CH670828A5 - - Google Patents

Description

DESCRIPTION The compounds of formula I

RX-NH

[2

i R-

* ch-

I

• hr yZ N-C-NH-SO - R,

J / He - ^

S -

as well as their pharmaceutically acceptable salts, show an antibacterial action.

In formula I, and throughout the description, the symbols have the definitions below.

R is o

40

,, o rf> -oh

1 hr 1

-AT. -N N-A- -C -N "

1 Y

H

iH

AT""

/ \ n dd m i i j rr

-AT. -N N-A-'C-AgN ', -A, -N, N-A_

45 1/2 6 ^ 1 b j

-NH-A-—

3 I H

-nh-a4- <ü-ä £ -1

itVoh with an acyl radical R, derived from a carboxylic acid.

Ri is an acyl radical derived from a carboxylic acid; 60 R2 and R3 are the same or different and are each a hydrogen atom, an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, or phenyl radical, or a 4,5,6 or 7-membered heterocycle (hereinafter denoted by Rx), or one of R2 and R3 is a hydrogen atom and the other is an azide, halom-östhyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phe-nylethenyl, 2-phenylethynyl, carboxyl radical, - CH2Xi [where X! is an azide, amine (NH2), hydroxy, carboxyl, alkoxycarbonyl, alkanoylamine, phenylcarbonylamine, (substituted phenyl) radical -

5

670,828

carbonylamine, alkylsulfonyloxy, phenylsulfonyloxy (substituted phenyl) sulfonyloxy, phenyl, substituted phenyl, cyano,

-A-C-NXgX7,

-S-X2, or -0-X2 (where A, X2, X6 and X7 are as defined below)], -S-X2 or -0-X2 [where X2 is an optionally substituted alkyl radical, optionally phenyl substituted, phenylalkyl, (substituted phenyl) alkyl, alkanoyl, phenylalkanoyl (substituted phenyl) alkanoyl, phenylcarbonyl, (substituted phenyl) carbo-nyl, or heteroarylcarbonyl],

O O

-NH-C-NH-NH, -C-NH-NH-, or -N-

ch2x where X is a hydrogen atom or a carboxyl or carbamoyl group and p is 0 or 1, and y is 2, 3 or 4; A5 is a single bond or a group of formula

-CH2-, -NH-CH2 ", -N = CH-,

10

h

? 3

-0-C-X4 or -S-C-X4 Xr X „

[where one of X3 and X4 is a hydrogen atom and the other is a hydrogen atom or an alkyl radical, or else X3 and X4 form, with the carbon atom to which they are attached, a radical cycloalkyl; and X5 is a formyl, alkanoyl, phenylcarbonyl, (substituted phenyl) carbonyl, phenylalkylcarbonyl, (substituted phenyl) alkylcarbonyl, carboxyl, alkoxycarbonyl, ami-nocarbonyl radical

(NH2-C-),

(substituted amino) carbonyl or cyano (-C = N)], or O

-A-C-NXgX-,

[where A is -CH = CH-, (CH2) m-, - (CH2) m-0- (CH2) m-NH-, or -CH2-S-CH2-, m is zero, one or two , and X6 and X7 are the same or different and are each a hydrogen atom or an optionally substituted alkyl or phenyl radical, or else Xg is a hydrogen atom and X7 is an optionally substituted amine group, alkanoylamine or alkoxy, or still XfS and X7 form, with the nitrogen atom to which they are attached, a heterocycle with 4, 5, 6 or 7 members];

AT! is a single bond or a group of formula

O O

-NH-C-, -NH- or -NH-NH-C-;

A2 is a single bond or a group of formula

O

-NH-, -CH2-CH2 ~ NH-, or -C-NH-NH-;

A3 is - (CH2) p- where p is 0 or 1,

- (CH2) - where p is 0 or 1,

or -C-NH- (CH ~) -2 q or q is 0 or 1;

15 Â6 is a single bond or a group of formula -CH = CH- or (CH2) t- where t is equal to 1, 2, 3 or 4,

The preceding symbols (Ab A2, A3, A4, Aset A6 for example) are used to represent groupings of multiple atoms. These groupings are inserted into the developed formulas shown here, in the order in which they appear (i.e. from left to right). For example, if R is

25

30

and Al is -NH-C-,

O II

35 the group R would be -NH-C-N ^, N-

Y

h

40

and no

1? r-

-c-nh-n n-

Y

dd 8

-NH-C-NH-, -NH-C-

fl

• NH-CH2-, -NH-CH2-, -O-CH2-

CH - C-NH-, or -CH2 ~ C-NH-CH2-;

A4 is

-NH-, - (CH2) -, - (CH2) y-NH-,

Below are definitions of the various terms "used to describe the β-lactams of this invention. These definitions apply to terms as used throughout the description (unless more limited in specific cases), either singly or as parts of larger groupings.

50 The terms "alkyl" and "alkoxy" refer to straight or branched chain radicals. Radicals having 1 to 10 carbon atoms are preferred.

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

The term “substituted alkyl” designates alkyl radicals substituted by one or more (preferably 1,2 or 3) atoms or groups azide, amine (-NH2), halogen, hydroxy, carboxy, cyano, alkoxycarbonyl, aminocarbonyl, alkanoyloxy, alkoxy , co phenyloxy, (substituted phenyl) oxy, mercapto, alkylthio, phenyl-thio, (substituted phenyl) thio, alkylsulfinyl or alkylsulfonyl.

The terms "alkanoyl", "alkenyl" and "alkynyl" refer to straight or branched chain radicals. Radicals having 2 to 10 carbon atoms are preferred.

65 The terms "halogen" and "halo" refer to fluorine, chlorine, bromine and iodine atoms.

The term "substituted phenyl> denotes a phenyl radical substituted by 1,2 or 3 atoms or amine groups (-NH;),

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halogen, hydroxyl, trifluoromethyl, alkyl (from 1 to 4 carbon atoms), alkoxy (from 1 to 4 carbon atoms), alkanoyloxy, aminocarbonyl or carboxy.

The expression “4,5,6 or 7-membered heterocycle” (designated by “Rx”) denotes aromatic and non-aromatic radicals, optionally substituted, which contain one or more (preferably 1,2 or 3) atoms of nitrogen, oxygen or sulfur. Examples of substituents are the atoms and groups oxo (= 0), halogen, hydroxy, nitro, amine, cyano, trifluoromethyl, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylsulfonyl, phenyl, phenyl substituted, 2-furfuryli-deneamine

((

Gr

, CH = N-

),

The following list of acyl radicals is presented to give further examples of the term "acyl"; it should not be considered as limiting this term. Examples of acyl radicals are:

(a) the aliphatic radicals of formula

0

M

R -C-a in which Ra is an alkyl radical; cycloalkyl; alkoxy; alkenyl; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amine, mercapto, alkylthio or cyanomethylthio atoms or groups. (B) carbocyclic aromatic radicals of formula

10

benzylideneamine and substituted alkyl (in which the alkyl radical has from 1 to 4 carbon atoms). One type of "4-, 5.6, or 7-membered heterocycle" is the "heteroaryl" radical. The term "heteroaryl" refers to 4,5,6 or 7 membered heterocycles which are aromatic. Examples of heteroaryl radicals are the pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazo-lyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyri-midinyl, oxazolyl, triazinyl and tetrazolyl radicals possibly substituted. Examples of non-aromatic heterocycles (that is to say totally or partially saturated heterocycles radicals) are the azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrro-lidinyl, tetrahydropyrimidinyl, and diahythiazol radicals. droazepinyl, optionally substituted. Examples of substituted 4,5,6 or 7 membered heterocycles are 1-alkyl-3-azetidinyl, 2-oxo-1-imidazolidinyl, 3-alkylsulfonyl-2-oxo-1-imidazolidinyl, 3-benzylideneamino radicals 2-oxo-l-imidazoli-dinyl, 3-alkyl-2-oxo-l-imidazolidinyl, 3-phenyl (or substituted phenyl) -2-oxo-l-imidazolidinyle, 3-benzyl-2-oxo-l-imidazoli -dinyl, 3- (2-aminoethyl) -2-oxo-l-imidazolidinyl, 3-amino-2-oxo-l-imidazolidinyle, 3- [alkoxycarbonyl) amino] -2-oxo-l-imi-dazohdinyl, 3 - [2 - [(alkoxycarbonyl) amino] ethyl] -2-oxo-l-imida-zolidinyle, 2-oxo-l-pyrrolidinyle, 2-oxo-3-oxazolidinyle, 4-hydroxy-6-methyl-2-pyrimidinyl , 2-oxo-1-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-3-tetrahydrofuranyl, 2,3-dioxo-1-piperazinyl, 2,5-dioxo-1-piperazinyl, 4-alkyl-2 , 3-dioxo-1-pipé-razinyle and 4-phenyl-2,3-dioxo-1-pipérazinyle.

The term “substituted amine” designates a group of formula -NHgXg in which Xs is a hydrogen atom or an alkyl, optionally substituted phenyl, phenylalkyl or (substituted phenyl) alkyl radical, and X9 is an optionally substituted alkyl, phenyl, phenylalkyl radical , (substituted phenyl) al-kyle, hydroxy, cyano, alkoxy, phenylalkoxy, or amine (-NH2).

The term "acyl" designates all the organic radicals deriving from an organic acid (that is to say from a carboxylic acid) by elimination of the hydroxyl group. Certain acyl radicals are, of course, preferred, but this preference should not be considered as limiting the scope of this invention. Examples of acyl radicals are acyl radicals which have been used in the past to acylate antibiotics of the ß-lactam series, including 6-amino-penicillanic acid and its derivatives and 7-aminocephalo-sporanic acid and drifts; see, for example, "Cephalosporins andPenicillins", edited by Flynn, Academic Press (1972), • German patent application No. 2,716,677 published on October 10

1978, Belgian Patent No. 867,994 published December 11, 1978, U.S. Patent No. 4,152,432 issued May 1

1979, U.S. Patent No. 3,971,778 issued July 27, 1976, United States Patent No. 4,172,199 issued October 23, 1979, and British Patent No. 1,348,894 issued March 27 1974. Parts of these references which describe various acyl radicals are incorporated herein by reference. The

20

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30

35

40

45

50

55

O 11

(ch2) n-c-,

I W

('NV- ch - 0-c-

* b c? ° -

0

J-,

R

R,

0 ^ -

O II

c ^ -c- or

R

AT-

where he

—CH2-S-C-

'where n is 0.1,2 or 3; Rb, Rc and Rd are each, independently 60, a hydrogen or halogen atom, a hydroxyl, nitro, amine or cyano group, or a trifluoromethyl radical, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 atoms carbon or aminomethyl; and Re is an amine or hydroxyl group, a carboxylic salt, a protected car-65 boxyl group, a formyloxy radical, a sulfosel, a sulfoamine salt, an azide group, a halogen atom, or a hydrazine, alkylhydrazine radical, phenylhydrazine or [(alkyl-thio) thioxomethyl] thio.

Preferred carbocyclic aromatic acyl radicals include those having the formula

HO

ch - c-,

-vs-,

ho '

CK-C-

(Re is preferably a carboxylic salt or a sulfosel) and

(Re is preferably a carboxylic salt or a sulfosel).

(c) The hetero aromatic radicals of formula

O

Bf- {CH2) n ^ - '

O 1 /

rf-ch-c-

R

e

O 11

rf — o — ch2-c-,

O ti rf-s — ch2-c-,

O O

n n where n is 0.1,2 or 3; Re is as defined above; and Rf is a heterocyclic ring with 5.6 or 7 members, optionally substituted, containing 1,2,3 or 4 (preferably 1 or 2) nitrogen, oxygen or sulfur atoms. Examples of heterocyclic rings are, thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thia-diazolyl and tetrazolyl rings. Examples of substituents are halogen atoms, hydroxyl, nitro, amine, protected amine, cyano groups, trifluoromethyl radicals, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or

O

• He hooc-ch-chi-o-c-nh—.

! 2

nh2

Preferred heteroaromatic acyl radicals include radicals of the preceding formulas in which Rf is a 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1 radical , 2,4-thiadiazol-3-yl, 2-thi-enyl, 2-furanyl, or 6-aminopyridin-2-yl.

670,828

d) [[(4-substituted-2,3-dioxo-1-piperazinyl) carbo-nyl] amino] arylacetyl radicals of formula

He II f \

-c-ch-nh-c-n n-r,

I \ / 11.

R J ^

g o o in which Rg is an aromatic group (including carbocyclic aromatic groups such as those which have the formula and heteroaromatic groups which are included in the definition of Rf); and Rh is an alkyl radical, optionally substituted by one or more halogen, cyano, nitro, amine or mercapto atoms or groups, or an arylmethylene-amine radical (that is to say of formula -N = CH-Rg in which Rg is as defined above), arylcarbonylamine (i.e. of formula

O

-NH-C-R '9

in which Rg is as defined above) or alkylcarbonyl-amine.

Preferred [[(4-substituted-2,3-dioxo-1-piperazinyl) carbo-nyl] amino] arylacetyl radicals include those in which Rh is an ethyl, phenylmethyleneamine or 2-furylmethyleneamine radical.

(e) Arylacetyl (substituted oxyimino) radicals of formula

-f-C = N-0-R.

I l in which Rg is as defined above and Rj is a hydrogen atom or an alkyl or cycloalkyl radical,

^ V 2 1,2 or 3 —c-cooh

2-pyrrazolylmethyl, (2-oxo-3-pyrrolidinyl) methyl, alkylami-nocarbonyl, arylaminocarbonyl (i.e. of formula

O

-C-NH-Rg in which Rg is as defined above) or substituted alkyl (the alkyl radical being substituted by one or more atoms or groups of halogen, cyano, nitro, amine, mercapto, alkyl-thio, aromatics (such as defined by Rg), carboxyl (including salts), amide, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkoxyphosphinyl, dihv-droxyphosphinyl, hydroxy (phenylmethoxy) phosphinyl, dial-coxyphosphinyl or tetrazolyl).

Preferred arylacetyl (substituted oxyimino) radicals include those in which Rg is a 2-amino-4-thiazo-lyl radical. Also preferred are the radicals in which R; is a methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluorethyl or 1-carboxycyclopropyl radical.

7

5

10

15

20

25

30

35

40

45

50

55

60

65

670,828

(f) (acylamino) arylacetyl radicals of formula

O O

I! he

-C-CH-NH-C-R.

I J

R

g in which Rg is as defined above and Rj is a group

<ch2> "tramine, alkylamine (cyanoalkyl) amine, amide, alkylamide, (cya-noalkyl) amide,

NH II

NH-l 2

O II

-CH2-NH-C

-CH-CH2-C-NH-CH3,

-O "'

H0V

2H ° 2-N (CE2-CE2- ° H) 2 ("Ctf3 '

OH

: N ^ if' — N N -C H 'or

The preferred (acylamino) arylacetyl radicals of the above formula include radicals in which Rj is an amine or amide group. Also preferred are radicals in which Rg is a phenyl or 2-thienyl radical.

(g) The [[[3-substituted-2-oxo-1-imidazolidinyl] carbo-nyl] amino] arylacetyl radicals of formula

O O

It II '

-C-CH-NH-C-N

I

R

g o n c

rRk

CH2 — CH2

in which Rg is as defined above and Rk is a hydrogen atom or an alkylsulfonyl, arylmethyleneamine radical (that is to say of formula -N = CH-Rg in which Rg is as defined above ),

O

ft

-C-R

m

(where Rm is a hydrogen atom or an alkyl radical optionally substituted by halogen), an aromatic group (as defined by Rg above), or an alkyl radical optionally substituted by one or more halogen, cyano atoms or groups, nitro, amine or mercapto.

Preferred [[3-substituted-2-oxo-1-imidazolidinyl] carbonyl] -amino] arylacetyl radicals of the above formula include those in which Rg is a phenyl or 2-thienyl radical. Also preferred are radicals in which Rk is a hydrogen atom or a methylsulfonyl, phenylmethylene-amine or 2-furylmethyleneamine radical.

The compounds of this invention form, with various mineral and organic bases, basic salts which also fall within the scope of this invention. These salts include 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 usable, for example to isolate or purify the product.

Some of the compounds of this invention can be crystallized or recrystallized from solvents containing water. In these cases, hydration water may form. This invention encompasses stoichiometric hydrates as well as compounds containing varying amounts of water which can be produced by methods such as lyophilization.

The β-lactams of formula I contain at least one chiral center - the carbon atom in position 3 of the β-lactam nucleus to which the substituent acylamine ("RrNH-") is attached. This invention relates to the ß-lactams which have been described above, in which the stereochemistry at the chiral center occupying position 3 of the ß-lactam nucleus is the same as the configuration on the carbon atom occupying the position 6 of natural penicillins (penicillin G for example) and that the configuration on the carbon atom in position 7 of natural cephamycins (cephamycin C for example). Also included within the scope of this invention are racemic mixtures which contain the β-lactams described above.

The ß-lactams of formula I, as well as their pharmaceutically acceptable salts, are active against gram-positive and gram-negative organisms. The compounds of this invention can be used as agents to fight bacterial infections (including urinary tract infections and respiratory infections) in mammalian species, such as pets, e.g. dogs, cats , cow, horse, and similar animals and in humans.

To combat bacterial infections in mammals, a compound of this invention can be administered to a sick mammal in an amount of from about 1.4 mg / kg / day to about 350 mg / kg / day, preferably from about 14mg / kg / day to around 100 mg / kg / day. All modes of administration which have been used in the past to bring penicillins and cephalosporins to the site of infection are also contemplated with the β-lactams of this invention. These modes of administration include oral, intravenous and intramuscular administration, and in the form of suppositories.

Ss-lactams of formula I can be prepared from a 3-protected amino-2-azetidinone of formula II

R, -m

4 \

55

/

CH-

AT_

R, i 2

-C-R-I --NH

In formula II, and throughout the description, the symbol "R4" denotes a group protecting the amine function. These groups are well known in the field of β-lactam chemistry, and the particular group chosen is not crucial. The benzyloxycarbonyl, trityl and t-butoxycarbonyl radicals are examples of protective groups. The reaction of a ß-lactam of formula II with an isocyanate of formula III

0 = C = N-S02-Y,

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in which Y is a labile substituent such as a chlorine atom, gives the corresponding compound, of formula IV

r r4-nh

/

ch i

2

-R.

-n-c-nh-so - y.

U 2

The reaction is preferably carried out in an inert organic solvent, for example ethyl acetate, tetrahydrofuran, dimethoxyethane, dichloromethane, acetonitrile or a mixture of these solvents. The labile substituent "Y" can be displaced by the desired group "R" using the appropriate nucleophile, of formula V

HR,

optionally in the presence of a base (triethylamine for example), which gives the corresponding compound of formula VI

R ~

i 2

r4-nh-

0 ^

■ N-j> NH-S02-R

removal of protection by treatment of a compound of; formula VI with an acid (formic acid or trifluoroacetic acid, for example). If, for example, R4 is a benzyloxycarbonyl protecting group, it is possible to effect the removal of protection by catalytic hydrogenation of a compound of formula VI. Alternatively, the protective group R4 can be removed at the same time as the other protective groups of Pyridine immediately after the displacement reaction described above.

Well-known acylation techniques can be used to transform an intermediate of formula VII into a corresponding product of formula I. Examples of techniques include reacting a compound of formula VII with a carboxylic acid (RrOH) or with a carboxylic acid halide or a corresponding carboxylic acid anhydride. The reaction with a carboxylic acid is best carried out in the presence of a carbodiimide such as dicyclohexylcarbodiimide and a substance capable of forming an active ester in situ, such as N-hydroxybenzotriazole. In cases where the acyl radical (RJ -20 contains reactive functional groups (such as amine or carboxyl groups), it may be necessary to protect functional groups first, then to carry out the acylation reaction, and finally to remove the protection of the resulting product.

Another possible method of preparing the compounds of formula i is to first acylate (acylation techniques have been described above) a 3-amino-2-azetidinone of formula VIII

30

Alternatively, the labile substituent can be displaced by reacting a compound of formula IV with a protected form of a compound of formula V. After the displacement reaction, the protective groups can be removed, using techniques recognized by specialists, to obtain a compound of formula VI.

The protected forms of a compound of formula V, and of all the reactants which are described here which contain a 3-hydroxy-4-pyridone part, include the compounds in which the hydroxyl group is protected, the compounds in which the group hydroxyl and ring nitrogen are protected, and compounds in which the two pyridone oxygen are protected. Examples of protective groups are the silyl (trimethylsilyl for example), benzyl and acyl (acetyl for example) radicals. If a silyl radical is used, the protection can then be removed by hydrolysis or by cleavage using a fluoride. If a benzyl radical is used, the protection can then be removed by hydrogenolysis. If an acyl radical is used, it is then possible to remove the protection by hydrolysis.

By removing the protection of a compound of formula VI using conventional techniques, the corresponding key intermediate of formula VII is obtained

35

to obtain an intermediary of formula IX

R „

40

r, -nh

1 \

ch-

h-

I I

- <T-R3 -nh

45

nh „

-ch-

S-

? 2 1

-è-r,

I 3 -n-c-nh-s02-r s

An activating group of formula can be introduced.

O

-c-nh-so9-r

50 z in position 1 of a compound of formula IX (using the procedures described above) to obtain the corresponding product of formula I. In cases where the acyl side chain "Rj" contains reactive functional groups (such as the 55 amine groups), it may be necessary to protect these functional groups first, then proceed with the addition of the activating group in position 1, and finally to remove the protection of the resulting product.

