25 0 jpV-OH -A, -N N ^ 1 5 30 | T H 0 170 5. A compound according to claim 1 in which R represents / \ iV- -A, -N> V * 0 ^ 0 5 -A-C-NX6X7; X ^ represents an azido group, an amino group, a hydroxy group, a carboxy group, an alkoxycarbonyl group, an alkanoylamino group, a phenylcarbonylamino group, a (substituted phenyl) car-bonylamino group, an alkylsulfonyloxy group, a phenylsulfonyloxy group, a sulfonyloxy (substituted phenyl) group, a phenyl group, a substituted phenyl group, a cyano group, 0 5 -A -N VaM ο 5 CH— C ^ t I I N-C-NH-SOg-R o 8 or a pharmaceutically acceptable salt thereof, 10 formula in which 0 π: JUT 15. represents -A. -NJ) J-Ap-C-Afi ^ N ^ Y "0 0 2 ° Il -OH /" Λ? AJ -A, -N N-A0-CA / ^ ^ N ^ 1 \ / H 25 0 ^ ^ 0 0 ΓΊ-0H 1. ir -A, -N N-Ac Nn 'Y' * 0 166 Ο 6. Compound according to claim 1 in which R represents 0 ιε jÔ "0H -m-A * 0 I * H 7. Compound according to claim 1, in which R represents 20 0 11 OH 0. f -NH-A.-C-A ^ * ^^ 4 6, 8. A compound according to claim 2 wherein A ^ represents a single bond. 9. A compound according to claim 2 in which A ^ represents -NH-. 10. A compound according to claim 2 wherein Ag represents a single bond. 10 II χν ° Η -NH-Ag '^^ N or Η 15 Ο X ΟΗ 2 1 Γ 20 -ΝΗ-Α.-C-Ac ^ \ n ^; 46, Η represents an acyl group deriving from a carboxylic acid; R2 and Rg are the same or different and each represents a hydrogen atom, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, a phenyl group, a substituted phenyl group or a tetragonal, pentamonial heterocycle , hexagonal or heptagonal or one of the radicals Rg and Rg represents a hydrogen atom and the other represents an azido group, a halomethyl group, a dihalomethyl group, a trihalomethyl group, an alkoxycarbonyl group, a 2-phenylethenyl group, a 2-phenylethynyl group, carboxy group, 35 167 X3 X3 -CH ^, -S-X2, -0-X2, -0-C-X4, -SC-X4 or X5 X5 O 11. A compound according to claim 1 in which R ^ represents 171 Ο - ° Η 5 l Y ά Ο 12. The compound of claim 1 wherein and each represents a hydrogen atom. 13. A compound according to claim 1 in 0 II wherein R. ^ represents -CC = N-0-R ^ and R ^ represents an R g 2-amino-4-thiazolyl group, while R. ^ represents a methyl group , an ethyl group, a carboxy-methyl group, a 1-carboxy-1-methylethyl group, a 1-carboxy-1-ethyl group or CH "- (CH0) where s represents V / ^ s -C-C00H 20 1 , 2 or 3. 14. Compound according to claim 1, in which R ^ represents 0 11 -C-C = N-0-R. , R represents a 2-amino-4-thia-I 1 S group 15. A compound according to claim 2 in 0 II wherein R ^ represents -CC = N-0-R ^ and R ^ represents R g a 2-amino-4-thiazolyl group, while R ^ represents a methyl group , an ethyl group, a 172 carboxymethyl group, a 1-carboxy-1-methylethyl group, a 1-carboxy-1-ethyl group or MVs -C-1500H where s represents 1, 2 or 3. -A-C-NX6X7, -S-X2 or -0-X2; X2 represents an alkyl group, a> substituted alkyl group, a phenyl group, a substituted phenyl group, a phenylalkyl group, an ((substituted