Yet another mode of synthesis for preparing the “o compounds of formula I consists in using a 3-azido-2-azetidi-none of formula X

* 2

not,

or a salt thereof. The particular protection removal reaction used will, of course, depend on the protective group ("R4") that is present. If, for example, R4 is a t-butoxycarbonyl protecting group, the

65

: h-

• c-r - llh

670 828 10

We can introduce an activating group of formula i O

-c-nh-s02 "r in position 1 of a compound of formula X (using the procedures described above) to obtain the corresponding compound of formula XI

R-12

or a salt thereof, as the starting material. By adapting procedures which are described in the literature, 3-acylamino-2-azetidinone can be obtained from the corresponding 6-acyl-aminopenicillanic acid of formula XII: see, for example, Chem. Soc. Special Publication No. 28, page 288 (1977), The Chemistry of Penicillins, Princeton University Press, page 257, and Synthesis, 494 (1977).

As described in the literature, it is possible to desulfurize 6-acylamino penicillanic acid, or a salt of this acid, to obtain a xo compound of formula XIII

not-

'CH C-Rn

-n-ç-nh-s02-r s

The reduction of an intermediate of formula XI gives the corresponding intermediate of formula VII

nh0

R-

-h-r- | 3

-n-c-nh-so ^ -r. there 2 o

The reduction can be carried out by catalytic hydrogenation (palladium on charcoal or platinum oxide for example) or using reducing agents such as zinc or triphenylphosphine. A 3-amino-2-azetidinone of formula VIII can be reacted as described above (i.e. acylate it first and then treat it as described above to introduce an activating group of formula o

-c-nh-so2-r in position 1) to obtain the products of formula I.

Yet another mode of synthesis for preparing the compounds of formula I in which r2 and r3 are both hydrogen consists in using a 6-acylaminopenicillani-que acid of formula XII

R-j ^ -NH

"NpH-

-NOT-

(ch3) 2

• ch-cooh r-j-nh

/

£ -

-CH.

-ll- (j: K-CE (CH3) 2 COOH

by reduction with Raney nickel acid. The reaction can be carried out in reflux water.

By replacing the carboxyl group of a compound of formula XIII with an acetate group, then hydrolysis, the corresponding 3-acylamino-2-azetidinone is obtained, of formula XIV

25

r, -nh

1

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

Alternatively, a 3-azido-2-azetidinone of formula X can be reduced to the corresponding 3-amino-2-azetidinone of formula VIII

-Ah

30

Treatment of a compound of formula XIII with cupric acetate and lead tetraacetate in an organic solvent (acetonitrile for example) makes it possible to replace the carboxyl group with an acetate group. The resulting compound can be hydrolyzed using potassium carbonate in the presence of sodium borohydride.

We can introduce an activating group of formula

40

-c-nh ~ so2-r in position 1 of a compound of formula XIV (which gives the 45 products of formula I in which R2 and R3 are both hydrogen) using the procedures which are described below- above.

Yet another variant of the synthetic routes described above for preparing a compound of formula I in which R2 and 50 Rj are both hydrogen consists in first desulfurizing 6-aminopenicillanic acid, in acylating the resulting compound to obtain a compound of formula XIII, then proceed as described above to first obtain a 3-acylamino-2-azetidi-none of formula XIV, then a product of formula I. 55 The azetidinones of formula I can also be prepared from amino acids of formula XV

OH

nh „

60

vch-

0r2

-C — R-,

y

-Oh

65

We start by protecting the amine group (with a protective group "R4", the t-butoxycarbonyl radical for example). The carboxyl group of

11

670,828

amino acid protected with an amine of formula XVI Z-0-NH2

in which Z is an alkyl, benzyl or triphenylmethyl radical, in the presence of a carbodiimide, to obtain a compound of formula XVII

r4-nh

"CH-

OH

aR2

C -— R „

-NH-O-Z _

The hydroxyl group of a compound of formula XVII is transformed into a labile substituent ("OL") using a reagent such as methanesulfonyl chloride or a pyridine-SO 3 complex.

The fully protected compound, of formula XVIII 2o hydroxylated corresponding, which is cyclized, which, by treatment with titanium trichloride, gives an intermediate of formula II. If Z is a triphenylmethyl radical, treatment with formic acid or with 70% acetic acid in water initially gives the corresponding N-hydroxylated compound.

We can introduce an activating group of formula

-c-nh-sq2-r in position 1 of a compound of formula II using the procedures which are described above, and it is possible to remove the protection of the resulting compound and acylate it.

The nucleophiles of formula V in which Rest "can be prepared

i — i h JmT ° h

H

and Ai and A2 are each a single bond, reacting a silylated 2-imidazdlidinone derivative

25

NH-O-Z

by treating it with a base, potassium carbonate for example. The reaction is preferably carried out in an organic solvent or in a mixture of organic solvent and water, at reflux, and a compound of formula XIX is obtained.

(IN NH),

Y

30 or the anion of 2-imidazolidinone formed with a strong non-nucleophilic base, with an activated derivative, suitably protected, of an acid of formula XX

R4-NH

'CH-

-f-

R, \ 2

y

3

• N-O-Z

35

40

OH

to obtain, after removal of protection, the corresponding compound of formula XXI

Or, the cychsation of a compound of formula XVII can be carried out without first transforming the hydroxyl group into a labile substituent. By treating a compound of formula XVII with triphenylphosphine and diethylazodicarboxylate, a compound of formula XIX is obtained.

Examples of procedures allowing the transformation of a compound of formula XVIII into a compound of formula XIX are described in J. Amer. Chem. Soc., 102.726 (1980) and J. Org. Chem., 47.5160 (1982). so

Each of the two processes described above for the cyclization of a compound of formula XVII results in the inversion of the stereochemistry on the carbon atom carrying the substituents R2 and

R3, when the latter two are not identical. The reaction can be carried out in an inert organic solvent such as

We can achieve the elimination of the protective group of 55 that I dimethylformamide, acetonitrile, dichloromethane or

: itînn 1 H'nnp n7ptiriinrvnp Hp fnrmulp VTVr \ nr rpHnrtinn svpr * i .. r o ~ W oimr position 1 of an azetidinone of formula XIX by reduction with sodium when Z is an alkyl radical, which gives an intermediate of formula II

R4-NH

CH-

AT-

r_

2

• C — R-

I 3

-NH

(at least one of R2 and R3 is a hydrogen atom). If Z is a benzyl radical, a catalytic hydrogenation (palladium on carbon for example) initially gives the compound N-

tetrahydrofuran. 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 combination triphenylphos- carbon phine-tetrachloride) or a mixed anhydride (prepared with reagents such as diphenylphosphoryl chloride, pivaloyl chloride or isobutyl chloroformate).

The compound of formula XX can be prepared in which A (; is a single bond, as described in the literature; see Helv. Chem. Acta 43,469 (1960) and J. Med. Chem., 17.1 (1974) .

670,828

12

The compound of formula XX can be formed in which A6 is -CH = CH- by oxidizing XXII

protected, having the formula XXVIII

O

HO.

H

V

| | l CH2-OH

(suitably protected) into the corresponding aldehyde of formula XXIII

O

(suitably protected) by reacting this aldehyde with a derivative with a protected carboxyl function, of formula X} QV

O ^ ch-5-oh

10

(in which La is a labile substituent such as a chlorine or bromine atom or a methanesulfonyloxy or to-luenesulfonyloxy radical) with a cyanide, then hydrolysis and removal of protection, to obtain the compound of formula XXVII in

Where t is equal to 1. A compound of formula XXVIII can be prepared from a compound of formula XXII (suitably protected) by methods common in the art (for example using thionyl chloride or a methanesulfonyl chloride-triethylamine combination).

The nucleophile of formula V in which R is i-i »iVH can be prepared.

25 -A1-N ^ / N-A2-C-A6 — j,

oh

H

and removing the protection to obtain XXV O

HO

| || ^ CH = CH-C-OH.

NOT'

i h

Compounds of formula XX can be formed in which A6 is - (CH2) r and t is equal to 2.3 or 4 by conjugation of a compound of formula XXHI (suitably protected) with a Wittig reagent having the formula XXVI

Ai is a single bond and A2 is -NH-, reacting an activated and optionally protected derivative of a compound of formula XX with 1-amino-2-imidazolidinone

(hlt

, n-nh2)

35

to obtain, after removal of protection, XXIX

40

° H

HN._ Jr-NH-C-i

V

-Ar —- N H

l-OH

The nucleophiles of formula V in which 45 R is

O

i 1 11 JM)

~ A1 ~ N \ / N ~ A2 ~ C ~ AS N '

(suitably protected on the carboxyl function), then hydrogenation of the resulting exocyclic double bond, and removal of the protection to obtain XXVII

50

AT

AT! is a single bond and A2 is -CH2-CH2-NH- by reacting an activated and optionally protected derivative of a compound of formula XX with l- (2-aminoethyl) -2-imidazolidinone

O

55

HO

_ <ch2)

v t-H: -OH,

"N" i

H

(HN N-CH2CH2NH2)

T

to obtain, after removal of protection, XXX

65

where t is 2, 3 or 4.

Compounds of formula XX can be formed in which A6 is - (CH2), and t is 1 by reaction of a suitable compound-

HN .N-CH0-CH_-NH-C-Ac- ^ N-

V 2 2- 6 k

13

670,828

The nucleophiles of formula V in which R is d H can be prepared

Ai is a single bond and A2 is O

-C-NH-NH-

by making XXXI react

S ïï

</ y-eH2-0-C-NH-NK-C-Cl with silylated infoime 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 XXXII

V

By catalytic hydrogenation of the compound of formula XXXII, the compound of formula X2ÖQII is obtained

Aj is

-NH-C-

and A2 is a single bond, by reacting a compound of formula XXXVI

H i 1 ÏÏ

Cl-C-tt Jl-C-,

10

V

(suitably protected) with hexamethyldisilazane to obtain, after hydrolysis and removal of protection, a compound of formula XXXVII

O

?

H-N — C-N N-C-Ac

20 ^

H

Compounds of formula XXXVI (suitably protected) can be prepared 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, then hydrolyzing the resulting intermediate and cutting off the protecting groups.

The nucleophiles of formula V in which R is h, n-nhJ-0-h can be prepared

V

which can be combined with an activated and optionally protected derivative of a compound of formula XX to obtain, after removal of the protection, XXXTV

35

-Al "N-y'H" A2 "C" A6

S u

I

H

DH

40

AT! is -NH-C-

and A2 is -NH-, by reacting a silylated form of the compound XXXVIII

HM ~~ N-I-NH-NH-C-A

V ° i

Alternatively, the compound of formula XXXIII can be prepared by first reacting 1-chlorocarbonyl-2-imidazolidinone with hydrazine protected by the t-butoxycarbonyl radical, to obtain XXXV

45

HN.

-NH-Prot where the symbol Prot can denote a group protecting the amine function, such as the t-butoxycarbonyl or ben-zyloxycarbonyl radical, with phosgene to obtain XXXIX

55

-C-NH-NH-C-0-C (CH3) 3,

and removing protection from the compound of formula XXXV.

The nucleophiles of formula V in which R is

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

Ö

that can be reacted with hexamethylsilazane to obtain, after removal of the protection, XL

60

65

NH, -C-Ì -N-NH-.

V

The reaction of the compound of formula XL with an activated and optionally protected form of a compound of formula XX gives.

670,828

14

after removal of protection, XLI removal of protection, XLV

a höh

Alternatively, a compound of formula XL may be prepared in. Alternatively, a compound of formula XLV may be prepared by reacting the compound of formula XLII reacting a protected form of a compound of formula

XXXIV with chlorosulfonyl isocyanate, then by hydrolyzing the resulting intermediate and by cutting the protective groups. Alternatively, compound XXXII can be reacted with chlorosulfonyl isocyanate and then hydrolyzed the resulting intermediate to obtain XLVI

20

i S R jr \

n-c-nh-nh-c-o-ch ^ k>.

-2W-

Removal of XLVI protection by hydrogenolysis gives XLVII

jLC 114ÌICUICUI UC CC tUiUpUov pal Uli aUUC aXJUCUA UUilUC UH Sd UU q q composed of formula XL. 25 m F 1 q

The nucleophiles of formula V can be prepared in which nh, cn .n-c-nh-i

R is *

which can be combined with an activated and optionally protected derivative of a compound of formula XX to obtain, after

- a .. -n _ ^ n-a ~ -c-ar n ^, removal of protection, a compound of formula XLV.

I We can prepare the formula V nucleophiles in which

O H * D ni * 4-

O

a est -a, -A Ì-a.j-

R is q

1—1 2 UT®

c-ac-—

1 2 6,

and A2 is -CH2-CH2-NH-by first removing the protection of q g lal- (aminocarbonyl) -3- [2 - [[(t-butoxy) -carbonyl] amino] ethyl] -2-

imidazolidinone and by combining the resulting compound with a 40 Ai is -NH- and A2 is a single bond by combining the compound activated form of a compound of formula XX (optionally of formula XXXVIII with an activated form of a protected compound) to obtain, after removal of the protection, XLIV formula XX (optionally protected) and by cutting the protective grouping to obtain XLVIII

S 9

S I 1 9 Wf-OH 45 o. > V-OH

'. BJwTll.lUp "'.

Ó H <3 h

50 The nucleophiles of formula V in which can be prepared The nucleophiles of formula V in which R is R is

OH

1 1 H 11

55 ~ A1 ~ NV ^^ N-A2-C-Ag Ijl

H

1 2 6 1 'Ai is NH-and A2 is-NH-by combining a monoprotected derivative

H (preferably by a t-butoxycarbonyl or benzyloxy-

60 carbonyl) of the 1,3-diamino-2-imidazolidinone with a form

O O

Ai is -NH-C- and A2 is -C-NH-NH-

activated of a compound of formula XX (optionally protected), and by removing the protection of the resulting compound to obtain XLIX

by reacting a silylated form of a compound of formula | ] ÏÏ ___

XXXIV (optionally protected) with phosgene, then with ^ N-N-.N-NH-C-Ag "

hexamethyldisilazane, to obtain, after hydrolysis and

15,670,828

Or, we can form a compound of formula XLIX by selective elimination of the protective group of hydrazide, nitrosating a protected form of a compound of formula XXIX, LV is obtained then by reducing the nitroso group and cutting the i—> O

gr ° C ^ ^ ut prep ^ rTes'nucléophiles of formula V in which s Prot-NH-N \ ^ N-Ü-NH-NH2

R is Ö

By combining a compound of formula LV with an activated and optionally protected form of a compound of formula -A, -Nv. ^, N-A -C-Ar- "io XX, followed by removal of the protection, a jç I compound of formula LU is obtained.

0 E The nucleophiles of formula V in which

Rest q

> ".! is -Ml and is -CHr CH2-NH- by nitrosating a compound of 11

formula XXX (suitably protected) to obtain a com- i5, -, O fili—

laid of formula L A _vl L. _U_A

O 1 2 5 I '

ff t ^ oh h

O

0 = N-N ^ -N-CH_-CH0-NH-C-A; - 20

2 2 H Al6St ~ NH_NH-C "

(suitably protected) and by reducing and removing the and A2 is a single bond, reacting a protective compound therefrom to obtain LI 25 formula XXXVI (preferably a protected derivative thereof)

O with hydrazine (preferably in monoprotected form),

in the presence of a base, or else with a silylated form of hydrazine or of monoprotected hydrazine, in order to obtain a H2N-NXv ^ N-CH2-CH2 -NH-C-Ag— "^ ^. protected derivative of LVI

H

The nucleophiles of formula V in which EL I can be prepared

Rest

35 'H

-A -N N-A whose protection can be removed using techniques

1 2 ° I 'classics.

O H Or, we can react a compound of formula XXXV

q 40 (either in the form of a silylated derivative or in the form of an anion

„Formed by reaction with a strong base) with an activated form of

Ai is -NH- and A2 is -C-NH-NH- formula XX (suitably protected), then remove the protection to obtain a compound of formula LVI.

by nitrosating, reducing and suppressing the protection of a derivative The nucleophiles of formula V in which protected from a compound of formula XXXIV can be prepared. The resulting compound “Rest has the formula LII

t! H 2 (f J ~ ° H -A1-N> ^ N-A2

jN-N ^^. N-C-NH-Ì ^ H-C-Ag—. 50 ^ ^

-A, -N. / N-A - C-A-

h n-tt lt * ™ 1 2 5

2 y

Alternatively, a compound of formula LII can be prepared by „

reacting a compound of formula XXXVIII with phos- Ai is - NH - NH - C -

gene to obtain LIII 55

1 1 $ and A2 is -NH- by selective elimination of the protected group

Prot-NH-N -NC-Cl tor, not protecting the hydrazide function, of a compound of formula LIV, followed by a combination with a protected compound “o and optionally activated of formula XX, then suppression of the which, by reaction with a monoprotected hydrazine in the presence of protection, to obtain a compound of formula LVII of a base, gives LIV

f

Prot-NH-N. ..N-C-NH-NH-Prot; 65 Q 1 1 O | J> j OH

H2N-NH-C-N. ^ N-NH-C-Aj ^ "^ N

6 d

(the two protective groups must be different). By Ö g

670 828 16

The nucleopiles of formula V can be prepared in which R which can be combined with a protected derivative of hydrazine is _ to obtain a protected derivative of LXI

5 H 1 1 8

-a, -î, h2n-nh-c-n, n-c-nh-nh2.

V

q The groups used to protect the amine groups

„Io terminals in a compound of formula LXI must have been

A [is -NH-NH-C- chosen so that one of the protecting groups can

be selectively eliminated. The resulting compound can be combined

with phosgene, then with hydrazine (or with a derivative of formula XX to obtain (after removal of the protection) a monoprotected thereof), in the presence of a silylating agent such as compound of formula LXII

N-methyl-N- (trimethylsilyl) trifluoroacetamide, to obtain, O

after removal of protection, LVIII ^ ^ oh x 20 h-n-nh-ü-n. ^ -s-nh-nh-c-afi-

lr-1 ï irH 2 Y k

C-N. Jî-CH - CH_-NH-C-A-. 0

h2n — v -— "- c- _i, <"

{f J, The nucleophiles of formula V can be prepared in which

H R is

Alternatively, a protected amine derivative of l- (2-aminoethyl) -2-imidazolidinone can be reacted (optional- _

mentilylated) withphosgene, thenwith a protected proton / \ n n hydrazine, in the presence of a base or a silylating agent (le - A ^. -n n-A_ -c-Ar ^ N

N-methyl-N- (trimethylsilyl) trifhioracetamideoulebis (trimethylsilyl) acetamide for example), to obtain a protected derivative 30 "

of the compound of formula LIX using the methodology described above for the preparation of nucleophiles of formula V in which R is

H i 1

h2n-nh-c-n, v ^ n-ch2-ch2-nh2. 35

I 1 ï

-year. jtf-a, -c-a,

The groups used to protect the terminal amine groups in a compound of formula LIX must have been 0

chosen so that the protective group carried by 40 but by reacting, in place of 2-imidazolidinones, 2,3-aminoethyl radical can be selectively removed. Can be piperazinediones appropriate.

combine the resulting compound, one of the two protections of which can be prepared nucleophiles of formula V in which has been deleted, with an activated form of an acid of formula XX R is

(or with a protected derivative thereof) to obtain (after O

removal of protection) a compound of formula LVIII. 45 / \ _ nh

The nucleophiles of formula V in which | d J | he

R is

50 A] is a single bond and A5 is a single bond using -A, -ti a suitably protected derivative of the compound LXIII

O H0 '

A, is -NH-NH-C- N

Oh

II

andA2est -C-NH-NH- A compound of formula LXIV can be prepared

60

by reacting the compound of formula XXXII (optionally in the form of a silylated derivative) with phosgene to obtain a protected derivative of the compound of formula LX

»R ~ i î

h-n-nh-c-n jtf-c-cl

at

65

17

670,828

by transforming a protected form of the compound of formula LXV removal of protection, the formula LXIX

î

> H

s Cl-CH0-CH0-NH-t-NH-CHx ^ N-

Z £. Z |

H

Treatment of LXIX (or a suitably protected derivative in a protected form of the compound of formula LXIV by the mode thereof) with a base gives the compound having the operating formula of K. Heyns et al., Chem. Ber., 87.1440 (1954), then io LXX by removing the protection, to obtain the compounds of formula LXIV, per se. , , -OH

A compound of formula LXV can be prepared from a

HN

r

N-CH,

suitably protected form of a compound of formula LXIII, by conversion to an ester (such as ethyl or methyl ester), reaction with hydrazine and removal of protection. Alternatively, an activated form can be reacted and a compound of formula LXVIII can be prepared from one suitably protected from a compound of formula LXIII with compound of formula XXVIII (suitably protected) with a monoprotected hydrazine to obtain, after suppression of treatment with an azide, reduction of the azide, and suppression of protection, a compound of formula LXV. 20 protection.

The reaction of the compound of formula LXIV (or of a derivative It is possible to prepare the nucleophiles of formula V in which suitably protected from this) with 2- (chlorethyl) iso-R is cyanate, optionally in the presence of a base, (such as triethylamine) or a silylating agent, gives, after removal of OH

protection, the compound of formula LXVI 25 1.

i?

C1-CH2-CH2-NH-C-NH

1 V

N / A

AT! is a single bond and A5 is -N = CH- or -NH-CH2 by condensing 1-amino-2-imidazolidinone with the aldehyde of formula XXIII (optionally protected) to obtain (after removal of protection) the compound of formula LXXI

Treatment of LXVI (or a suitably protected derivative thereof) with a base gives, after removal of protection, the compound of formula LXVII

HNX ^ N-N = CH

Ö

40 The reduction of the compound of formula LXXI (optionally protected), by catalytic hydrogenation or using sodium cyanobrohydride, gives the compound of formula LXXII

45

The nucleophiles of formula V in which R is

"V

N-NH-CH,

The nucleophiles of formula V in which 50 R is q can be prepared

AT! is a single bond and A5 is -CH2- by reacting the compound of formula LXVIII

ch2nh2

(or a derivative in which the pyridone is suitably protected and the primary amine is not protected) with 2- (chlorethyl) isocyanate to obtain the compound having, after

55

-vhy1-A5

'H

T

H

65

11

Ai is a single bond and A5 is -C-NH- (

by reacting l-chlorocarbonyl-2-imidazolidinone with a compound of formula LXXIII

O

OH

H2N- (CH2) 9 — Vn

670,828

18

(or with a suitably advanced derivative thereof) in the presence of a base, or else with a silylated derivative of a compound of formula LXXIII, to obtain, after removal of the protection, the compound of formula LXXIV

hn ^ .n-c-nh- (ch2) ^

6

and Ai is -NH- by nitrosating a suitably protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII or LXXIV (using nitrous acid for example), reducing the resulting compound (for example using acidic zinc) 5 and removing the protection, to obtain LXXVII

10

h2n-n.

Y

n / A

Rest

The nucleophiles of formula V can be prepared in which Oubian, the compounds of formula LXXVII can be prepared

~ A1 ~ N \ ^ - N-A5

O

and Ai is -NHC-

by reacting with phosgene a suitably protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII or LXXTV, to obtain a protected derivative of LXXV

in which A5 is

//

-c-nh- (ch2) q by reacting a compound of formula XXXIX with an optionally protected form of a compound of formula LXTV or LXVIII, in the presence of a base or a silylating agent, to obtain, after removal of protection, LXXVHI

25

h2n-n>

-NOT

O

-a H-

<CH2> q ci-LN ~ 3T-A5-J

Ö

Alternatively, the compounds of formula LXXVII can be prepared in which A5 is -N = CH- or -NH-CH2- by reacting the monoprotected 1,3-diamino-2-imidazolidinone with a compound of formula XXIII (or a protected derivative thereof) and removing protection from the resulting product to obtain the derivative of formula LXXVII in which A5 is -N = CH. La which can be reacted with hexamethylsilazane to ^

obtain, after removal of the protection and hydrolysis, LXXVI reduction of this derivative gives the compound of formula LXXVII

in which A5 is -NH-ŒL-. O The nucleophiles of formula V can be prepared in which

-CT-0 * / ea h-n-c-nl ^ n-ac

2 Y '5'

h

Alternatively, the nucleophiles of formula V in which R is

45

o and A, is -NHC-

andAjest -NH-NH-C-

50 by reacting a compound of formula LXXV (suitably protected) with a monoprotected hydrazine, in the presence of a base or a silylating agent. The products, after removal of protection, have the formula LXXIX

55

S

n-a5- n by reacting a suitably protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII or LXXIV with chlorosulfonyl isocyanate to obtain, after hydrolysis and removal of protection, a compound of formula LXXVI . 60

You can prepare nucleophiles of formula V in which You can prepare nucleophiles of formula V in which R is r is

-a, -n

1 V

n / A

65

19

670,828

Ai is a bond and A5 is a single bond or -CH2-, making A! is a single bond and A5 is reacting a compound of formula LXIV or LXVIII (or a derivative

suitably protected therefrom) with aziridine or an activated aziridine q (activated by groups such as "

acyl or sulfonyl groups) to obtain, after deletion 5 -C-NH- (CH ~) _

of protection, LXXX "

O

h2n-ch2 -ch2 -nh (ch2) f h

A compound of formula LXXX (or a suitably protected derivative thereof) can be transformed into the desired piperazidine-dione having the formula LXXXI

10

by reacting an optionally protected derivative of LXXXIV Ï N-C-C

hn

■ Cl

by reaction with a dialkyl oxalate (then, optionally, removal of the protection).

The nucleophiles of formula V can be prepared in which Rest

15 with a compound of formula LXXIII (or a suitable derivative mentally protected from it) in the presence of a base or a silylating agent. The protection of the resulting intermediary can be removed to obtain LXXXV

20

/ "~ \ J

hn n-c-nh- (ch2)

25

-a-, -n.

n / A

The nucleophiles of formula V can be prepared in which Rest

8

30

/ \ Jir- ° E

-a- -n n-ac- ^ n- ^

// 5 I

0 = i h

Aj is a single bond and A5 is -N = CH- or -NHCH2- using the methodology described above for the preparation of nucleophiles of formula V in which R is

-A, -N.

35 and Ai is -NH- by nitrosation of a protected derivative of a compound of formula LXXXI, LXXXII, LXXXIII or LXXXV (using nitrous acid for example), reducing the resulting compound (using of zinc in an acid medium for example) and by removing the protection, to obtain LXXXVI

40

1 V

/ ~ \

45

Ai is a single bond and A5 is -N = CH- or -NHCH2-, but replacing l-amino-2-imidazolidinone with l-amino-2,3-piperazinedione. The resulting compounds would have the form

h-n-n n — ac

2o ^ - ^ o5

Alternatively, the compounds of formula LXXXVI may be prepared in which A5 is -N = CH- or -NH-CH2 by reacting the monoprotected 1,4-50 diamino-2,3-piperazinedione with a compound of formula XXIII (or a protected derivative thereof) and removing the protection of the resulting product to obtain a compound of formula LXXXVI, in which As is -N = CH-, which can then be reduced to a compound of formula LXXXVI in which A5 is -NH-CH2-. Alternatively, the reduction of -N = CH-may precede the removal of the protection.

The nucleophiles of formula V in which R is

The nucleophiles of formula V in which R is

60

65

OH"

O

and A, is -NH-NH-C-

670,828

20

by reacting with a phosgene a derivative suitably Or, the nucleophiles of formula V can be prepared in protected with a compound of formula LXXXI, LXXXII, LXXX3II, which R is or LXXXV, to obtain LXXXVII

-nh-a which can be reacted with hexamethyldisilazane to obtain, after removal of the protection from hydrolysis, LXXXVIII

S / \ 'jO 011

I ^ N-C-N ^ / N-A5 '^ N ^

i

-a- -n

- Vi

. jrv

N-A ^ \ ir 5 i

»H

10

and A3 is -NH-C-NH- or -NH-C-NH ~ CH2

from a suitably protected form of a compound of formula LXIV or LXVIII, by reaction with phosgene, followed by treatment with a monoprotected derivative of hydrazine, in the presence of a base or an agent silylant, then removal of protection. •

The nucleophiles of formula V in which 2o R is

Alternatively, the nucleopiles of formula V in which R is

-nh-a

25

30

and A3 is -CH2 ~ C-NH- or -CH2-CO-NH-CH2-

and Ax is -NHC or -CH2-CO-NH-CH2- by combining an N-protected and activated glycine derivative with a compound of formula LXIV or LXVIII by reacting a suitably protected derivative of a com- (optionally protected ), then by removing the protection, posed of formula LXXXI, LXXXII, LXXXIII or LXXXV with 35 The nucleophiles of formula V can be prepared in which chlorosulfonyl isocyanate to obtain a compound of R is formula LXXXVIII, after hydrolysis and deletion of the protec- O

tion.

The nucleophiles of formula V in which R is

O

-nh-a, - n '

3 hrs

40

-nh-a.

> h t h and A3 is - (CHo) p- have been described; see formulas LXIV and LXVIII.

The nucleophiles of formula V in which V in which R is R is and A3 is -NH-CH2- can be prepared by reacting an optionally protected aldehyde derivative of formula XXIII with hydrazine or hydrazine monoprotected, then reducing the carbon-nitrogen double bond, then removing the protection.

Alternatively, a monoprotected hydrazine can be subjected to a monoalkylation on the free amine group using a compound of formula XXVIII (suitably protected), and then remove the protection, to obtain a nucleophile of formula

-nh-a

I H

NOT'

ih

55

-nh-a and A-i is

O O

-NH-C-NH- or -NH-C-NH-CH2 ~

and A3 is -NH-CH2.

The nucleophiles of formula V in which “R is

-nh-a by reacting a compound of formula XXXI with a compound 65 of formula LXIV or LXVIII (optionally protected) in the presence of a base or of a silylating agent, then eliminating them and A3 is -0-CH2- by reacting a derivative suitably any protective groups. protected from the compound of formula XXII with N-hydroxyphthali-

21

670,828

mide, under the conditions of Mitsunobu (in the presence of triphé- The nucleophiles of formula V in which nylphosphine and diethylazodicarboxylate can be prepared) to obtain an R is a protected derivative of the compound LXXXIX

, ch2-o-n whose protection can be removed to obtain the compound XC

o 15

-NH-A ^ -C-Ag and A4 is - (CH2) p- and p is equal to 1 by treatment of an activated derivative io and suitably protected of a compound of formula XX with diazomethane, then with l hydrochloric acid, to obtain a protected derivative of a compound of formula XCIII

| it ch_-0-nh.

* 20 in which “Lb” is a chlorine atom. We can then treat a compound of formula XCIII in which Lb is a chlorine atom, with a uniodide or a bromide (such as sodium iodide or lithium bromide) to obtain a protected derivative of Or preparing the compound of formula XC into a compound of formula XCIII in which Lb is bromine or reacting a compound of formula XXVIII (suitably iodine. By displacement of labile substituent "Lb" (where Lb is protected) with N -hydroxyphthalimide in the presence of a base, chlorine, bromine or iodine) by an azide group, then by We can prepare the nucleophiles of formula V in which reduction and suppression of protection, XCIV R is obtained

- "- - 8 ■ -fV—

AT

nh2 -ch2 - fc-ag ^ n

AT

35

and A4 is -NH- by reacting a monoprotected hydrazine with. The nucleophile of formula V can be prepared in which R an activated and optionally protected derivative of an acid of formula is XX to obtain, after removal of the protection, a compound

of formula XCI Q ^ ^

nh2-nh-c-a

40

-nh-a4-c-a6

45 and A4 is - (CH2) y-NH by reacting a compound (optional-Alternatively, the compounds of formula XCI can be prepared as monoprotected) of formula XCV reacting a carboxylic acid ester of a suitably derivative protected from a compound of formula XX with hydra-NH2- (CH2) y-NH2 zine, then by removing the protection.

The nucleophiles of formula V can be prepared in which so with an activated and optionally protected derivative of an acid of R is formula XX to obtain, after removal of the protection, a compound of formula XCVI

S

-nh-a4-c-a6

55

fi nh2- (ch2) y-nh-c-ag -n h

and A4 is - (CH2) P- and p is equal to 0 by reacting ammonia The nucleophiles of formula V can be prepared in which or hexamethyldisilazane with an activated and optional derivative - 60 r is mentally protected with an acid of formula XX to obtain , after removal of protection, a compound of formula XCII

-nh-a.-ü-ar-

o -oh "to

nh2-c-a5

and A4 is -NH-C-NH-NH-

670,828

22

by reacting a compound of formula XCI (suitably protected) with a compound of formula XCVII

Prot-NH-NH-C-Cl

The compounds of formula I in which R is

R

'h

■ r "" I- "

Y '° TO

in the presence of a silylating agent, then eliminating the protective groups. have preference. Particularly preferred are the compounds

The nucleophiles of formula V in which 10 of formula I in which R is R is can be prepared

-nh-a4-c-a5

o

15

and A4 is -C-NH-NH-0

20

by reacting

Preference is also given to the compounds of formula I in which Ri is

O

-c-c = n ~ 0-r.

1

nh2-c-nh-nh2

(in the presence of a base or of a silylating agent) with an activated and optionally protected derivative of formula XX to obtain, after removal of the protection, a compound of formula xcvm

O O

NH2-ï-NH-NH-â-i

And Rg is the 2-amino-4-thiazolyl radical, and R; is the methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1-ethyl radical or

"Sz-Wb

30 -c-cooh,

is in which s is equal to 1,2 or 3. The use of these preferred acyl radicals Ri gives a product which exists in the form of the syn or anti isomer or in the form of a mixture of isomers. The isomer The nucleophile of formula V can be prepared in which R 35 syn provides for greater activity than the anti isomer.

The following examples are specific embodiments of this invention.

-nh-a4-c-a6

ch-x i z

40

and A4 is -IT-

by reacting an optionally protected hydrazine derivative, of formula XCIX

NHrNH-ŒrX

with an activated and optionally protected derivative of an acid of formula XX to obtain, after removal of the protection, a compound of formula C

nh2-n-

Alternatively, the compounds of formula C in which X is a hydrogen atom can be prepared by reacting methylhydrazine with a carboxylic ester derivative of the acid of formula XX (or a suitably protected derivative of that -this).

Example 1

Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [[(1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl) carbo-nyl] amino] -2-oxo-l-imidazolidmyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene ] amino] oxy] -2-45 methylpropanoic

A) 2- (Hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one 69 g (3 moles) of sodium were dissolved in 51 of methanol.

Then 425.3 g (3 moles) of 5-hydroxy-2- (hydroxy-methyl) -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 warm, very dark solution was poured into 151 of ice water. The product immediately crystallized. The crystals were collected and washed first with 81 of water, then twice with 55 2.51 of ether. The product was allowed to stand overnight and finally dried at 50 ° C for 16 h. Yield: 646 g = 92.6%.

B) 4-oxo-5- (phenylmethoxy) -4H-pyran-2-carboxylic acid 60 232 g (1 mole) of 2- (hydroxymethyl) -5- (phenylmere-

thoxy) -4H-pyran-4-one in a 101 shaker flask containing 6.61 acetone and 400 ml of water. The clear solution was cooled to +5 ° C using an ice bath. While maintaining the temperature between +5 ° C and 10 ° C, 65,640 ml of Jones reagent (202 g of Cr03,600 ml of water and 174 ml of H2SO4) was added dropwise over one hour . Stirring was continued for 2 h without cooling. The reaction mixture was filtered through sintered glass and the dark green residue was washed with 500 ml

23,670,828

acetone. The filtrate was then evaporated until added 5.63 ml (0.0626 mole) of chlorosulfonyl isocyanate.

all of the acetone has been removed. To the aqueous product and The mixture was stirred for 1 h at partially crystalline room temperature 1.21 methanol was added, then there was formed to form a solution of (S) -l - [[(chlorosulfonyl) amino] car-

heated this mixture to its boiling point. The solution bonyl] -3 - [[(phenylmethoxy) -carbonyl] amino-2-azetidinone was placed. The resulting clear dark green was in an ice bath and the solution was allowed to cool to 0 ° C, to which temperature was added

crystallize the product. The crystalline product was filtered and a solution of 1,4-dihydro-5-hydroxy-4-oxo-N- (2-

with 500 ml of a cold solvent mixture consisting of oxo-1-imidazolidinyl) -2-pyridinecarboxamide silylated (prepared at

250 ml of methanol and 250 ml of water, and dried. Yield: from a suspension of 14.9 g (0.0626 mole) of 1,4-dihydro-5-

195 g = 79%. It was possible to isolate from the mother liquor 5% of hydroxy-4-oxo-N- (2-oxo-1-imidazolidinyl) -2-pyridinecarboxa-additional product. io mide in 500 ml of ethyl acetate, by addition of 46.4 ml of N-

methyl-N- (trimethylsilyl) trifluoroacetamide (0.25 mol) and stirred

C) Acid 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecar- tion for 30 min). 150 ml of dichlorome-

thane boxylic, and the mixture was stirred at room temperature

300 g (1.22 mole) of 4-oxo-5- (phenylme-) were placed overnight. To the clear solution, 26.2 ml of thoxy) -4H-pyran-2-carboxylic acid were added to a flask and triethylamine (0.188 mol) was added, then 300 g of ice and 200 ml of water,

carefully 51 of 33% ammonia, shaking. The pH was 6.5. After stirring for 1.5 hours, the reaction mixture was then stirred at reflux. After 3 h, the two phases were separated and the aqueous phase was washed with three more, added slowly, 11 of 33% ammonia. There are 200 ml fractions of ethyl acetate. After elimination of continued stirring for a further 2 h at reflux. The ethyl acetate was then left under vacuum, the pH of the phase was adjusted and the reaction solution was evaporated until the aqueous product at 2 by slowly adding 47 ml of crystalline hydrochloric acid thereto. The product was transferred back to the 2 N reaction flask, while cooling. The crystals were filtered out, added and water added until a clear solution was obtained (51 suspended in 200 ml of ethyl acetate and stirred

approximately, ph6.38). This solution was vigorously stirred for one hour. The crystals were then separated by filtration,

while adding hydrochloric acid drop by drop, they were washed twice with 30 ml of ethyl acetate and twice concentrated dric until a pH equal to 3 was obtained. With 50 ml of petroleum ether and the white product which had precipitated was dried in vacuo to obtain filtration, washed thoroughly with 28.6 g of the title compound, melting point 190-200 ° C , decomposed

with water and it was dried. Yield: 273 g (1.12 sition.

mole) 91.8%. q-j Trifhiciracetate (1: 2) of (3S) -3-amino-N - [[3 - [[(1,4-di-

D) 1,4-Dihydro-4-oxo-N- (2-oxo-1-imidazolidinyl) -5- (phenylme-30 hydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2 -oxo-l-

thoxy) -2-pyridinecarboxamide imidazolidinyl] -sulfonyl] -2-oxo-l-azetidinecarboxamide

Was suspended in 120 ml of room temperature dimethylformamide, 4 g (0.00713 mol) were added

1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecar- ^ phenylmethyl acid ester (3S) - [l - [[[[3 - [[(1,4-dihydro- 5-

boxylic (12.26 g, 0.05 mole) and l-amino-2-imidazolidi- hydroxy4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l-imidazoli-

none (5.56 g, 0.055 mole). To the suspension was added 0.3 g of dinyl] sulfonyl] ammo] carbonyl] -2-oxo-3-azetidinyl] carbamic acid to dimethylaminopyridine and 0.4 g of N-hydroxybenzotriazole. ur | mixture of 15rnld trifluoroacetic acid and 3.5 ml of

After stirring for 30 min at room temperature, thioanisole is stirred at 10 C. The clear solution is stirred for a dropwise solution of 11.35 g (0.055 mole) of grit at ^ "C. After evaporation under vacuum at dicyclohexylcarbodiimide temperature in 50 ml of dimethylformamide, and ambient, the remaining syrup was treated with 1 ether to obtain the mixture was stirred overnight at temperature 40 the title compound as a yellowish solid The ambient The precipitate (dicyclohexylurea) was separated by filtration was almost quantitative.

tionetonafaitévaporerlefiltratsousvide.Lesiroprestant ^ ~ rm, ^

crystallized by treatment with sodium bicarbonate at air, ^^ 7? rrî 5 5 ßS (Z)] - 2 - [[[1- (2-amino-

aqueous, yielding 11.7 g of the title compound, melting point 4-thiazoIyl) -2 - [[l - [[[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo- 2-pyridi-

158-160 ° C. An additional harvest of 0.8 g of product, 45 nyl) carbonyl] amino] -2-oxo4-imidazolidmyl] sulfonyl] amino] -

melting point 162-164 ° C, crystallized from the aqueous filtrate. carbonyl] -2-oxo-3-azetidinyl] anuno] -2-oxoethylidene] ami-

noJoxyJ-2-methylpropanoic

To a solution of 3.08 g (0.007 mole) of (Z) -2-amino-a- acid

E) 1,4-Dihydro-5-hydroxy-4-oxo-N- (2-oxo-l-imidazolidinyl) -2- [[2-diphenylmethoxy) -1, l-dimethyl-2-oxoethoxy] imino] - 4-thia-pyridinecarboxamide 50 zoleacetic in 70 ml of dimethylformamide, was added

To a suspension of 12 g (0.0365 mole) of 1,4-dihydro-4-oxo 2.9 ml (0.021 mole) of triethylamine, then, after cooling

N- (2-oxo-1-imidazolidinyl) -5- (phenylmethoxy) -2-pyridinecar- at -30 ° C under nitrogen, 1.55 ml (0.007 mole) of boxamide chlorophosphate in 150 ml of acetonitrile, on 36.1 ml (0.146 diphenyl) was added. The mixture was stirred for one hour at -30 ° C. Bis (trimethylsilyl) acetamide was mole so as to form an then 1.95 ml (0.014 mole) was added. triethylamine, then 0.007

slightly cloudy solution. After filtration, 6 g of ss mole of trifluoroacetate (1: 2) of (3S) -3-amino-N - [[3 - [[(1,4-dihy-

10% palladium on carbon and hydrogen was passed dro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l-imi-

in the stirred reaction mixture. After 60 min of hydrogen dazolidinyl] -sulfonyl] -2-oxo-1-azetidinecarboxamide. We waved

tion, the catalyst was filtered off and 15 ml of the reaction mixture was added at -10 ° C for 2 h and at 0 ° C for 1 h.

methanol and 2 ml of acetic acid. Stirring was continued. The solvent was then removed in vacuo. By treating the residue overnight; the title compound separated by crystallization with water and ethyl acetate, a product was obtained, yield 6.6 g, melting point 270-275 ° C. insoluble which solidified by treatment with ether to give 8.0 g of crude compound.