phenyl) alkyl group, an alkanoyl group, a phenylalkanoyl group, a (substituted phenyl) group - alkanoyl, a phenylcarbonyl group, a (substituted phenyl) carbonyl group or a heteroarylcarbonyl group; one of the radicals X ^ and X4 represents a hydrogen atom and the other represents a hydrogen atom or an alkyl group, or X ^ and X4, taken together with the carbon atom to which they are attached, form a cycloalkyl group; * Xg represents a formyl group, an alkanoyl group, a phenylcarbonyl group, a (substituted phenyl) carbonyl group, a phenylalkyl-carbonyl group, a (substituted phenyl) alkylcarbonyl group, a carboxy group, an alkoxycarbonyl group, an aminocarbonyl group, a (substituted amino) carbonyl group or a cyano group; 168 Xg and are the same or different and each represents a hydrogen atom, an alkyl group, a phenyl group or a substituted phenyl group or Xg represents a hydrogen atom and X ^ 5 represents an amino group, a substituted amino group, an alkanoylamino group or an alkoxy group, or alternatively Xg and X7, taken together with the nitrogen atom to which they are linked, form a tetragonal, pentagonal, hexagonal or heptagonal heterocycle; 10. represents -CH = CH-, “(3Η2 ^ ιϊΓ '- (CH2) m-NH- or -CH2-S-CH2-; m represents 0, 1 or 2; 0 11 A1 represents a single bond, -NH -C-, 15 0 -NH- or -NH-NH-C-;> A2 represents a single bond, -NH-, 0 -CH2-CH2-NH- or -C-NH-NH-; 20 0 Aq represents - (0Ho) -, -NH-C-NH-, O dp 0 0 -NH-C-NH-CH2-, -nh-ch2-, -0-CH2-, -CH2-C-NH- or 0 16. A compound according to claim 2 in 0 '' ... which R1 represents -CC = N-0-R1, Rg represents a R g 2-amino-4-thiazolyl group and R ^ represents a carboxymethyl group, a 1-carboxy-1-methylethyl group, C ^ 2-> ° VS a 1-carboxy-1-ethyl group or -C-C00H where s represents 1, 2 or 3. 17. A compound according to claim 11 in 15 0 II wherein R1 represents -C-C = N-0-R. and R represents R g a 2-amino-4-thiazolyl group, while represents a methyl group, an ethyl group, a carboxymethyl group, a 1-carboxy-1-methylethyl group, °,? 2-j, 0Vs un 1-carboxy-1-ethyl group or -C-C00H where s represents 1, 2 or 3. 18. A compound according to claim 11 25 0 II in which R. represents -C-C = N-0-R. , R represents i i 1 g R g a 2-amino-4-thiazolyl group and Ri represents a carboxymethyl group or a 1-carboxy-1-methyl-ethyl group. 19. A compound according to claim 11 in which R2 and R ^ each represent a hydrogen atom. 20. The compound according to claim 1, namely iT3S (Z) Ο-Ζ-ΠΤ 0 l- (2-amino-4-thiazo- 173 lyO-2-Γ C1-C CCC 3-ΓΓ (1 , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl Jamino J-2-oxo-l-imidazoli-dinyl Jsulfonyl Jamino Jcarbonyl J-2-oxo-3-azétidi-nyl Jamino J-2-oxoethylidene Jamino Joxy J-2-methyl-; propanoic or a pharmaceutically acceptable salt thereof. 20 -A1 -N N-A0-C-A_ 21. Compound according to claim 1, namely the acid J3S (Z) J-2-CCC l- (2-amino-4-thiazo-ΐγΐ) -2-ΓΓι-ΓΓΓΓ2- £: (1,4-dihydro -5-hydroxy-4-10 oxo-2-pyridinyl) carbonyl Jhydrazino Jsulfonyl J- amino JcarbonylJ-2-oxo-3-azetidinyl Jamino J-2-oxo-ethylidene Jamino Joxy J-2-methylpropanoic or a pharmaceutically acceptable salt thereof . 