F) Phenylmethyl ester of (3S) acid - [l - [[[[3 - [[(1,4-di-

hydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l- I) Disodium salt of the acid [3S (Z)] - 2 - [[[l- (2- amino-4-thiazolyl) -2-

imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] car- 65 [[l - [[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -

amino bamic] -2-oxo-l-imidazolidinyl] -sulfonyl] amino] carbonyl] -2-

To a suspension of 13.8 g of (S) -3 - [[(phenylmethoxy) - oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methyl-

carbonyl] amino] -2-azetidinone in 500 ml of ethyl acetate, propanoic

670,828

24

8 g of [3S (Z)] diphenylmethyl acid ester - 2 - [[[1- (2-amino-4-thiazo-lyl) -2 - [[ l - [[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) car-bonyl] amino] -2-oxo-3-azetidinylamino] -2-oxoethylidene] friend -no] oxy] -2-methylpropanoic crude. After cooling to -10 ° C, 80 ml of trifluoroacetic acid was added dropwise and the mixture was stirred at -10 "C for 1 h. Addition of ether at 0 ° C precipitated the trifluoroacetate free acid of the product (4.1 g of crude substance). This crude substance was suspended in water; the pH was adjusted to 5.5 by adding a solution of sodium bicarbonate , and the solution formed was lyophilized, and the crude sodium salt was then purified by chromatography on HP-20 *. The product was eluted with water to give 0.52 g of product.

* HP-20: macroreticular resin of styrene and divinylbenzene copolymer sold by Mitsubishi Chemical Industries Ltd.

NMR (DMSOd6: 6 = 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 (wide, s, 1H ).

Example 2

Disodium salt of [3s (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2-

[[l - [[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] ammo ] -2-oxoethylidene] amino] oxy] -2-methylpropanoic

A) 2 - [(1,1-dimethylethoxy) carbonyl] hydrazide of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid Acid 1,4 was suspended -dihydro-4-oxo-5- (phe-

nylmethoxy) -2-pyridinecarboxylic (61.3 g, 0.25 mole) in 500 ml of dimethylformamide at room temperature, then 39.65 g (0.3 mole) of N- (t-butoxycarbonyl) were added hydrazine, 1.5 g of dimethylaminopyridine and 2.0 g of N-hydroxybenzotri-azole, and the mixture was stirred for 30 min at room temperature. Then, 57.7 g (0.28 mole) of dicyclohexylcarbodiimide dissolved in 100 ml of dimethylformamide was added dropwise with stirring over 30 min, and the mixture was stirred at room temperature overnight. The precipitate (dicyclohexylurea) was separated by filtration and the filtrate was evaporated in vacuo. The remaining syrup crystallized upon treatment with a dilute solution of sodium bicarbonate. The dried crude product was recrystallized from 21 ethyl acetate to obtain 69.5 g of the title compound, mp 173-175 ° C. A second harvest was obtained after evaporation of the mother liquor; 3.2 g, melting point 160-165 ° C.

B) Acid hydrazide, 4-dihydro-5-hydroxy-4-oxo-2-pyridi-

necarboxylic acid 1,4 - dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid (69 g, 0.191 mole) was added 2 - [(1,1-dimethylethoxy) -carbonyl] hydrazide , at 0 ° C, 370 ml of trifluoroacetic acid. The mixture was stirred for one hour at room temperature and then evaporated. The remaining syrup was treated with ether to obtain 68.2 g of trifluoroacetate (1: 2) 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecar- acid hydrazide crude boxylic in the form of a solid.

The crude 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid trifluoroacetate (1: 2) was dissolved in 250 ml of acetonitrile, and stirred while cooling for 1 hr. The crystals were then separated by filtration and resuspended in 600 ml of acetonitrile. 135 ml of bis (trimethylsilyl) acetamide were added, followed by 28 g of 10% palladium on charcoal. Hydrogen was then passed through the stirred solution. The hydrogenation was complete after 90 min. After filtration, 70 ml of methanol and 2 ml of acetic acid were added.

After stirring overnight, the crystals which had formed were filtered off, giving 19.4 g of the title compound, melting point 290-340 ° C, decomposition.

C) Phenylmethyl ester of (3S) acid - [1 - [[[[[[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] -hydrazino] sulfo-nyl] amino] carbonyl] -2-oxo-3-azetindlyl] -carbamic A suspension of 5.19 g (0.0236 mole) of (S) -3 - [[(phenyl-iso methoxy) carbonyl] amino] -2- azetidinone in 160 ml of ethyl acetate, 2.05 g (0.0236 mol) of chlorosulfonyl isocyanate was added, with stirring, at room temperature. The mixture was stirred for 1 h at room temperature to form a solution of (S) -1 - [[(chlorosulfonyl) amino] carbonyl] -3-15 [[(phenylmethoxy) -carbonyl] amino] -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-pyridinecarboxylic (obtained from a suspension of 3.99 g 2o (0.0236 mol) of 1,4-dihydro-5-hydroxy-4-oxo-2 acid hydrazide -pyridinecarboxylic acid in 50 ml of ethyl acetate and 8.75 ml of N-methyl-N- (trimethylsilyl) trifluoroacetamide (8.75 ml = 0.0472 mole) The mixture was stirred at room temperature for overnight, then ice water was added and stirring continued for another 30 min, the aqueous phase was extracted with ethyl acetate and acidified to pH 2.5. The precipitate crystallized after one hour of investigation, giving 6.6 g of the title compound.

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

D) (3S) -3-amino-N - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] trifluoroacetate (1: 2) -2-oxo-1-azetidinecarboxamide Phenylmethyl ester of acid (3S) - [1 - [[[[[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2- pyridinyl] carbo-40nyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] carbamic (6.6 g, 0.0133 mole) to a stirred mixture of 22 ml of trifluoroacetic acid and 5.3 ml of thioanisole at room temperature, and stirred overnight at room temperature. The trifluoroacetic acid was removed in vacuo and the remaining syrup was treated with ether to obtain the title compound in quantitative yield.

E) [3S (Z)] diphenylmethyl ester - 2 - [[[l- (2-amino-50 4-thiazolyl) -2 - [[l - [[[[2 - [(l, 4 -dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azéti-dinyl] amino] -2-oxoethylidene] amino] oxy] - 2-methylpropano noic

To a solution of 5.84 g (0.0133 mole) of acid (Z) -2-amino-55 a - [[2- (diphenylmethoxy) -1, l-dimethyl-2-oxoethoxy] imino] -4 -thiazoleacetic 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. The mixture was stirred for 1 h at -30 ° C, then 3.72 ml of triethylamine was added, followed by 0.0133 trifluoroacetate (1: 2) mole of (3S) -3-amino-N- [ [2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] hydrazino] sulfonyl] -2-oxo-l-azetidinecarboxamide.

The mixture was stirred at -10 ° C for 2 h and at 0 ° C for 1 h, the solvent was removed in vacuo and the remaining syrup was treated with 150 ml of ethyl acetate and 70 ml of ice water, which was adjusted to pH 1.5-2 by addition of 2N hydrochloric acid. The insoluble substance was separated and triturated with ether to give 5.3 g of product. gross.

25

670,828

F) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[2 - [(l, 4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amrao] -2-oxoethylidene] amino] oxy] -2-methylpropanoic On suspended in 10.6 ml anisole of the diphenylmethyl ester of [3S (Z)] - 2 - [[[[1- (2-amino-4-thiazo-lyl) -2 - [[ l - [[[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-nyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] - amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic (5.3 g, 0.0069 mole). The suspension was cooled to -10 ° C and 53 ml of trifluoroacetic acid was added, with stirring. The mixture was stirred at this temperature for one hour, then 200 ml of ether was added at -10 ° C to precipitate the trifluoroacetic acid salt of the free acid of the title compound; the yield was 7.3 g.

The crude substance 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 remaining aqueous solution was lyophilized to give 8.1 g of crude product, which was purified by chromatography on HP-20, eluting with water. Chromatography gave 1.05 g of product.

NMR (DMSOd6): ô = 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 (broad s, 1H).

Example 3

Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [[(1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -amino] -2-oxo-l-imidizolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino ] oxy] -2-acetic

A) [3S (Z) -2 - [- [[1- (2-amino-4-thiazolyl) -2 - diphenylmethyl ester of [- [[1 - [[[[3 - [[(l, 4- dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) carbonyl] amino] -2-oxo-l-imidizolidinyl] sulfonyl] amino] car-bonyl] -2-oxo-3-azetidinyl] amino] -2 -oxoethylidene] amino] oxy] -

2-acetic

To a solution of 2.06 g (0.005 mol) of (Z) -2-amino-a - [[2- (diphenylmethoxy) -2-oxoethoxy] imino] -4-thiazoleacetic acid in 100 ml of dimethylformamide, added 2.1 ml (0.015 mole) of triethylamine. The mixture was cooled to -30 ° C and 1.1 ml (0.005 mole) of diphenyl chlorophosphate was added, with stirring. After stirring for 1 h at -30 ° C, another 1.4 ml (0.1 mole) of triethylamine at -30 ° C was added, followed by 2.7 g of trifluoroacetate (1: 2 of (3S) - 3-amino-N - [[3 - [[(1,4-dihydro-5-hy-droxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l-imidazolidi-nyl] sulfonl] -2-oxo-l-azetidinecarboxamide.

The reaction mixture was stirred at-10 ° C for 2 h and at 0 ° C for 1 h. The solvent was evaporated in vacuo, the oily residue was suspended in water and the pH of the suspension was adjusted to 2 by adding 2N hydrochloric acid to it. The suspension was stirred for 30 min at room temperature, filtered, the solid was resuspended in water and filtered again. After drying under vacuum over phosphorus pentoxide, 5.0 g of crude product were obtained. This substance was used in the next step without further purification.

B) Disodium salt of [3S (Z)] acid - 2 - [[[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [[(l, 4 -dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-

nyl] amino] -2-oxo-l-imidazolidinyl] -sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-acetic

5.0 g of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - diphenylmethyl ester -2 - [[1 - [[[[ 3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l-imidizolidinyl] sulfonyl] amino] carbony 1] -2-oxo-3- azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-acetic, at -10 ° C, in a mixture of 10 ml of anisole and 50 ini of trifluoroacetic acid. The reaction mixture was stirred at-10 ° C for 1 h, then carefully added 100 ml of ether to precipitate the crude trifluoroacetate from the title compound. Yield 3.7 g. The crude substance was dissolved in a mixture of 30 ml of water and 60 ml of acetone, and the pH of the mixture was adjusted to 5-5.5 by adding 0.1 N sodium hydroxide thereto. evaporated acetone and the aqueous phase was lyophilized to obtain 3.9 g of crude product. The crude material was purified by HP-20 chromatography. The product was eluted with water (10 ml fractions each). The product containing fractions were lyophilized to obtain 0.6 g of a substance which was rechromatographed on HP-20 to obtain 0.25 g of pure product.

Example 4

15 [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[[1,4-dihy-dro-5-hydroxy-4 -oxo-2-pyridinyl) methyl] amino] sulfonyl] ami-no] carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] -amino] -oxy] -2-methylpropanoic A) 2- (Hydroxymethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone

20

A mixture of 2- (hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one (9.65 g, 41.59 moles), 15 ml of concentrated ammonia and 20 ml of ethanol. Another 75 ml of ammonia was added, the mixture was refluxed for 2 h and cooled. The resulting brown solid was filtered and washed with water until the washings were neutral. The crude product was suspended in ethanol, onafiltered, washed with ethanol and hexane and dried in vacuo. The yield of the title compound was 7.61 g.

B) 2- (chloromethyl) -5- (phenylme-) hydrochloride

thoxy) -4- (1H) pyridinone A suspension of 2-35 (hydroxymethyl) -5- (phenylmethoxy) -4 (1H) -pyridinone (3 g, 12.99 moles) was cooled to 0 ° C under argon. 15 ml of chloroform, and treated with thionyl chloride (6.1 ml, 83.62 mmol). A homogeneous solution was obtained in a few minutes. After another 5 min of irrigation, a cream-colored solid precipitated. The cooling bath was removed and the mixture was heated to reflux for 45 min. 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.

45

C) 2- (Azidomethyl) -5- (phenylmethoxy) -4- (1H) pyridinone Was stirred at room temperature under argon for 3.5

days a mixture of 2- (chloromethyl) -5- (phenylmethoxy) -4- (1H) -pyridinone monohydrochloride (3.59 g, 12.54 mmol), so of sodium azide (4.08 g, 62 , 7 mmol) and diisopropylethylamine (2.19 ml, 12.54 mmol) in 70 ml of dimethylformamide. A further 4.08 g of sodium azide was added and the mixture was heated to 45-50 ° C for 2 h. After cooling, the reaction mixture was poured into 500 ml of water, which produced an insoluble white solid. The pH of the supernatant was lowered from 8.5 to 7.5 using 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.

60

D) 2- (Aminomethyl) -4- (phenylmethoxy) -4- (1H) pyridinone A mixture of 2- (azidomethyl) -5- (phenylmethoxy) was stirred for 6 h at room temperature, under an atmosphere of hydrogen. ) -4 (1H) -pyridinone (2.03 g, 7.93 mmol) and 65,200 mg of platinum oxide in 100 ml of dimethylformamide. The catalyst was filtered off and the solution was concentrated in vacuo to give 1.5 g (82% yield) of the title compound as a gray powder.

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26

E) Phenylmethyl ester of (3S) acid - [1 - [[[[[[[1,4-dihydro-4-oxo-5- (phenyhnethoxy) -2-pyridinyl] methyl] amino] sulfonyl] ami-no ] carbonyl] -2-oxo-3-azetidinyl] carbamic

To a stirred suspension of 2- (aminomethyl) -5-phenylme-thoxy) -4 (1H) pyridinone (2.330 g, 10.13 mmol) in 60 ml of ethyl acetate, N-methyl was added. N- (trimethylsilyl) tri-fluoracetamide (3.76 ml, 20.26 mmol). The resulting solution was stirred for 30 min at room temperature, then cooled to 0 ° C. At the same time, to a stirred suspension of (S) -3 - [[(phenylmethoxy) -carbonyl] amino] -2-azetidinone (2.228 g, 10.13 mmol) in 60 ml of ethyl acetate, added chlorosulfonyl isocyanate (882 ni, 10.13 mmol). The resulting solution was stirred for 30 min at room temperature, cooled to 0 ° C, and finally treated with triethylamine (4.23 ml, 30.39 mmol), then with solution of 2- (aminomethyl) -5- (phenylmethoxy) -4 (1H) silylated pyridinone described above. The mixture was stirred for two 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, and a thick oil was then separated. By cooling to 5 ° C, this oil solidified. The solid was separated, washed four times with water, and dried in vacuo to obtain 3.4 g of crude product. This crude product was dissolved in a minimum volume of dimethylformamide and the solution was loaded into a column of 11 of HP-20 resin. The column was eluted with a progressive gradient of acetone and water. The desired product was eluted with a mixture of approximately 65% acetone. The fractions of interest were pooled and lyophilized to obtain 2.69 g of the title compound.

F) [3S (Z)] diphenylmethyl ester - 2 - [[[l- (2-amino-4-thiazolyl) -2 - [[l - [[[[[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridi-nyl) methyl] amino] sulfonyl] amino] carbonyI] -2-oxo-3-azetidi-

nyl] amino] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] -amino] oxy] -2-methylpropanoic acid (in the form of a mixture of monopòtassium and monotriethylammonium salts) Ona stirred under an atmosphere of hydrogen a mixture of phenylmethyl ester of (3S) acid - [l - [[[[[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] methyl] amino] sulfonyl ] ami-no] carbonyl] -2-oxo-3-azetidinyl] carbamic (912 mg, 1.64 mmol), p-toluenesulfonic acid monohydrate (625 mg, 3.28 mmol) and 10% palladium on carbon (190 mg) in 16 ml of dimethylformamide, until 3.28 mmol (73 ml) of hydrogen has been consumed (approximately 3 h).

To a stirred solution of (Z) -2-amino-a - [[2- (diphenyl-methoxy) -1,-dimethyl-2-oxoethoxy] imino] -4-thiazoleacetic acid (846 mg, 1,804mmole) in 16 ml of dimethylformamide at -20 ° C., diphenyl chlorophosphate (374 μl, 1.804 mmol) was added, followed by triethylamine (450 (il, 3.28 mmol). The solution was stirred for 1 h at -20 ° C, after which the mixture described above of phenylmethyl ester of (3S) acid - [1 - [[[[[[1,4-dihydro-4-oxo-5- (phenylmethoxy) ) -2-pyridinyl] mes-thyl] amino] solfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] hydrogenolysed carbamic The resulting mixture was stirred at -20 ° C for 1 h, then at 5 ° C overnight. The catalyst was filtered off, the volatiles were removed in vacuo and the resulting oil was dissolved in a minimal volume of acetone and water (75-25, pH 5.2 ), and the solution was added dropwise to a stirred suspension of 20 ml of Dowex 50x2-400 * (K +) in a 35-65 mixture of acetone and water. filtered the mixture and the filtrate was lyophilized to obtain 2.1 g of solid. This solid was dissolved in a minimum amount of acetonitrile and water (40-60, pH, 5.6), and the solution was loaded into an 800 ml column of HP-20 resin, eluting with a progressive gradient of acetonitrile and water. The desired product was eluted with a mixture of about 30% acetonitrile. The fractions of interest were pooled and lyophilized to obtain the title compound in the impure state (254 mg).

s * Dowex50x2-400: gyropolymerredyrene and divinyl-benzene to which are attached groups -SO3-, sold by Dow Chemical Co.

10 G) Help [3S (Z)] - 2 - [[[l- (2-amino-4-thiazolyl) -2 - [[l - [[[[[(1,4-di-hydro-5- hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] ami-no] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] ami-no] oxy] -2-methylpropanoic added dropwise 4.7 ml of trifluoroacetic acid to a stirred suspension of the diphenylmethyl ester of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] carbo-nyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic impure above (mixture of mono-potassium and monotriethylammonium salts) (131 mg) in 3 ml of dichloromethane and 0.3 ml of anisole 0 ° C. After stirring for 45 min at 5 ° C, 2 ml of toluene was added and the volatiles were removed in vacuo. The resulting oil was washed with 4 ml of hexane three times and triturated with 10 ml of ether until a solid was obtained. This solid was washed once with 10 ml of ether and dried in vacuo. The previous reaction and elaboration was repeated on 166 mg of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2] diphenylmethyl ester -2 - [[1- [[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] carbo-30 nyl] -2-oxo-3-azetidinyl] -amino] - 2-oxoethylidene] amino] oxy] -2-methylpropanoic (mixture of monopotassium and monotriethylammonium salts). The crude products were pooled, dissolved in 2 ml of a 40-60 mixture of acetonitrile and water (pH 2.5) and the solution was chromatographed in a column of 200 ml of HP resin -20, using a gradient of acetonitrile and water. The desired product was eluted with a 20-80 mixture of acetonitrile and water. The fractions of interest were pooled and lyophilized to give 103 mg of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[ [[[(1,4-dihydro-5-hydroxy-4-oxo-2-40 pyridinyl) methyl] amino] sulfony] amino] carbonyl] -2-oxo-3-azéti-dinyl] -amino] -2- oxo-3-azetidinyl] ammo] -2-oxoethylidene] ami-no] oxy] -2-methylpropanoic in the form of a white solid.

4S Example 5

Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[2 - [[2 - [(l, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-nyl] hydrazino] carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methyl-50 propanoic

A) 2 - [[(4-Methoxyphenyl) methoxy] carbonyl] 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic hydrazide A solution of 4.54 g (0.022 mol) was added of dicyclo-hexylcarbodiimide in 25 ml of dry dimethylformamide in a stirred suspension of 4.90 g (0.020 mole) of 4, 4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid, 50 g (0.022 mole) of 4-methoxybenzyl carbazate, 0.12 g (1.0 mmol) of 4-dimethylaminopyridine and 0.155 g (1.0 mmol) of 1-hydroxy benzotriazole hydrate in 25 ml of dimethylformamide 60 sec, at room temperature, and stirring is continued overnight. The precipitate was separated by filtration and the filtrate was evaporated in vacuo. The residue solidified by stirring with ether and aqueous sodium bicarbonate, and the solid was collected, washed with water and finally dried in vacuo. The crude substance (8.14 g) was extracted in a soxhlet with 800 ml of chloroform (7 h). 5.70 g (67%) of 2 - [[(4-methoxyphenyl) methoxy] carbonyl] 1,4-dihy-dro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide

27

670,828

directly coated with cold chloroform extract, and an additional impure product (1.5 g 18%) of the title compound could be obtained by evaporation of the chloroform solution in vacuo; melting point 174.5-178 ° C.

B) Trifluoroacetate (1: 2) of 1,4-dihydro-4- acid hydrazide

oxo-5- (phenylmethoxy) -2-pyridinecarboxylic A solution at -10 ° C of 3.81 ml (35.04 mmol) of anisole in 38 ml of trifluoroacetic acid was added to a suspension, cooled in the ice, 3.71 g (8.76 mmol) 2 - [[(4-methoxyphenyl) methoxy] carbonyl] 1,4-dihy-dro-4-oxo-5- (phenylmethoxy) -l acid hydrazide -pyridinecarboxylic in 15 ml of dry dichloromethane. After stirring at 0 ° C for 20 min, 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 suction and dried under vacuum. Yield: 3.25 g (99%); melting point 173-175 ° C, decomposition.

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

2-pyridinecarboxylic 3.84 ml (19.64 mmol) of N-methyl-N- (trimé-thylsilyl) trifluoroacetamide was added to a suspension of 3.19 g (8.55 mmol) of trifluoroacetate (1: 2) 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid hydrazide in 35 ml of dry acetonitrile, and stirring was continued for 30 min at room temperature. After evaporation under vacuum, the residue is taken up in ether, then 1 ml of methanol is added thereto dropwise. The precipitate was collected by suction, washed with ether and petroleum ether and dried in vacuo to give 2.05 g (92%) of the title compound (point melting 204-208 ° C, decomposition).

D) 2 - [[2- (Phenylmethoxy) carbonyl] hydrazino] carbonyl] hydra-zide of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridine- acid

carboxylic

While cooling, 11.69 ml (0.060 mole) of N-methyl-N-trimethylsilyltrifluoracetamide was added to a suspension of 5.19 g (0.020 mole) of 1,4-dihydro-4-oxo acid hydrazide 5- (phenylmethoxy) -2-pyridinecarboxylic in 20 ml of dry acetonitrile, and stirring was continued for 30 min at room temperature. The clear solution was evaporated in vacuo, and the residue was dissolved in 30 ml of dry dichloromethane. This solution was then added dropwise to a stirred solution of 4.57 g (0.020 mole) of

Where is

PhCH2OCNHNHCOCl

[J. Glove, Chem. Ber. 97.2551 (1964)] in 60 ml of dichloromethane at 0-5 ° C. After stirring at this temperature for 2.5 h, 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 in the form of a solid foam which became crystalline by stirring with dry ether. Yield: 8.87 g (98%); melting point> 120 ° C, decomposition.

E) 2,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid 2- (hydrazinocarbonyl) hydrazide dihydrochloride A solution of 4.02 g (8.9 mmol) of 2- was hydrogenated [[2- (phenylmethoxy) carbonyl] hydrazino] carbonyl] hydrazide of 1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecar-boxylic acid in 50 ml of methanol containing 2.94 ml (35.6 mmol) of concentrated hydrochloric acid, in the presence of 0.4 g of palladium (10%) on charcoal, for 10 min. The catalyst was filtered off and the solvent was removed by vacuum distillation to leave the title compound in the form of a solid (2.58 g) which was stirred with a few milliliters of dry ether, which was collected by suction and which was dried under vacuum. Yield: 2.47 g (92%); melting point 235-236 ° C, decomposition.

F) Phenylmethyl ester of (3S) acid - [l - [[[[2 - [[2 - [(1,4-di-hydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino ] carbo-nyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] car-îo bamic

4.86 ml (25.0 mmol) of N-methyl-N-trimethyl-silyltrifluoracetamide was added to a suspension of 1.5 g (5.0 mmol) of acid 2- (hydrazinocarbonyl) hydrazide dihydrochloride , 4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid in 20 ml of dry acetonitrile. After stirring for 45 min at room temperature, the clear solution was evaporated in vacuo, and the residue was dissolved in 20 ml of dry ethyl acetate (solution A).

To a suspension of 1.10 g (5.0 mmol) of (S) -3 - [[(20-phenyl methoxy) carbonyl] amino] -2-azetidinone in 40 ml of dry ethyl acetate, 0.45 ml (5.0 mmol) of chlorosulfonyl isocyanate was added, with stirring, and the mixture was stirred for 1 h at room temperature, then cooled to 0 ° C. After adding 10 ml of dry dichloromethane and 2.09 ml (15.0 mmol) of triethylamine, solution A was added dropwise with stirring at 0 ° C. After stirring overnight at 0 ° C, the reaction mixture was poured into ice water and the organic layer was separated. By acidification of the aqueous phase to pH 2 by addition of 1N hydrochloric acid, the title compound was obtained in the form of a sticky precipitate which was collected by suction, which was washed with water and that was vacuum dried. Yield: 1.76 g (64%).

35 G) Trifluoroacetate (1: 2) of (3S) -3-amino-N - [[2 - [[2 - [(1,4-di-hydro-5-hydroxy-4-oxo-2-pyridinyl] carbonyl] hydrazino] carbo-nyl] hydrazino] sulfonyl] -2-oxo-1-azetidinecarboxamide At 0 ° C, 1.73 g (3.1 mmol) of phenylmethyl ester of acid (3S) was added - [ l - [[[[2 - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-40 pyridinyl) carbonyl] hydrazino] carbonyl] hydrazino] sulfonyl] ami-no] carbonyl] - 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 was evaporated in vacuo and the residue was stirred with dry dichloromethane. The precipitate was collected by suction, washed with dichloromethane and dried in vacuo to give 1.78 g (88%) of the title compound.

H) [3S (Z)] diphenylmethyl ester - 2 - [[[l- (2-amino-50 4-thiazolyl) -2 - [[l - [[[[2 - [[2- [ (1,4-dihydro-5-hydroxy-4-oxo-2-pyri-dinyl) carbonyl] hydrazino] carbonyl] hydrazino] sulfonyl] amino] -carbonyl] -2-oxo-3-azetidinyl] -amino] -2 -oxoethylidene] ami-

no] oxy] -2-methylpropanoic A solution at -30 ° C of 1.10 g (2.5 mmol) of (Z) acid -2-55 amino-a [(2-diphenylmethoxy) -l, l- dimethyl-2-oxoethoxy] i-mino] -4-thiazoleacetic in 22 ml of dry dimethylformamide, 1.05 ml (7.5 mmol) of triethylamine was added, then 0.53 ml (2.5 mmol) of chlorophosphate of diphenyl. After stirring at -30 ° C for 1 h, 1.05 ml (7.5 60 mmol) of triethylamine was added dropwise, then 1.62 g (2.5 mmol) of trifluoroacetate (1 : 2) of (3S) -3-amino-N - [[2 - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl] carbonyl] hydrazino] carbonyl] -hydrazino ] sulfonyl] -2-oxo-1-azetidinecarboxamide The mixture was stirred for 2 h at -10 ° C and for another 1 h 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 adding dilute hydrochloric acid to it. The insoluble substance was collected by suction and stirred with

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28

a few milliliters of ethyl acetate until it becomes crystalline to obtain, after drying under vacuum, 1.72 g (82%) of the title compound.

I) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[2 - [[2 - [( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-nyl] hydrazino] carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methyl-propanoic

To a suspension of 1.68 g (2.0 mmol) of diphenylmethyl ester of [3S (Z)] acid - 2 - [[[[1- (2-amino-4-thiazolyl) -2 - [[1- [[[[2 - [[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydra-zino] carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo -3-aze-tidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoï-crude in 3 ml of dry dichloromethane, 2.0 ml of anisole was added, then 20 ml of trifluoroacetic acid at -10 ° C. After stirring at 0 ° C for 10 min, 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 6.0 by addition of dilute sodium hydroxide (1%). The organic phase and the insoluble matter were separated (0.38 g) and the aqueous phase was lyophilized (2.66 g). The lyophilization residue was purified on XAD-2 * resin (eluting with water) to obtain, after lyophilization, 0.25 g (17%) of the title compound as a colorless powder (melting point> 213 ° C, decomposition).

Example 6

Disodium salt of the acid [3S- [3a (Z), 4ß]] - 2 - [[[l- (2-amino-4-thia-zolyl) -2 - [[l - [[[[[2- [ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) car-bonyl] hydrazino] sulfonyl] amino] carbonyl] -4-methyl-2-oxo-3-azetidinyl] amino] -2-oxoethylidene ] amino] oxy] -2-methylpropio-

fuck

A) Phenylmethyl ester of (3S-trans) acid - [l - [[[[2 - [[1,4-dihydro-4-oxo-5-hydroxy-2-pyridinyl] carbonyl] hydrazino] sulfo-

nyl] amino] carbonyl] -4-methyl-2-oxo-3-azetidinyl] carbamic A suspension of 2.34 g of phenylmethyl ester of (3S-trans) - (4-methyl-2-oxo- 3-azetidinyl) carbamic in 50 ml of dry ethyl acetate, 1.41 g of chlorosulfonyl isocyanate was added. After one hour of stirring 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-pyridinecarboxylic acid hydrazide in 50 ml of dry ethyl acetate, 6 g of N-methyl were added -N- (trimethylsilyl) tri-fluoracetamide. After one hour of stirring at 50 ° C, 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. After cooling to -15 ° C, 3 g of triethylamine was added, followed by 150 ml of ice water. After stirring for 1 hour at 0 ° C., the organic phase was washed with 50 ml of water. The entire aqueous phase was adjusted to pH 2 with 1N hydrochloric acid 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) (1: 2) trifluoroacetate (3S-trans) -3-amino-N - [[2 - [(1,4-di-hydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino ] sul-

fonyl] -4-methyl-2-oxo-l-azetidinecarboxamide A 3.5 g of phenylmethyl acid ester (3S-trans) - [l - [[[[2 - [[1,4-dihydro-4 -oxo-5-hydroxy-2-pyridinyl] carbonyl] hydrazino] -sulfonyl] amino] carbonyl] -4-methyl-2-oxo-3-azetidinyl] carbami-that in 20 ml of thioanisole, 50 ml of d trifluoroacetic acid at room temperature, then the reaction mixture was stirred for 13 h. After adding 100 ml

* XAD-2 resin: Macroeticular copolymer of styrene and ether divinylbenzene, 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.

5

C) [3S- [3a (Z), 4ß]] diphenylmethyl ester of acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1- - [[[[2- [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] amino] carbonyl] -4-me-thyl-2-oxo-3-azetidinyl] amino] -2- oxoethylidene] amino] oxy] -2-io methylpropionic

To a solution of 1.8 g of (Z) -2-amino-a - [[2-diphenyl-methoxy) -1, 1-dimethyl-2-oxoethoxy] imino] -4-thiazoleacetic acid and 1, 2 g of triethylamine in 30 ml of dimethylformamide at -30 ° C, 2.1 g of diphenyl chlorophosphate were added. After stirring at -30 ° C for 45 min, 1.95 g of (3S-trans) -3-amino-N - [[2 - [(1,4-dihydro) trifluoroacetate (1: 2) was added -5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] 4-methyl-2-oxo-1-azetidinecarboxamide in 10 ml of dimethylformamide, then 0.8 g of triethylamine. After stirring at -10 ° C for 2 hours and at 0 ° C for 1 hour, dimethylformamide is added to the vacuum, the residue is stirred with 250 ml of ethyl acetate and 400 ml of ice water. The aqueous phase was adjusted to pH 1.5 with 2N hydrochloric acid and extracted twice with 200 ml portions of ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to obtain 1.3 g of the title compound in the raw state.

D) Disodium salt of the acid [3S- [3a (Z), 4ß]] - 2 [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[2- [ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridi-30 nyl) carbonyl] hydrazino] sulfonyl] amino] carbonyl] -4-methyl-2-oxo-3-azetidinyl] amino-2-oxoethylidene ] -amino] -oxy] -2-me-

thylpropionic To a solution of 1.2 g of diphenyl methyl ester of [3S- [3a (Z), 4ß]] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[ l - [[[[2 - [(1,4-35 dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfo-nyl] amino] carbonyl] -4-methyl-2-oxo- 3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -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 min, 100 ml of ether was added to obtain 0.8 g of 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 chromatographed on XAD-2 resin, with water as eluent, to obtain 0.28 g of the title compound in pure form.

Example 7

Disodium salt of [3S (Z)] acid - l - [[[l- (2-amino-4-thiazolyl) -2 -. [[L - [[[[3 - [[(l, 4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -50 amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene ] amino] oxy] -cyclo'pentane-carboxylic

A) [3S (Z) -l - [- [[1- (2-amino-55 4-thiazolyl) -2 - diphenylmethyl ester of -2 - [[l - [[[[3 - [[(1,4 -dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) carbonyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] -carbonyl] -2-oxo-3-azetidinyl] amino] -2 -oxoethylidene] ami-

no] oxy] cyclopentanecarboxylic To a suspension of 3.9 g (8.3 mmol) of (Z) -2-amino-60 acid a - [[[1- (diphenylmethoxy) carbonyl] cyclopentyl] oxy] imino] - 4-thiazoleacetic in 100 ml of dry acetonitrile, 3.5 ml (25 mmol) of triethylamine was added to form a clear solution. After cooling to -30 ° C, 1.8 ml (8.3 mmol) of diphenyl chlorophosphate was added, and the mixture was stirred at -30 ° C for one hour (solution A).

At the same time, friends in suspension 4.5 g (8.3 mmol) of trifluoroacetate (1: 2) of (3S) -3-amino-N - [[3 - [[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l-

29

670,828

imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide in 100 ml of dry ethyl acetate. Then 7.2 ml of bis (trimethylsilyl) acetamide was added at room temperature to obtain a clear solution after 5 min. After stirring for one hour, the solution was cooled to 0 ° C (solution B).

Solution B is added dropwise with stirring to solution A at -30 ° C in 10 min. The mixture was stirred for 1 h at -10 ° C and for 1.5 h at 0 ° C. The volatiles were evaporated and the residue was triturated with water. The residue solidified, and the solids were collected and resuspended in water at a pH of about 2. After stirring for 30 min, the solid was collected and dried to obtain 12.0 g of the title compound in the raw state.

B) Disodium salt of [3S (Z)] acid - l - [[[l- (2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [[(l, 4 -dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-nyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2- oxoethylidene] amino] oxy] cyclopen-tanecarboxylic

12 g of pS (Z) acid diphenylmethyl ester was suspended - 1 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[3- [ [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -amino ] -2-oxoethylidene] amino] oxy] cyclopentanecarboxylic in 20 ml of anisole, and, after cooling to -10 ° C, 100 ml of trifluoroacetic acid was added. The mixture was stirred at -10 ° C for one hour, and 300 ml of ether was added at -10 ° C to obtain a precipitate. After stirring for one hour, this precipitate was removed by filtration to obtain 5.7 g of a substance. This substance 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 0.1 N sodium hydroxide at 0 ° C with stirring. . The acetone was evaporated in vacuo, and the aqueous solution was lyophilized to obtain 5.7 g of a solid residue. This residue was chromatographed on HP-20 (eluting with water) to obtain 1.69 g (27%) of the title compound in the pure state.

'H-NMR (DMSO-d6 + CF3COOH): = = 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); ppm.

Example 8

Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1- - [[[[3 - [(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) methyl-2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidi-nyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic A) 2- (Azidomethyl) -5- (phenylmethoxy) -l- (phenylmethyl) -4- (1H) pyridinone

To a suspension of 2.0 g (6 mmol) of 2- (chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4 (1H) pyridinone in 20 ml of acetonitrile, 3.9 g was added (60 mmol) of sodium azide and 0.1 g of "18-crown-6" *, and the mixture was heated at reflux for 4 h. The salts were filtered by suction, and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel (8: 2 mixture of ethyl acetate and methanol) to give 1.86 g of the title compound, melting point 120 ° C.

* phase transfer agent sold by Abaldrich Chemical Company (1,4,7,10,13,16-hexaoxacyclooctadecane)

B) 2- (Aminomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -

4 (1H) pyridinone 2- (azidomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4 (1H) pyridinone (1.0 g, 2.89 mmol) was dissolved in 50 ml of methanol, and 0.10 g of platinum oxide was added. Hydrogen was bubbled through the mixture for 30 min and the catalyst was filtered by suction on Hyflo. The filtrate was evaporated in vacuo and the oily residue was triturated with ether to obtain the title compound in the crystalline state (0.89 g), melting point 207 ° C.

5

C) 2 - [[[[((2-Chlorethyl) amino] carbonyl] amino] methyl] -5- (phe-nylmethoxy) -2- (phenylmethyl) -4 (1H) pyridinone

To a suspension of 48.0 g (0.15 mole) of 2- (aminomethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4 (1H) pyridine in 1.51 ethyl acetate, added 12.8 ml (0.15 mole) of 2-chlorethylisocyanate. The mixture was stirred overnight at room temperature, the product was suction filtered, washed with ethyl acetate, and dried in vacuo to give 59.6 g of the compound titer, melting point 130 ° C.

15

D) 2 - [(2-Oxo-1-imidazoldinyl) methyl] -5- (phenylmethoxy) -l- (phenylmethyl) -4 (1H) pyridinone

A solution of 7.29 g (0.13 mole) of potassium hydroxide in 500 ml of ethanol was added dropwise to a mixture of 60.8 g (0.13

20 mole) de2 - [[[[(2-chlorethyl) amino] carbonyl] amino] methyl] -5- (phenylmethoxy) -2- (phenylmethyl) -4 (1H) pyridinone and 1.31 ethanol. The reaction mixture was heated at reflux for 3 h 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 product, which was further obtained. purified by recrystallization from acetonitrile to give 17.0 g of the title compound, melting point 190 ° C, decomposition.

E) 5-hydroxy-2 - [(2-oxo-1-imidazoli-dinyl) -methyl] -4 (1H) pyridinone para-toluenesulfonate

To a solution of 2 - [(2-oxo-1-imidazolidinyl) -methyl] -5- (phenylmethoxy) -1- (phenylmethyl) -4 (1H) pyridinone (4.98 g;

12.8 mmol) in 90 ml of dimethylformamide, p-toluenesulfonic acid monohydrate (4.86 g; 25.6 mmol) and 1.0 g of palladium on carbon were added, and bubbled with hydrogen in the mixture for 30 min. The catalyst was filtered off with suction and the filtrate was evaporated in vacuo. The residue was triturated with dichloromethane and ether, and the product was filtered by suction, which gave 4.12 g of the title compound, melting point 195 ° C.

25

40

45 F) 5-Hydroxy-2 - [(2-oxo-1-imidazolidinyl) methyl] -4 (1H) pyridi-

none

5-hydroxy-2 - [(2-oxo-1-imidazolidinyl) methyl] -4 (1H) pyridinone (4.0 g; 10.5 mmol) was dissolved in 50 ml of water and the pH was adjusted to 6.5 by adding 2N sodium hydroxide solution. The precipitate was filtered by suction, washed with water, and dried under vacuum, which gave gave 1.5 g of the title compound, melting point 280 ° C, decomposition.

G) Phenylmethyl ester of acid (S) - [l - [[[3 - [(1,4-dihydro-5-55 hydroxy-4-oxo-2-pyridinyl) methyl] -2-oxo-l- imidazolidinyl] sul-fonyl] amino] carbonyl] -2-oxo-3-azetidinyl] carbamic

1.10 g (5 mmol) of (S) -3 - [[(phenyl-methoxy) carbonyl] amino] -2-azetidinone was suspended in 20 ml of dry ethyl acetate, and added 0.44 ml (5 mmol) of chlorosulfonyl soocyanate. The mixture was stirred at room temperature for 1 h (solution a).

To a suspension of 1.04 g (5 mmol) of 5-hydroxy-2 - [(2-oxo-1-imidazolidinyl) methyl] -4 (1H) pyridinone in 10 ml of dry ethyl acetate, 3.70 ml (20 mmol) of N-methyl-N-65 (trimethylsilyl) trifluoroacetamide was added, and the mixture was heated to 60 ° C. The resulting clear solution was evaporated in vacuo at 60 ° C and the residue was dissolved in 10 ml of dry ethyl acetate (solution b).

670,828

30

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 give 2.91 g of the title compound, melting point 180 ° C, decomposition.

H) (S) -3-amino-N - [[3 - [(1,4-dihydro-5-hy-droxy-4-oxo-2-pyridinyl) methyl] -2-oxo-l-imidazolidinyl trifluoroacetate ] sul-fonyl] -2-oxo-l-azetidinecarboxamide

Phenylmethyl ester of (S) - [l - [[[[3 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] -2-oxo was added -l-imi-dazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] carbamic (0.50 g, 0.93 mmol) 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 suction, and dried in vacuo to give 0.49 g of the title compound, melting point 155 ° C.

I) [3S (Z)] diphenylmethyl ester - 2 - [[[l- (2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [(l, 4- dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) methyl] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino ] oxy] -2-methyl-propanoic

To a suspension of 0.41 g (0.93 mmol) of (Z) -2-amino-a [[2-diphenylmethoxy) -1,-dimethyl-2-oxo-ethoxy] -imino] -4 acid -thiazoleacetic in 20 ml of dry acetonitrile, 0.39 ml (2.8 mmol) of triethylamine was added. The mixture was cooled to -30 ° C, and 0.19 ml (0.93 mmol) of diphenyl chlorophosphate was added dropwise. The reaction mixture was stirred for 1 h at -30 ° C (solution a).

(S) -3-amino-N - [[3 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] -2-oxo-1 trifluoroacetate was suspended -imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide (0.48 g, 0.93 mmol) in 20 ml of dry acetonitrile, and 0.78 ml (3.2 mmol) of debis-trimethylsilylacetamide was added. The suspension was stirred for 30 min at room temperature, then added to solution (a).

The reaction mixture was stirred for 1 h at -10 ° C, then for 1.5 h at 0 ° C. The resulting clear solution was evaporated in vacuo, and 50 ml of water was added to the oily residue. The mixture was adjusted to pH 2 by adding 2N hydrochloric acid to it, and the disodium salt of [3S (Z)] - 2 - [- [[1- (2-amino-4-thiazolyl) - acid. 2 - [[l - [[[[3 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbo-nyl ] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic crystallized from the solution. The product was filtered off with suction, washed with water, and dried in vacuo to give 0.7 g of the title compound.

J) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thia-zolyl) -2 - [[l - [[[[3 - [(l, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene ] -amino] oxy] -2-methylpropa-noic

Suspended diphenylmethyl ester of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1- - [[[[3- [ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] -2-oxo-l-imidazolidinyl] sul-fonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] - 2-oxoethylidene] amino] oxy] -2-methylpropanoic (0.7 g, 0.85 mmol) in 1.4 ml of anisole, and cooled to -10 ° C. Trifluoroacetic acid was added, and the solution was stirred for 1 h at -10 ° C. 100 ml of ether was added, and the precipitate was filtered by suction, 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 was lyophilized, which gave 0.5 g of the title compound. This was purified by MPLC (medium pressure liquid chromatography): melting point 250 ° C, decomposition.

5 Example 9

Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1- - [[[[4 - [(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl) methyl] -2,3-dioxo-1-piperazinyl) sulfonyl] amino] carbonyl] -2-oxo-3-azetidi-nyl] amino] -2-oxoethylidene] amino ] oxy] -2-methylpropanoic 10 A) 2- (Chloromethyl) -5- (phenylmethoxy) -1-phenylmethyl) -4 (1H) pyridinone hydrochloride A suspension of 3.21 g ( 10 mmol) of 2- (hydroxymethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4 (1H) pyridinone in 20 ml of chloroform, and 4.65 ml (64 mmol) was added dropwise thionyl chloride. The mixture was stirred for 10 min at 0 ° C, then heated to reflux for 1 h. The solvent was evaporated in vacuo and the residue was washed with petroleum ether and dried in vacuo to give 3.66 g of the title compound, melting point 85 ° C, 20 decomposition.

B) 2- (Chloromethyl) -5- (phenylmethoxy) -1- (phenylmethyl) -4- (ÎH) pyridinone

2- (Chloromethyl) -5- (phenyl-methoxy) -1- (phenylmethyl) -4 (1H) pyridinone hydrochloride (3.5 g, 9.3 mmol) was dissolved in a mixture of water and 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, melting point 115-120 ° C, decomposition .

C) N- (Triphenylmethyl) piperazine-2,3-dione 35 A mixture of 2,3-piperazinedione (11.4 g, 100 mmol), debistrimethylsilylacet-amide (55.7 g, was refluxed for 1 h. 270 mmol) and 150 ml of acetonitrile. Over 30 min, triphenylmethyl chloride (22.2 g, 80 mmol) was added dropwise and the mixture was again brought to reflux for 2 h. After stirring overnight at room temperature, 21.6 ml of water was added to the clear solution. The resulting precipitate (3.13 g) was filtered off 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 recrystallized from ethanol. Yield of the pure product: 12.19 g, melting point 230-235 ° C.

D) l - [[1,4-Dihydro-4-oxo-5- (phenylmethoxy) -l- (phenylme-thyl) -2-pyridinyl] methyl] -4- (triphenylmethyl) -2,3-piperazine-50 dione

To a solution of N- (triphenylmethyl) piperazine-2,3-dione (4.19 g, 11.77 mmol) in 95 ml of diphenylformamidesec, 0.35 g (11.77 mmol) of hydride was added. sodium (80% in oil). After the evolution of hydrogen had ceased, a solution of 2- (chloromethyl) -5- (phenylmethoxy) -l- (phenylmethyl) -4 (1H) pyridinone was added (4.0 g, 11.77 mmol ) in 25 ml of dry dimethylformamide with a thick suspension, which is then transformed into a clear solution. After 1 h of stirring at room temperature, the precipitation started. After 60 hrs 2, the crystals were filtered off, washed and dried in vacuo to give 5.13 g of the title compound, mp 165-168 ° C.

65

E) l - [[1,4-Dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinyl] methyl] -2,3-piperazinedione A solution of l - [[1.4 -dihydro-4-oxo-5- (phenylmethoxy) -l- (phenylmethyl) -2-pyridinyl] methyl] -4- (triphenylmethyl) -2,3-piperazinedione (8.77 g, 13.23 mmol) in 65 ml of dichloro-

31,670,828

methane, was added dropwise at room temperature, I) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2-65 ml formic acid. After stirring for three days, the volatiles are [[l - [[[[4 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] -2,3- by vacuum distillation and dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidi-

triturated the residue twice with ether to obtain 5.24 g of 1- nyI] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic [[1,4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2- s To a suspension of pyridinyl] methyl] -2,2-piperazinedione diphenylmethyl ester, melting point [3S (Z)] - 2 - [[l - (2-amino-4-thiazolyl) -2 - [[l - [[[[4 - [(1,4-dihydro-5-

260-265 ° C. hydroxy-4-oxo-2-pyridinyl) methyl] -2,3-dioxo-1-piperazinyl) sul-

fonyl] amino] carbonyl] -2-oxo-3-azétidinyI] amino] -2-oxoéthyIi-dène] amino] oxy] -2-methylpropanoic (0.8 g, 0.94 mmol) in

F) Phenylmethyl ester of acid (S) - [l - [[[[[4 - [[1,4-dihydro-4- io i; 4 ml of anisole, was added at -10 ° C, 7 ml of trifluoraceti-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridinyl] methyl] - qUe acid. After stirring for 1 h, 30 ml of ether were added and 2,3-dioxo-1-piperazinyljsulfonyl] amino] carbonyl] -2-oxo-3-azéti- separated by filtration the resulting precipitate, which was dried under empty dinylcarbamic. We friends this salt of trifluoroacetic acid suspended in

To a solution of (S) -3 - [[(phenylmethoxy) carbonyl] amino] - water and the pH was adjusted to 6.5 with 2N sodium hydroxide. By 2-azetidinone (0.44 g , 2.0 mmol) in 25 ml of ethyl acetate lyophilization of the solution, 0.66 g of crude product was obtained, dry, 0.28 g (2.0 mmol) of isocyanate was added of chlorosulfo- which is chromatographed with a second sample, and the solution was stirred for 30 min at the Ion temperature prepared in the same way (total: 1.55 g) on an ambient copolymer. It was then added 12 ml of dichloromethane, macroreticular of styrene and divinylbenzene in these condi-0.61 g (6 mmol) of triethylamine and a mixture, stirred with MPLC, which gave 0.34 g of the compound of the title. A prerequisite for 3 h of l - [[1,4-dihydro-4-oxo-5- (phenylmethsecond) column chromatography on copolymer ox.v) -l- (phenylmethyl) -2-pyridinyl] methyl ] -2,3-piperazinedione macroreticular styrene and divinylbenzene gave 0.18 g (0.83 g, 2.0 mmol) and N-methyl-N- (trimethylsilyl) trifluora- of the title compound, period melting 242-270 ° C.

ketamide (1.59 g, 8.0 mmol) in 25 ml of dry ethyl acetate.

After stirring for three days at room temperature,

ice water was added and the pH was adjusted to 1 with acid Example 10

hydrochloric. The insoluble residue was filtered off and the disodium salt of the acid [3S (Z)] - 2 - [[[[1- (2-amino-4-thiazolyl) -2-1 dried in vacuo which gave gives 1.15 g of the title compound with [[1 - [[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methylè-72% purity. ne] amino] -2 -oxo-l-imidazoldinyl] sulfonyl] amino] carbonyl] -2-

30 oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methyl-propanoic

G) Salt of 4-methylbenzenesulfonic acid of (S) -3-amino-N - [[4- A) Phenylmethyl ester of 4,5-bis (phenylmethoxy) acid -2 - [(1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl) methyl] -2,3-dioxo-1-pyridinecarboxylic piperazinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide Qn added 21.5 g (156 mmol) of carbonate potassium to

To a solution of phenylmethyl ester of acid (S) - [[l - [[[[4- 4- 35 suspension of 29.4 g (120mmol) of O-benzylcomenaa acid - [[1,4-dihydro-4 -oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2- mique in 350 ml of dimethylformamide, and was stirred during pyridinyl] methyl] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] car- 1 h at room temperature. Bonyl] -2-oxo-3-azetidinyl] carbamic bromide (0.98 g, 1.32 mmol) was added to benzyl (31 ml, 264 mmol) and the mixture was heated to 100 ° C 20 ml of dimethylformamide, 0.5 g (2.64 mmol) was added while stirring for 25 h. After having cooled to the temperature of p-toluzenesulfonic acid and 0.5 g of palladium on ambient charcoal, the dimethylformamide was distilled off under (10%). Hydrogen was bubbled through the empty mixture and the residue was triturated with ethyl acetate for 1 h. The catalyst was filtered off, the heater was removed quickly at 60 ° C. 40 g of solvent were filtered off by vacuum distillation and the residue was triturated with mineral salts, the filtrate was concentrated to about 75 ml and dichloromethane was obtained to obtain, after drying, 0.82 g of the compound chromatographed on silica gel using one of the title as eluent, melting point 160-185 ° C, decomposition. 45:10:10 mixture of ethyl acetate and petroleum ether to give 35.5 g of the title compound, mp 116.7 ° C.

H) [3S (Z)] - 2 - [- [[1- (2-amino- B) 4,5-Bis (phenylmethoxy) -2-pyridinemethanol 4-thiazolyl) -2 - [[diphenyl methyl ester of [3S (Z)] acid - [[ l - [[[[4 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridi- To a suspension of 95 mg (25 mmol) of lithium nyl) methyl hydride) -2, 3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] - 50 and aluminum in 10 ml of ether and 10 ml of tetrahydrofuran, 2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy ] -2-me 1.06 g (25 mmol) of 4,5-bis (phenylmethoxy) -2-pyridinecarboxylic acid phenylmethyl ester was added in three portions

To a solution of (Z) -2-ammo- <x - [[2- (diphenylations at 0 ° C.) After stirring for 20 min at 0 ° C, was added

methoxy) -1, 1-dimethyl-2-oxoethoxy] imino] -4-thiazoleacetic 0.2 ml of a saturated solution of sodium bicarbonate, 0.2 ml

(0.57 g, 1.3 mmol) in 30 ml of dimethylformamide, there are 55 of a 10% potassium hydroxide solution, and a solution supplement added, at -30 ° C, of triethylamine (0.39 g, 3.9 mmol) and saturated sodium bicarbonate until the precipitate

triphenyl chlorophosphate (0.31 g, 1.3 mmol). After having mineral collects at the bottom of the container. The stirred mixture was decanted for 1 h, triethylamine (0.39 g, 3.9 clear organic phase and evaporated in vacuo for mmol) and 4-methylbenzenesulfonic acid salt was added. (S) -3- obtain an oil, which crystallized slowly. Yield: 0.6 g,

amino-N - [[4 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) me- 6 "melting point 96.6 ° C. thyl] -2,3-dioxo- l-piperazinyl] sulfonyl] -2-oxo-l-azetidinecar-

boxamide (0.98 g, 1.3 mmol). The mixture was stirred for 2 h C) 4,5-Bis (phenylmethoxy) -2-pyridinecarboxaldehyde

at -10 ° C and for 1.5 h at 0 ° C. Water and A solution of 0.54 g (1.7 mmol) of 4,5-bis (phenylme-

ethyl acetate, and the pH was brought to 1 with thoxy acid) -2-pyridinemethanol in 15 ml of acetone, was added

3N hydrochloric acid. The precipitate was separated by filtration, it was 65 1.5 mg (17 mmol) of manganese dioxide, and the mixture was stirred with ethyl acetate and dried. under vacuum, which mixed overnight at room temperature. 0.86 g of the title compound was given, melting point 130-190 ° C, then the mixture was filtered through a column of silica gel (61 to

decomposition. 210 (i), and the aldehyde was eluted with acetone. By evaporation

670,828

32

eluent and trituration of the residue with petroleum ether, 0.3 g of the title compound was obtained, melting point 104.3 ° C.

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

To a solution of 4,5-bis (phenylmethoxy) -2-pyridinecar-boxaldehyde (1.9 g, 6.0 mmol), in 25 ml of dry dimethylformamide, was added 0.2 g of palladium on carbon serving as catalyst, and hydrogen was bubbled through the mixture for 3 h. The catalyst was filtered off, the solvent was distilled off in vacuo and the residue was triturated with ether to obtain 0.64 g of the title compound, melting point 174-177 ° C, decomposition.

E) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [[(1,4 -dihydro-5-hydroxy-4-oxo-2-pyridinyl) methylated] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2- oxoethylidene] amino] oxy] -2-methyl-propanoic

To a solution of monosodium salt of [3S (Z)] acid - 2 - [[[2 - [[l - [[[(3-amino-2-oxo-l-imidazolidinyl) sulfonyl] amino] carbonyl] - 2-oxo-3-azetidinyl] -amino] -l- (2-amino-4-thiazolyl) -2-oxoethylidè-ne] amino] oxy] -2-propanoic (0.64 g, 1.1 mmol) in 15 ml of dry dimethylformamide, 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxaldehyde (0.18 g, 1.3 mmol) was added and, after having been stirred for 4.5 h, added another 0.02 g (0.14 mmol) del, 4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxaldehyde. After stirring overnight at room temperature, the solvent was evaporated in vacuo, the residue was taken up in 30 ml of water, filtered and the solution lyophilized. The crude substance (0.82 g) was dissolved in 5 ml of water and chromatographed on a macroeticular resin of styrene-divinylbenzene copolymer, using water as eluent, which gave 0, 22 g of pure product, melting point 248 ° C, decomposition.

Example 11

Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[4 - [[(1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -amino] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidmyl] amino] -2-oxoethylidene ] amino] oxy] -2-methyl-propanoic

A) 4,5-bis (phenylmethoxy) -2-pyridinecarboxylic acid To a solution of 11.8 g (28 mmol) of phenylmethyl ester of 4,5-bis (phenylmethoxy) -2-pyridinecarboxylic acid in 115 ml of tetrahydrofuran, 16 ml of water and 35 ml of 1N potassium hydroxide were added. After stirring overnight at room temperature, 115 ml of water were added and the pH was adjusted to 2.5 with 1 ml. hydrochloric acid 1 N. The acid was separated by filtration, washed with water and dried in vacuo to give 8.6 g of the title compound, melting point 203 , 6 ° C.

B) N- (2,3-Dioxo-1-piperazinyl) -4,5-bis (phenylmethoxy) -2-pyri-dinecarboxamide A suspension of 4,5-bis (phenylmethoxy) -2-pyridi-necarboxylic acid (7.1 g, 21.17 mmol), hydroxybenzotriazole (0.29 g, 2.12 mmol) and N-aminopiperazine-2,3-dione (273 g, 21.17 mmol) in 140 ml of dry dimethylformamide, after stirring for 15 min, 4.80 g (23.3 mmol) of dicyclohexylcarbodiimide was added. After stirring for 21 h at room temperature, the dicyclohexylurea (4.0 g) was filtered off and the solvent was evaporated in vacuo. The solid residue was triturated for 40 min with 240 ml of tetrahydrofuran, filtered, washed with tetrahydrofuran and dried in vacuo to obtain 7.76 g of the title compound, melting point 231.1 ° C.

C) Phenylmethyl ester of acid (S) - [l - [[[[[4 - [[[4,5-bis (phe-nylmethoxy) -2-pyridinyl] carbonyl] amino] -2,3-dioxo- l-pipérazi-

nyl] sulfonyl] amino] carbonyl-2-oxo-3-azetidinyl] carbamic A suspension of (S) -3 - [[(phenylmethoxy) -carbonyl] -5 amino] -2-azetidinone (2.02 g, 9 , 18 mmol) in 130 ml of ethyl acetate, chlorosulfonyl isocyanate (1.43 g, 10 mmol) was added and, after stirring for 1 h, triethylamine (2.79 g, 27.54 mmol) at 0 ° C. To this mixture was added a solution, stirred beforehand for 1.5 h, of N-10 (2,3-dioxo-1-piperazinyl) -4,5-bis (phenylmethoxy) -2-pyridine-carboxamide ( 4.10 g, 9.18 mmol) and N-methyl-N- (trimethyl-silyl) -trifluoracetamide (5.4 g, 27.54 mmol) 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 treated the organic phase separated by brine, the title compound precipitated, and it was filtered, washed with water and dried under vacuum, yield 5.35 g. When 2.5 g of this substance was triturated for 1 h with a mixture of 25 ml of water and 37.5 ml of acetone at pH 6.3, 2.12 g of the title compound were obtained .

D) (S) -N- [4 - [[[3-Amino-2-oxo-1-azetidinyl) carbonyl] amino] sul-fonyl] -2,3-dioxo-1-piperazinyl] -1,4 dihydro-5-hydroxy-4-oxo-5-

pyridinecarboxamide 25 To a solution of phenylmethyl ester of (S) acid - [l - [[[[4 - [[[4,5-bis (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2,3- dioxo-1-piperazinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidi-nylcarbamic (1.54 g, 2 mmol) in 30 ml of dimethylformamide, 0.77 g of palladium on carbon was added, and the mixture was hydrogenated for 45 min. The catalyst was removed by filtration through Hyflo and the resulting solution was used in the next step without isolating the title compound.

E) Diphenylmethyl ester of [3S (Z)] acid - 2 - [[[l- (2-amino-35 4-thiazolyl) -2 - [[l - [[[[4 - [[(l, 4 -dihydro-5-hydroxy-4-oxo-2-pyridi-

nyl) carbonyl] amino] -2,3-dioxo-1-piperazinyl] sulfonyl] amino] -carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] ami-

no] oxy] -2-methylpropanoic acid To a solution of (Z) -2-amino-a - [[2- (diphenylmeth-40 oxy) -l, l-dimethyl-2-oxoethoxy] imino] -4- thiazoleacetic (0.88 g, 2.0 mmol) in 20 ml of dimethylformamide, triethylamine (0.60 g, 6.0 mmol) was added and, at -30 ° C under nitrogen, triphenyl chlorophosphate ( 0.54 g, 2.0 mmol). After stirring for 1 h at -30 ° C, triethylamine (0.20 ng, 2 mmol) and the solution of (S) -N- [4 - [[[3-amino]) were added dropwise -2-oxo-1-azetidinyl) carbonyl] amino] sulfonyl] -2,3-dioxo-1-piperazinyl] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarbox-amide in dimethylformamide. The mixture was stirred for 2 h at -10 ° C and for 17 h 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 dried in vacuo to give 1.35 g of the composed of the title.

55

F) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[[4 - [[(l, 4 -dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-

nyl] amino] -2,3-dioxo-1-piperazinyl] sulfonyl] ammo] carbonyl] -2-60 oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methyl-propanoic A mixture of 2.6 ml of anisole and 13 ml of trifluoroacetic acid, diphenylmethyl ester of [3S (Z)] - 2 - [[[1- (2-amino-4- thiazolyl) -2- [l - [[[[4 - [[1,4-65dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2,3-dioxo-1-piperazinyl] sulfonyl ] amino] carbonyl] -2-oxo-3-azetidi-nyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic (1.3 g, 1.48 mmol) at -10 ° C, and stirred the mixture for 2 h

33

670,828

25

at 0 ° C. The volatiles were removed by vacuum distillation and the residue was triturated with ether to give 1.06 g of trifluoroacetic acid salt after drying. This trifluoroacetic acid salt was suspended in 20 ml of water, and the pH was adjusted to 6.5 with 1 N sodium hydroxide solution. The lyophilized solution gave 1.10 g of crude product, which was chromatographed on macroreticular copolymer of styrene and divinylbenzene under MPLC conditions, using water as eluent. Yield: 0.48 g. This substance was again chromatographed twice, together with other samples prepared in the same manner. The second chromatography was carried out in a column of macroreticular copolymer of styrene and divinylbenzene and the third on Organogen, each time using water as eluent. Final yield 0.10 g, melting point> 300 ° C. 15

Example 12

[3S (Z)] ethyldiisopropylamine salt - 3 - [[(2-amino-4-thia-zolyl) - [(2-fhiorethoxy) imino] acetyl] amino] -N - [[3 - [[( 1,4-di-hydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecarboxamide To an acid solution (Z) -2-amino-a - [(2-fluorethoxyimino] -4-thiazoleacetic (0.33 g, 1.4 mmol) in 5 ml of dry dimethylformamide, N-hydroxybenzotriazole (0.19 g, 1 is added) , 4 mmol) and N-ethyl-diisopropylamine (0.18 g, 1.4 mmol). At 0 ° C., dicyclohexylcarbodiimide (0.29 g, 1.4 mmol) was added and the mixture was stirred for 1 h . (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)) trifluoroacetate (1: 2) solution was added carbonyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] -2-oxo-l-azetidinecarboxamide (0.87 g, 1.6 mmol); see Example 1G) and N-ethyldiisopropyl-amine , (0.41 g, 3.2 mmol) in 3 ml of dry dimethylformamide. The mixture was stirred for 2 h at 0 ° C, then for another 16 h at room temperature. The dicyclohexylurea was separated by filtration, and the solvent was removed by vacuum distillation. The residual oil was triturated with water until crystallization was complete. The solid (0.82 g) was collected by filtration, the filtrate was brought to pH 6.1 and lyophilized. The solid was suspended in 40 ml of water and the pH was brought to 6.0 with 0.25N sodium hydroxide. The undissolved material was filtered off and the filtrate was lyophilized. Two fractions (about 0.6 g) of the lyophilized material were pooled and chromatographed on a macroreticular copolymer of styrene and divinylbenzene using water and a 95: 5 mixture of water and acetonitrile as the eluent. . After lyophilization, the appropriate fractions gave 0.22 g of the title compound, mp 163-165 ° C.

Example 13

Trisodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1- - [[[[2- (carboxymethyl) -2 - [( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2 -methylpro-

panoic

A) N, 0-dibenzyl-comenamyl hydrochloride 55 To a suspension of 16.77 g (50.0 mmol) of N, 0-dibenzylcomenamic acid in 360 ml of dry dichloromethane, 11.45 g was added (55.0 mmol) of phosphorus pentachloride,

little by little at 0-5 ° C. Stirring was continued for 1 h at room temperature, and the precipitate was collected by suction, washed with 20 ml of dry dichloromethane and dried in vacuo to give 15.02 g of the title compound, melting point 126-127 ° C, decomposition.