22. A compound according to claim 1, namely 3S (Z) J-2-JJJ 1- (2-amino-4-thiazo-iyi) -2-rn-z: rf Γ3-ΓΖ: (1 , 4-dihydro-5-hydroxy-4-f oxo-2-pyridinyl) carbonylJaminoJ-2-oxo-l-imidazoli- dinyl JsulfonylJamino Jcarbonyl J-2-oxo-3-azétidi-nyl Jamino J-2-oxoethylidene Jamino Joxy J-2-acetic 20 or a pharmaceutically acceptable salt thereof. 23. A compound according to claim 1, namely the acid J3S (Z) J-2- ΓΓΓ l- (2-amino-4-thiazo-iyD-2-Γ C i- £ "CCCC (1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl) methylJ amino J suifonylJamino J carbo- nyl J-2-oxo-3-azetidinyl Jamino J-2-oxoethylidene J- aminoJoxyJ-2-methylpropanoic or a pharmaceutically salt thereof acceptable. 24. The compound according to claim 1, namely the acid £ 3S (Z) J-2-ΓΓΓ 1— (2-amino-4-thia-zolyl) -2-J J1-J CCH 2 -JC 2- J (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl Jhydrazino J-carbonyl Jhydrazino J tallow onyl J amino Jcarbonyl J-2-oxo-3-azetidinyl Jamino J-2-oxoethylidene Jamino J-oxyJ -2-methylpropanoic or a pharmaceutically acceptable salt thereof. 174 25. The compound according to claim 1, namely the acid £ "3S- £ * 30 ((z), 4ß 77-2-ΓΖΓΓΜ2-amino-4-thiazolyl) -2- £ / 7 £ * £, 2 - £, (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl.7hydrazino J- 5 suifonyl ^ carbonyl ^ 7-4-methyl-2-oxo-3-azeti- dinylJ7aminoJ7 “2- ox ° 6thylidene J7amino .7oxyJ-2-methylpropanoic acid or one of its pharmaceutically acceptable salts. 25 R g zolyl and R ^ represents a carboxymethyl group, a 1-carboxy-1-methylethyl group, a 1-carboxy-ch2- (0h2) s 1-ethyl or -C-C00H group where s represents 1, 2 or 3 . 'm. 25 h -CH2-C-NH-CH2-; A. represents -NH-, - (CH?) -, - (CH?) -NH-, d p d y 0. CH2X -NH-C-NH-NH-, -C-NH-NH- or -N-; Ag represents a single bond, -CH2-, 30 -NH-CH -, -N = CH- or -C-NH- (CH) -; C. Ac represents a single bond, -CH = CH- ° U "(αΗ2} ΐ" '' p represents 0 or 1; 35. represents 2, 3 or 4; 169 q represents 0 or 1; t represents 1, 2 , 3 or 4; and X represents a hydrogen atom, a carboxy group or a carbamoyl group. 26. The compound of claim 1, namely ras (z) Ji-CCC 1- (2-amino-4-thiazolyl) -2- rci-nncc 3- £ £ (1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl) carbonyl j [amino ^ -2-oxo-l-imidazo-lidinyl J7 suifonyl ^ amino J7carbonyl J7-2-oxo-3-azéti-dinyl "Jssalno J7-2- oxoethylidene "cyclopentane carboxylic acid or a pharmaceutically acceptable salt thereof. 27. Process for the preparation of compounds according to claims 1 to 26, characterized in that it comprises the steps which consist in: (1) acylating a compound of formula:? 2 Nh2 „. j CH— C-R0 II 25 ^^. C -......... NC-NH-S02-R 0 ^^ 0 with an acyl group R ^ derived from an R ^ -carbo-xylic acid , or (2) introduce an activating group 30 -CO-NH-SOgR into a compound of formula:! -? 2 R1-NH; CH-C-R0 I I 3 C-_NH 35 0 ^