B) 1,1-Dimethylethyl ester of [2 - [(phenylmethoxy) - 6s carbonyl] hydrazino] acetic acid To a stirred solution of 6.65 g (0.040 mole) of N - [(phenyl-methoxy) carbonyl] hydrazine in 40 ml of dimethylformamide,

a solution of 8.58 g (0.044 mol) of t-butyl bromacetate in 20 ml of dimethylformamide was added dropwise, followed by a solution of 8.2 ml (0.048 mmol) of N, N-diisopropylethylamine in 8 ml of dimethylformamide. After the mixture was stirred at room temperature for one day, the solvent was removed by vacuum distillation and the residue was taken up in ether and water. The organic layer was washed three times with water, dried over magnesium sulfate and evaporated in vacuo to leave an oil (10.6 g), which was purified by column chromatography 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 give 6.0 g of the title compound, mp 61-62 ° C.

C) 1,1-Dimethylethyl ester of [1 - [[1,4-dihydro-4-oxo-5-phenylmethoxy) -2-pyridinyl] carbonyl] -2 - [(phenylmethoxy) -carbonyl] hydrazino] acid acetic 15.6 ml (80.0 mmol) of N-methyl-N-trimethyl-silyltrifluoracetamide was added to a solution of 11.2 g (40.0 mmol) of 1,1-dimethyl ethyl acid ester [2 - [(phenylmethoxy) car-bonyl] hydrazino] acetic in 60 ml of dry acetonitrile. After stirring for 30 min at room temperature, the clear solution was evaporated in vacuo and the residue was dissolved in 45 ml of dry dichloromethane. This solution was poured dropwise into a suspension of 15.61 g of N, 0-dibenzylcomenamyl hydrochloride in 60 ml of dichlorome-thanesec 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 chromatographed on silica gel, eluting with ethyl acetate and then with 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 177-178 ° C, decomposition.

D) 1,1-Dimethylethyl ester of [l - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] acetic acid A suspension of 7.17 g was hydrogenated (12.0 mmol) 1,1-dimethyl ethyl ester of [l - [[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] -2 - [(phenylmethoxy ) car-bonyl] hydrazino] acetic acid in 400 ml of methanol, in the presence of 1.6 g of 10% palladium on charcoal, for 40 min. The catalyst and the precipitate were filtered off and washed thoroughly with 300 ml of dry dimethylformamide to dissolve the precipitate. Solvents were removed from all of the filtrates to obtain a residue which was crystallized by stirring with ether (1.68 g; melting point 221 ° C, decomposition). By recrystallization from methanol, the pure compound was obtained. Yield: 1.26 g; melting point 225 ° C, sintering at 229 ° C, decomposition.

E) 1,1-Dimethylethyl ester of (3S) acid - [l - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -2 - [[[[2- oxo-3 - [[(phenyl-methoxy) carbonyl] amino] -1-azetidinyl] carbonyl] amino] sulfo-nyl] hydrazino] acetic 9.0 ml (46.2 mmol) of N-methyl-N was added -trimethylsi-lyltrifluoracetamide to a suspension of 3.2 g (11.0 mmol) of 1,1-dimethylethyl ester of [l - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) ester ) carbonyl] hydrazino] acetic in 120 ml of dry ethyl acetate. At room temperature, stirring was continued for 1 h to obtain a clear solution (solution A).

To a suspension of 2.42 g (11.0 mmol) of (S) -3 - [[(phenyl-methoxy) carbonyl] amino] -2-azetidinone in 80 ml of acetate

670 828 34

of dry ethyl, 0.99 ml (11.0 mmol) of isocyanate of H) was added. Trifluoroacetic acid salt of [3S (Z)] - 2 - [[[1- (2-

chlorosulfonyl, with stirring. The mixture was stirred for 1 h at amino-4-thiazolyl) -2 - [[l - [[[[2- (carboxymethyl) -2 - [(1,4-dihydro-room temperature, then cooled to 0 ° C. 5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] ami was poured

solution at A ° O Cetonacontinuagitation no] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] ami-

overnight at room temperature. After adding 5 no] oxy] -2-piethylpropanoic

4 ml of triethylamine, the mixture was evaporated in vacuo. 0.17 g (0.2 mmol) of diphenyl ester was added slowly, the residue was dissolved in 10 ml of a 4: 1 mixture of methanol and thylic acid [3S (Z)] - 2- [[[1- (2-amino-4-thiazolyl) -2 - [[1- - [[[[2-water. This solution was poured dropwise into a mixture (carboxymethyl) -2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -of 30 ml of methanol and water, of which kept the pH at 2, for carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azétidi-obtain a residue (10.25 g) which became crystalline when we have 10 nyl] amino] -2 -oxoethylidene] amino] oxy] -2-methylpropanoic stirred with a few milliliters of water and methanol. A stirred solution cooled to -10 ° C. of 0.62 ml (8.0 mmol) is precipitated from the precipitate by successive washings (with stirring) with a mixture of trifluoroacetic acid and 0.087 ml (0.8 mmol) of thioani-4 : 1 of isopropanol and water, with methanol, with a silk mixture Qn continued stirring for 15 min at 0 ° C. 1: 1 was made of methanol and ether and with ether. Yield after evaporating the suspension under vacuum at 0-5 ° C, and the drying residue was stirred under vacuum: 2.39 g. 15 with dry ether, collected by suction, washed with dry ether and dried in vacuo, yield 0.14 g; melting point> 230 ° C, decomposition.

F) (S) -3-amino-1 - [[[[2- (carboxymethyl) -2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazi)] trifluoroacetate -

no] sulfonyl] amino] carbonyl] -2-azetidinone 2Q I) Trisodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -

'At 0 ° C, 2.39 g (3.9 mmol) of ester 1,1-dimethyl- 2 - [[1 - [[[[2- (carboxymethyl) -2 - [(1,4 -dihydro-5-hydroxy-4-oxo-2-ethylic acid (3S) - [l - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyri-pyridinyl) carbonyl] hydrazmo] sulfonyl] ammo] carbonyl] -2-oxo-dinyl) carbonyl] -2 - [[[[2-oxo-3 - [[(phenylmethoxy) -carbonyl] - 3-azétidinyl] amino] -2-oxoéthyhdène] ammo] oxy] -2-methylpro-

amino] -1-azetidinyl] carbonyl] amino] sulfonyl] hydrazino] aceto-panoic only to a mixture of 7.0 ml of trifluoroacetic acid and 1.66 ml was suspended in 1.5 ml of water 115 mg (0.146 thioanisole. After stirring overnight at temperature) of trifluoroacetic acid salt of [3S (Z)] acid - 2 - [[[1- (ambient 2-ture, evaporated the solution under vacuum. Washed amino-4-thiazolyl) -2 - [[l - [[[[2- (carboxymethyl) -2 - [(1,4-dihydro-the residue successively (at all) stirring) with ethyl acetate, 5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] ami-un 1: 1 mixture of ethyl acetate and ether oil, ether no] carbonyl ] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] petroleum friend, and dichloromethane, then dried in vacuo. No] oxy] -2-methylpropanoic acid, and the pH was adjusted to 5.5 using this crude salt in the next step without any other adding dropwise diluted sodium hydroxide. We passed the purification. Yield 2.15 g. solution in two successive columns of macrored copolymer

styrene and divinylbenzene (0.05 to 0.1 mm) and a cross-linked dextran gel (25 to 100 [im), eluting with water.

G) [3S (Z)] - 2 - [[[1- (2-amino-) diphenylmethyl ester of the appropriate fractions were pooled and lyophilized 4-thiazolyl) -2 - [[1- [[[[2- (carboxymethyl) -2 - [(1,4-dihydro-5-hy- to obtain 100 mg of the title compound. Droxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] amino ] -

carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino

no] oxy] -2-methylpropanoic Example 14

0.70 ml (3.24 mmol) of chloro was poured in 40 [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) - acid disodium salt Diphenyl 2-phosphate in a mixture, cooled to -30 ° C, of [[l - [[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) acetyl]] -1.42 g (3.24 mmol) of acid (Z) -2-amino-a - [[2- (diphenylmethamino) -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2 -oxo-oxy) -1,1-dimethyl-2-oxoethoxy] imino] -4-thiazoleaceticand 3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpro-1,81 ml (12,96 mmol) of triethylamine in 30 ml of dry panoic acetonitrile (solution A). 45 A) 2- (Cyanomethyl) -5- (phenylmethoxy) -l- (phenylmethyl) -4-

3.27 ml (12.96 mmol) of bistrimethylsilylacet- (ÎH) pyridinone amide was added to a suspension of 2.13 g (about 3.3 mmol) of A suspension of 2.0 g (6 mmol) of 2- (chloromethyl) -5-

(S) -3-amino-1 - fluoroacetate - [[[[[2- (carboxymethyl) -2 - [(1,4 - (phenylmethoxy) l- (phenylmethyl) -4 (1H) pyridinone in 5-hydroxy-hydroxy) -4-oxo-2-pyridmyl) carbonyl] hydrazino] sulfo- 200 ml of acetonitrile, 3.9 g (60 mmol) of nyl cyanide] amino] carbonyl] -2-crude azetidmone was added in 30 ml of acetate so potassium and 0.1 g of "18-crown-6"; the mixture was heated with dry ethyl to room temperature. After stirring at reflux for 2.5 h. The salts were separated by filtration for 1 hour, the clear solution was cooled and suctioned, and the filtrate was evaporated in vacuo. The droplet was purified in solution A at -30 ° C. The resulting residue mixture was stirred by gel column chromatography for 1 h at -10 ° C, another 1.5 h at 0 ° C, then silica, using an 8: 2 mixture of acetate 'ethyl and evaporate in vacuo. The residue was stirred with a few milliliters 55 methanol as the eluent; yield 0.55 g of the title compound, water, the pH of which was adjusted to 2 by addition of hydrochloric acid, melting point 175-180 ° C.

that diluted. The precipitate was separated by filtration, washed with water, redissolved in a mixture of water and acetone at pH

5.5-6.0 (addition of dilute sodium hydroxide) and was purified by MPLC on Acid 1,4-dihydro-5-hydroxy-4-oxo-l- (phenylmethyl) -2-pyri-a copolymer macroreticular of styrene and divinylbenzene, 60 dineacetic eluting with a gradient (0 to 100%) of water and methanol. By A mixture of 2.45 g (7.16 lyophilization of the appropriate fractions was obtained for 4 h at 70 ° C., 270 mg of mmoles were obtained) of 2- (cyanomethyl) -5- (phenylmethoxy) -1- ( phenylme-purified products. A suspension of this salt in thyl) -4 (1H) pyridinone and 40 ml of concentrated hydrochloric acid was acidified.

a few milliliters of cold water with very hydrochloric acid (37%), then evaporated in vacuo. The residue was diluted to pH 2 to precipitate hydrochloric acid diluted to 65 suspension in 15 ml of ice water and the pH was adjusted to 2.0 by pH2 to precipitate the free acid, which the was collected by addition of 5N sodium hydroxide. The precipitate was separated by filtration, suction and dried in vacuo; yield 0.19 g; point washed with ice water and ether and dried under vacuum> 280 ° C, decomposition. (1.71g). On the raw acid in 20 ml or 0.5N soda,

35

670,828

it was reprecipitated by acidification (pH 1.8) with 2N hydrochloric acid, it was collected by suction and 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-pyridineacetamide 4.99 ml (35.83 mmol) was added of triethylamine to a suspension of 9.29 g (35.83 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-l- (phenylmethyl) -2-pyridineacetic acid, of 0.28 g (1 , 79 mmol) of N-hydroxybenzotriazole, 0.22 g (1.79 mmol) of N-dimethylaminopyridine, 3.62 g (35.83 mmol) of N-aminoimidazolidinone and 8.13 g (39.41 mmol ) of dicyclohexylcarbodiimide in 115 ml of dry dimethylformamide. Stirring was continued overnight at room temperature. The precipitated dicyclohexylurea was filtered off, washed with dimethylformamide, and the filtrate was evaporated in vacuo to give a residue, which became crystalline when stirred with 110 ml of dichloromethane. The precipitate was collected by suction and dried in vacuo. To a suspension of this crude product in 65 ml of dry acetonitrile was added 14.0 ml (71.6 mmol) of N-methyl-N-trimethylsilyltri-fluoracetamide. After stirring for 30 min at room temperature, the undissolved dicyclohexylurea was filtered off and the filtrate was evaporated in vacuo. The oily residue was boiled in 70 ml of methanol for 15 min, then cooled. The precipitate was collected by suction, washed successively with methanol, a 1: 1 mixture of methanol and ether, and ether, and dried in vacuo. Yield: 8.7 g; sintering at 242 ° C, melting point 260-265 ° C, decomposition.

D) Monosodium salt of the phenylmethyl ester of acid (S) - [l - [[[[3 - [[[1,4-dihydro-5-hydroxy-4-oxo-l- (phenylmethyl) -2 -py-ridinyl] acetyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] -

carbonyl] -2-oxo-3-azetidinyl] carbamic 5.86 ml (30.0 mmol) of N-methyl-N-trimethyl-silyltrifluoroacetamide was added to a suspension of 3.42 g (10.0 mmol) of , 4-dihydro-5-hydroxy-4-oxo-N- (2-oxo-1-imidazolidinyl) -l- (phenylmethyl) -2-pyridineacetamide in 50 ml of dry ethyl acetate, and continued for 1 stirring for 1 h at room temperature (solution A).

To a solution of 2.20 g (10.0 mmol) of (S) -3 - [[(phenyl-methoxy) carbonyl] amino] -2-azetidinone in 50 ml of dry ethyl acetate was added 0.90 ml (10.0 mmol) of chlorosulfonyl isocyanate, and the mixture was stirred for 1 h at room temperature, then cooled to 0 ° C. Solution A was poured dropwise into this mixture, with stirring, 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 lyophilized. By MPLC on a macroreticular copolymer of styrene and divinylbenzene, eluting with an 8: 1 mixture of water and acetone, and lyophilization of the pure fractions of interest, 0.40 g of the title compound was obtained. Ona purified the impure fractions by a second MPLC under the same conditions. Yield: 0.60 g.

E) (S) -N- [3 - [[- [[3-amino-2-oxo-1-azetidinyl) -carbonyl] amino] sulfonyl] -2-oxo-1-imidazolidinyl] -1,4-dihydro trifluoroacetate -

5-hydroxy-4-oxo-2-pyridineacetamide A solution of 0.90 g (1.3 mmol) of monosodium salt of phenylmethyl ester of (S) acid was hydrogenated - [1 - [[[[3- [[[1,4-dihydro-5-hydroxy-4-oxo-l- (phenylmethyl) ~ 2-pyridinyl] -acetyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2- oxo-3-azetidinyl] carbamic in 13 ml of dry dimethylformamide containing 0.50 ml (6.5 mmol) of trifluoroacetic acid, in the presence of 0.15 g of 10% palladium on carbon, for 20 min. The catalyst was filtered off and removed with a few milliliters of dimethylformamide. By evaporating the filtrate in vacuo, an oily residue was obtained which became crystalline when stirred with a few milliliters of ethyl acetate. Yield: 0.675 g; melting point> 150 ° C, decomposition.

By simple stirring of this title compound in the raw state, in dry ethyl acetate for 1 h, then by filtration, washing with ethyl acetate and drying under vacuum, its purity has been improved. ; yield 80%, melting point> 165 ° C, decomposition.

F) [3S (Z)] acid diphenylmethyl ester - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [[(l, 4-dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) acetyl] amino] -2-oxo-l-imidazolidinyl] -sulfonyl] amino] car-bonyl] -2-oxo-3-azetidinyl] amino ] -2-oxoethylidene] amino] oxy] -2-methylpropanoic acid 1.1 ml (4.45 mmol) of bistrimethylsilylaceta-mite was added to a suspension of 0.75 g (1.35 mmol) of trifluoroacetate ( S) -N- [3 - [[[((3-amino-2-oxo-l-azetidinyl) carbonyl] amino] sul-fonyl] -2-oxo-l-imidazolidinyl] -l, 4-dihydro-5- hydroxy-4-oxo-2-pyridineacetamide in 12 ml of dry ethyl acetate. After stirring for 1 h 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 of 0.60 g (1.35 mmol) of (Z) -2-amino-a - [[2- (diphenylmethoxy) -1,1-dimethyl-2-30 acid oxoethoxy] imino] -4-thiazoleacetic in 12 ml of dry acetonitrile, 0.57 ml (5.4 mmol) of triethylamine was added dropwise, then 0.29 ml (1.35 mmol) of diphenyl chlorophosphate . Stirring was continued for 1 h at -30 ° C and for an additional 1 h 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 filtration, it was washed with cold water, it was suspended in water at pH 2 (addition of a few drops of dilute hydrochloric acid), it was separated by filtration, it was washed successively with water, methanol 40 and ether, and dried in vacuo. Yield: 1.07 g; melting point> 180 ° C, decomposition. This crude product was used in the next step without any further purification.

45 G) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thia-zolyl) -2 - [[l - [[[[3 - [[( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -acetyl] amino] -2-oxo-l-imidazolidinyl] -sulfonyl] amino] carbonyl-2-oxo-3-azetidinyl] amino] - 2-oxoethylidene] amino] oxy] -2-methylpropanoic acid 1.01 g (1.17 mmol) of diphenylmethyl ester of [3S (Z)] - 2 - [[[l- ( 2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) acetyl] amino] -2-oxo -l-imidazolidinyl] sulfonyl] amno] carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic crude 55 at a solution at -10 ° C of 2.0 ml anisole in 10 ml of trifluoroacetic acid. After stirring for 20 min at 10 ° C, the solvent was removed in vacuo at +10 ° C. The residue was stirred with a few milliliters of dichloromethane, filtered, stirred once again with a few milliliters of dichloromethane, the precipitate was collected by suction, washed with hexane and washed. vacuum dried. This crude product (1.06 g) was suspended in a few milliliters of water and acetonitrile, then it was dissolved by adjusting the pH to 6.0 by adding 1N sodium hydroxide. After concentrating under vacuum, chromatographed (MPLC) 65 the aqueous solution on a macroreticular copolymer of styrene and divinylbenzene, eluting with water. The appropriate fractions were pooled and lyophilized. Yield: 0.10 g. melting point> 255 ° C.

670,828

36

Example 15

Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1- - [[[[3 - [[3- (1.4 -dihydro-5-hydroxy-4-oxo-2-pyridinyl) -l-oxo-2-propenyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbo-nyl] -2-oxo-3- azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic

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

9.0 g of 2- (hydroxymethyl) -5- (phenylmethoxy-4 (1H) -pyridinone and 26 g of manganese dioxide (activated) in 100 ml of methanol were stirred overnight at room temperature. The product crystals are formed. After boiling the reaction mixture for 10 min, then filtering it hot on Hyflo, and after washing the filter cake twice with 50 ml of boiling methanol, evaporate all the filtrates and the residue was stirred with 50 ml of ethyl acetate, white crystals of product formed, yield: 9.7 g, melting point 156 ° C., decomposition.

B) Ethyl ester of 3- [1,4-dihydro-4-oxo-5- (phenyl-

methoxy) -2-pyridinyl] -2-propenoic

0.5 g of p-toluenesulfonic acid, 6.26 g of 2- (1-hydroxy-1-methoxymethyl) -5- (phenylmethoxy) -4 (1 H) -pyridi-none and 8.35 g of was stirred. carbethoxymethylenetriphenyl-phosphorane for 3 h 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 and triphenylphosphine oxide was obtained. This residue was dissolved in 30 ml of isopropanol, and product crystals began to separate. After allowing 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) Acid 3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -

propenoic

1.5 g of 3- [1,4-dihydro-4-oxo-5- (phenylmeth-oxy) -2-pyrdinyl] -2-propenoic acid and 0.29 g of potassium hydroxide were stirred in 30 ml of ethanol for 2 hours at 50 ° C. After evaporating the solvent, the residue was dissolved in 100 ml of water and filtered. 2N hydrochloric acid was added to the filtrate until the pH was 5.0. Crystals of the title compound separated from the solution. They were filtered and washed with water and then dried under vacuum. Yield: 1.14 g, melting point 236 ° C.

D) 3- [1,4-Dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -N- (2-

oxo-l-imidazolidinyl) -2-propenamide

10.85 g of 3- [1,4-dihydro-4-oxo-5- (phenyl-methoxy) -2-pyridinyl] -2-propenoic acid, 1 g of N-hydroxybenzo-triazole, 0.01 g were stirred. of N, N-dimethylaminopyridine and 8.24 g of dicyclohexylcarbodiimide for 30 min in 100 ml of dimethylformamide. After cooling to 0 ° C, 4 g of N-aminoimidazolidinone was added and stirring was continued for 1 h at 0 ° C and for 10 h at room temperature. The resulting suspension was then heated to 60 ° C and filtered. It was resuspended in 50 ml of dimethylformamide, then it was heated to 60 ° C and again filtered. All of the filtrates were evaporated at 40 ° C (under 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 solid were obtained. O stirred it with 8 g of p-toluenesulfonic acid in 100 ml of dichloromethane for 1 h. Filtration gave 12.98 g of a white solid. We are friends with this substance suspended in water. By recrystallization from a mixture of water and dimethylformamide, 8.49 g of the title compound were obtained, melting point 271 ° C.

E) Phenylmethyl ester of (3S) acid - [12 - [[[[3 - [[3- [1,4-di-hydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -l -oxo-2-propes-

nyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] carbamic 5 3.55 g of 3- [1,4-dihydro-4 were suspended -oxo-5- (phenylmethoxy) -2-pyridinyl] -N- (2-oxo-1-imidazolidinyl) -2-propenamide in 100 ml of ethyl acetate, and 6.3 g of N-methyl were added -N- (trimethylsilyl) trifluoroacetamide. After stirring for 1 h, a clear solution was obtained. This solution was then added over 10 min to a cooled (0 ° C) solution of 3.3 g of (S) -l - [[(chlorosulfonyl] amino] carbonyl] -3 - [[(phenyl- methoxy) -carbonyl] amino] -2-azetidinone in 50 ml of ethyl acetate After stirring overnight, the solvent was evaporated and the oily residue was stirred for 1 h with 50 ml of isopropanol The resulting precipitate was isolated by filtration and washed with isopropanol and ether Yield: 5.91 g.

F) (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hy-droxy-4-oxo-2-pyridinyl) -1-oxo-2-propenyl] trifluoroacetate amino] -2-oxo-l-imi-

dazolidinyl) sulfonyl] -1-azetidinecarboxamide 6.8 g of phenylmethyl (3S) acid ester were stirred overnight at room temperature - [l - [[[[3 - [[3- [l, 4 -dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -l-oxo-2-propenyl] -25 amino] -2-oxo-l-imidazoMnyl] suIfonyl] amino] carbonyl] -2-oxo- 3-azetidinyl] carbamic in 60 ml of a 3: 1 mixture of trifluoroacetic acid and thioanisole. After evaporating the resulting solution to one third of its volume, 50 ml of isopropanol and 10 ml of ether were added. 30 (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridi-nyl] -1-oxo-2-trifluoroacetate was obtained -propenyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] -1-azetidinecarboxamide in the form of a white precipitate. This was washed several times with ether and dried. 4.30 g.

20

35

G) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [[3- (l , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -1-oxo-2-propenyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] car-40 bonyl] -2-oxo -3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic acid 2.2 g (Z) -2-amino-a - [[2- (diphenylmeth-oxy) - 1,1-dimethyl-2-oxoethoxy] imino] -4-thiazoleacetic and 1.5 g of triethylamine in 150 ml of acetonitrile. At -30 ° C, 1.4 g of diphenyl chlorophosphate was added dropwise and the mixture was stirred for 1 h.

3.3 g of (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl] -1-oxo-trifluoroacetate) were treated 2-propenyl] -amino] -2-oxo-1-imidazolidinyl] sulfonyl] -l-azetidinecarbox-50 amide, suspended in 100 ml of ethyl acetate, with 6 ml of N-methyl-N- (trimethylsilyl ) trifhioracetamide, and stirred for 1 h at room temperature. The solution was added dropwise to the activated acid at -30 ° C (15 min). Then stirred for 1 h at -10 ° C and for 30 min at 0 ° C. The solvent was evaporated in vacuo and the remaining oil was stirred with ice water at pH 2 (2 N phosphoric acid). the residue was washed again with ice water and then dissolved in 100 ml of tetrahydrofuran, the solution was dried over sodium sulfate and the filtrate was evaporated. diphenylmethyl of the title compound in the form of a solid foam 1.81 g.

1.5 g of this substance were stirred in 30 ml of a mixture of trifluoroacetic acid and anisole at 0 ° C for 30 min and, after adding 100 ml of ether, it was isolated by filtration 1, 7 g of the 65 trifluoroacetic acid salt of the title compound. This was dissolved in 10 ml of water, and sodium bicarbonate was added until the pH was 5.5. The filtered solution was chromatographed on 400 g of macroreticular copolymer of

37,670,828

styrene and divinylbenzene, using water as the eluent. clear solution was added 100 ml of an 8: 2 mixture of ether and

The appropriate fractions contained 0.64 g of product. Isopropanol. The resulting precipitate was filtered off and bioautography revealed the presence of a side product and was washed with ether. Yield: 4.01 g after drying, minor bioactive. We put the substance through for a second

Chromatography in a column of Merck Lobar C, in s E) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -

using water as the eluent. The appropriate fractions contain 2 - [[1 - [[[[2- [3- (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) -l-oxo-

0.17 g of the title compound are born. 2-propenyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azéti-

dinyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropa-

Example no.16

„,,. , „., ^ Rrr,„ io 1.5 g of (Z) -2-amino-a- [T2-diphenylmeth-

rrrroM ^ 6 ^ ju Cj ßS (Z.)] - 2 - [[[l- (2- ^ mo-4-thi ^ olyl) -2- oxy) -l, l-dimethyl-2-oxoethoxy] imino] -4-thiazoleacetic and 1 g

[[l - [[[[2- [3- (l, 4- (hhydro-5-hyclrojgr-4-oxo-2-pyndmyl) -l-oxo-2- of triethylamine in 100ml of acetonitrile. A- 30 ° C, we added

propenyl] hydrazmo] sulfonyl] ammo] carbonyl] -2-oxo-3-azetidi- tte of diphenyl chlorophosphate and the nyl] amino] -2-oxoethylidene] ammo] oxy] -2-methylpropanoic mixture was stirred hour 0n stirred 2 g of trifluoroacetate from A) 2 - [(1,1-Dimethylethoxy) carbonyl] acid hydrazide 3- [1,4:15 2 - [[[((3-amino-2-oxo- l-azetidinyl) carbonyl] amino] sulfonyl] hy-

dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] -2-propenoic acid drazide (3S) -3- [1,4-dihydro-5-hydroxy-4-oxo-2-pyridi-

1.36 g of 3- [1,4-dihydro-4-oxo-5- (phenylnyl] -2-propenoic acid and 5.5 ml of N-methyl-N- (trimethylsilyl) tri- were stirred.

methoxy) -2-pyridinyl] -2-propenoic acid, 0.75 g of N-hydroxyben-fluoracetamide in 50 ml of ethyl acetate at zotriazole temperature, 0.01 g of N, N-dimethylaminopyridine and 1.06 g room for 1 h. A clear solution was formed which is dicyclohexylcarbodiimide in 20 ml of dimethylformamide 20, added dropwise, after having been refrigerated, to the activated acid, to

0 ° C for 20 min. 0.66 g of N- (5-butoxycarbonyl) - -30 ° C was added. The mixture was stirred for 1 h at -30 ° C, during hydrazine. After stirring overnight, the mixture was separated for 30 min at -10 ° C and for 1 h at 0 ° C. The dicyclohexylurea which had formed was then filtered off and the solvents were washed in vacuo, and the residue was stirred with 50 ml filtrate with 10 ml of dimethylformamide. The isopropanol was evaporated. It formed solid. It was isolated by filtration to a dry filtrate and the residue was suspended in 30 ml and stirred with 100 ml of ice water for 20 min at pH 2

of water, 1 g of sodium bicarbonate was added and, after having (phosphoric acid). By filtration, the diphenic ester was obtained.

stirred, the title compound was isolated by filtration. By recrystallinylmethyl of the title compound, which was washed three times with sation in a mixture of dimethylformamide and water, there are fractions of 50 ml of ice water and which was dried (1, 78 g). White crystals were obtained. Yield: 1.47 g, melting point stirred 1.5 g of this ester with 50 ml of a 4: 1 mixture of acid

141 ° C. 30 trifluoroacetic acid and anisole for 30 min at 0 ° C. After adding 150 ml of ether, the acid salt was filtered off

B) Hydrazidedacid3- [1,4-dihydro-4-oxo-5- (phenyltrifluoroacetic acid free of the title compound (1.65g).

methoxy) -2-pyridinyl] -2-propenoic acid 1 g of this substance was suspended in 5 ml of water

3.86 gde2 - [(1,1-dimethylethoxy) -carbonyl] hydra- was stirred and the pH was adjusted to 6.0 (sodium bicarbonate). Then, 3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridi- acid chromatide was chromatographed the clear solution on 400 g of nyl] -2-propenoic copolymer for half a hour in 30 ml of macroreticular acid of styrene and divinylbenzene, using trifluoroacetic at 0-5 ° C. The trifluoroacetic acid salt of water as the eluent, which gave 413 mg of the title compound,

title compound precipitated after addition of 50 ml of ether 400 mg of this substance was rechromatographed on diethyl Merck. The salt was suspended in 30 ml of water, Lobar C was used using water as eluent; yield: 160 mg.

stirred with 2 g of sodium bicarbonate for 20 min, and there are 40

separated the title compound by filtration, washed with water Example 17

and it was dried, which gave a beige powder. Yield: disodium sd of i> [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2-

2''5 g- [[l - [[[[[2 - [[(1,4-dihydro-5-hydroxy-4 »oxo-2-pyridinyl) carbonyl] -

4S amino] ethyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidi-

C) 2 - [[[[2-Oxo-3 - [[(phenylmethoxy) carbonyl] amino] -1-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic nyl] carbonyl] amino ] sulfonyl] hydrazide of (3S) -1,4-di- A) N- (4-methoxybenzyl) -0-benzylcomenamic acid hydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxylic acid at reflux for 4 h 10 g of O-benzylcomeni- acid

Stirred for 1 h, in 50 ml of ethyl acetate, 2.86 g and 10 ml of 4-methoxybenzylamine in 60 ml of water. With acid hydrazide 3- [1,4-dihydro-4-oxo-5- (phenylmethoxy) -2- 50 acidification of the reaction mixture at room temperature pyridinyl] -2-propenoic acid and 8.1 g of N -methyl-N- (trimethyl- with 2N hydrochloric acid up to pH 2, 15 g silyl) was obtained trifluoroacetamide. In the resulting clear solution there are crystals. By recrystallization from dioxane, a solution of 3.27 g of (S) -1 - [[(chlorosulfonyl) amino- 12.3 g of the title compound was obtained, melting point 175 ° C. ] carbonyl] -3 - [[(phenylmethoxy) carbonyl] amino] -2-azetidinone in 30 ml of ethyl acetate (addition in 10 min) at 0 ° C. After 55 B) 1,4-Dihydro-1 - [(4-methoxyphenyl) methyl] -4-oxo-5- (phenyl-

having stirred overnight, the solvent was evaporated and methoxy) -N- [2 - [(phenylmethyl) amino] ethyl] -2-pyridinecar-

stirred the residue with 50 ml of isopropanol and a drop of acid. Boxamide was filtered off the title compound and washed with Stirred for 1 hour at room temperature,

isopropanol and ether. Yield: 5.42 g. in 50 ml of dioxane, 3.69 g of N - [(4-methoxyphenyl) methyl-

60 thyl] -0-benzyl-comenamic, l, 50gdeN-hydroxybenzotriazole

D) 2 - [[[((3-amino-2-oxo-1-azetidinyl) carbo- and 2.05 g of dicyclohexylcarbodiimide) trifluoroacetate. Then added nyl] amino] sulfonyl] hydrazide of (3S) -3- [1,4-dihydro-5- acid a solution of 1.35 g of N-benzylethylenediamine in hydroxy-4-oxo- 2-pyridinyl] -2-propenoic 5 mi of dioxane. After stirring overnight, we separated

5.2 g of 2 - [[[[2-oxo-3 - [[(phenylmethoxy) carbonyl]] - were stirred by filtration the dicyclohexylurea which had formed and amino] -1-azetidinyl] carbonyl] amino] sulfonyl] hydrazide acid 65 evaporate the dioxane from the filtrate. The residue (oil) was dissolved in

(3S) -1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinecarboxyli- 50 ml of dichloromethane and the solution was extracted with two only in 50 ml of a 3: 1 mixture of acid trifluoroacetic acid and 50 ml fractions of 10% sodium bicarbonate, then washed

thioanisole at room temperature overnight. A la with water. After drying the solution in dichlorome-

670,828

38

thane on sodium sulfate and having evaporated, the remaining solid was recrystallized from ethanol, which gave 4.2 g of crystals of the title compound, melting point 112 ° C.

C) N- (2-aminoethyl) -1,4-dihydro-5-hy- P-toluenesulfonate

droxy-4-oxo-2-pyridinecarboxamide Onatraite9.95gdel, 4-dihydro-l - [(4-methoxyphenyl) methyl] -4-oxo-5- (phenylmethoxy) -N- [2 - [(phenylmethyl) ammo ] -ethyl] -2-pyridinecarboxamide and 7.7 g of p-toluenesulfonic acid in 100 ml of methanol with 3 g of 10% palladium on carbon, and hydrogen was bubbled through the reaction mixture to 45-50 ° C for 6 h. Argon was then passed through the reaction mixture for 10 min. 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 and 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-pyridinecarboxamide dihydrochloride 5.42 g of N- (2-amino-ethyl) p-toluenesulfonate were dissolved , 4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide in 50 ml of formic acid, and 7.5 ml of formic acid and gaseous hydrochloric acid (2.2 equivalents of acid were added) hydrochloric), then 150 ml of ether; white crystals were obtained. By isolating the product by filtration and washing it with 200 ml of ether, 2.60 g of the title compound were obtained, melting point 287 ° C.

E) Phenylmethyl ester of (3S) acid - [l - [[[[[[2 - [[(1,4-di-hydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] ethyl) ]friend-

no] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] carbamic A 4.38 g of (S) -3 - [[(phenylmethoxy) carbonyl] amino] -2-azeti-dinone suspended in 50 ml ethyl acetate, 2.83 g of chlorosulfonyl isocyanate was added at room temperature. After 30 min of stirring, a clear solution was obtained.

5.40 g of N- (2-aminoethyl) -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide dihydrochloride were stirred in 50 ml of acetonitrile with 24 g (6 equivalents) of N -methyl-N- (trimé-thylsilyl) trifluoroacetamide at 50 ° C for 1 h. The volatiles 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 with stirring. After stirring for one night, 200 ml of isopropanol was added, with stirring at 0 ° C, to obtain the title compound in the form of beige crystals. Yield: 8.77 g, melting point 145 ° C.

F) Trifluoracetate 2.0 of (3S) -N - [[[[((3-amino-2-oxo-1-azetidi-nyl) carbonyl] amino] sulfonyl] amino] ethyl] -1,4-dihydro-5-hy -

droxy-4-oxo-2-pyridinecarboxamide 2 g of phenylmethyl ester of acid (3S) - [1 - [[[[[2 - [[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl) carbonyl] amino] -ethyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] carbamic in 20 ml of thioanisole and 40 ml of trifluoroacetic acid at 0 ° C for 12 noon. After adding 100 ml of ether, fine white crystals of the title compound were isolated by filtration. By washing with 50 ml of isopropanol and 100 ml of ether, 2.12 g of the title compound were obtained, melting point 136 ° C, decomposition.

G) [3S (Z)] Diphenylmethyl ester - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[[2 - [[(l, 4-dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) carbonyl] ammo] ethyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -2-methyl-propanoic

4.40 g of (Z) -2-amino-a - [[2- (diphenylmethoxy) -1, l-dimethyl-2-oxoethoxy] -imino] -4- acid were dissolved in 150 ml of acetonitrile thiazoleacetic and 3 g of triethylamine. At -30 ° C, 2.8 g of diphenyl chlorophosphate was added dropwise, and the mixture was stirred for 1 h.

6.13 g of trifluoroacetate 2.0 of (3S) -N - [[[[[3-amino-2-oxo-1-azetidinyl] -carbonyl]] were stirred for 2 h in 100 ml of ethyl acetate amino] sulfonyl] amino] ethyl] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide and 17 g of N-methyl-N- (trimethylsi-io lyl) trifluoroacetamide. The solvent was removed by vacuum distillation from the clear solution and the remaining oil was evaporated for 2 h at 30 ° C (under oil vacuum <0.01 mm). The residue was again dissolved in 100 ml of ethyl acetate and the solution was added dropwise to the activated acid at -30 ° C (30 min). The mixture was stirred for 1-10 ° C while at 0 ° C. The solvent was evaporated and the resulting oily residue was stirred with ice water at pH 3 (2N phosphoric acid). We were ice water and the residue was washed with ice water and dried. Yield: 7.8 g of beige crystals.

20

H) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[[2 - [[(l, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-nyl] amino] ethyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-azeti-25 dinyl] amino] -2-oxoethylidene ] amino] oxy] -2-methylpropa-

noic

3 g of [3S (Z)] diphenylmethyl ester - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[[2 - [[( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] ethyl] amino] sulfonyl] amino] -30 carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] ami-no] oxy] -2-methylpropanoic acid for 30 min in 30 ml of trifluoroacetic acid and anisole. The trifluoroacetic acid 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 chromatographed on macroreticular copolymer of styrene and divinylbenzene, eluting with water, to obtain 0.24 g of product. This was again chromatographed on a column of Merck Lobar C; yield: 0.078 g, melting point 275 ° C, decomposition.

45

Example 18

Disodium salt of the acid [2S [2a, 3ß (Z)]] - 2 - [[[l- (2-amino-4-thiazo-lyl) -2 - [[l - [[[3 - [[ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-nyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2-methyl-4-oxo-3 -azetidinyl] amino] -2-oxo-ethylidene] ami-50 no] oxy] -2-methylpropanoic

A) Phenylmethyl ester of (2S-trans) acid - [l - [[[[3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-methyl-4-oxo-3-azetidinyl] carbamic 55 The mixture was stirred for one hour at 0-5 ° C in 50 ml of acetate d ethyl, 2.35 g of phenylmethyl ester of (3S-trans) - (4-methyl-2-oxo-3-azetidinyl) carbamic acid and 1.41 g of chlorosulfonyl isocyanate. A clear solution was obtained (solution A). 3.28 g of 1,4-dihydro-4-oxo-N- (2-oxo-l-imidazolidi-60 nyl) -5- (phenylmethoxy) -2-pyridinecarboxamide and 6 g of N-methyl were stirred N- (trimethylsilyl) trifluoroacetamide in 50 ml of ethyl acetate for 1 h at 40 ° C (solution B).

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

39

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B) (2S-trans) -N- [3 - [[((3-amino-2-mes-thyl-4-oxo-1-azetidinyl) carbonyl] amino] sulfonyl] -2-di-p-toluenesulfonate oxo-l-imi-dazolidinyl] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarbox-amide

Hydrogenated at room temperature for one hour 5.9 g of phenylmethyl ester of (2S-trans) acid - [1 - [[[[3 - [[[1,4-dihydro-4-oxo-5 - (phenylmethoxy) -2-pyridinyl] -carbonyl] -amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2-methyl-4-oxo-3-azetidinyl] carbamic in 50 ml of dimethylformamide and 3.8 g hydrated p-toluenesulfonic acid and 2.5 g 10% palladium on carbon. After filtering through Hyflo, the dimethylformamide was removed by vacuum distillation. The oily residue was stirred with 100 ml of dichloromethane. The title compound (5.8 g) formed immediately as a white crystalline substance.

to form a clear brownish solution, which was stirred for one hour at room temperature, then cooled to 0 ° C (solution B).

Solution B was added dropwise, with stirring, to mixture A, maintaining the temperature at -30 "C (about 10 min). The mixture was stirred at -10 ° C for 1 hour and at 0 ° C for another 1.5 hours, then evaporated in vacuo, the remaining syrup was dissolved in 50 ml of acetone, and 6 ml of 1M potassium ethylhexanoate was added to the solution to precipitate 3 0.0 g of crude product Addition of ether to the filtrate provided an additional 0.2 g of crude product 1. By chromatography of the crude product on macroreticular copolymer of styrene and divinylbenzene, 1.85 g of the compound of the compound were obtained title.

15

C) Disodium salt of the acid [2S- [2a, 3ß (Z)]] - 2 - [[[l- (l-amino-4-thiazolyl) -2 - [[l - [[[[3- [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) carbonyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] -carbonyI] -2-methyI-4- oxo-3-azetidinyl] amino] -2-oxoethyli- 20

dene] amino] oxy] -2-methylpropanoic In 40 ml of acetonitrile was dissolved 4.40 g of (Z) -2-amino-a - [[2-diphenylmethoxy) -1, l-dimethyl-2 -oxoethoxy] -imino] -4-thiazoleacetic and 3.0 g of triethylamine. At -30 ° C, 2.8 g of diphenyl chlorophosphate was added dropwise, and stirred for 1 h.

7.90 g of (2S-trans) -N- [3 - [[- [3-amino-2-methyl-4-oxo-1-azetidinyl) -carbonyl] amino] sulfo di-p-toluenesulfonate was stirred -nyl] -2-oxo-1-imidazolidinyl] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide and 2.02 g of triethylamine for 5 min at 30 -20 ° C in 50 ml of dimethylformamide.

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

2 g of the ester were stirred in 30 ml of a 4: 1 mixture of trifluoroacetic acid and anisole for 30 min at 0 ° C. By adding 40,100 ml of ether, the trifluoroacetic acid salt of the free acid was precipitated. It was suspended in 10 ml of water and the pH was adjusted to 6.0. After filtration, the filtrate was passed through a column of macroreticular copolymer of styrene and divinylbenzene, using water as the eluent. Yield: 45 0.48 g.

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

50

Example 19

[3S (Z)] - 2-amino-N- [l - [[[[3 - [[(1,4-di-hydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl) carbonyl salt] amino] -2-oxo-1-imidazolidinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidmyl] a- 55 (methoxyimino) -4-thiazoleacetamide A suspension of 0.6 g (0.003 mole) of (Z) -2-amino-a- (methoxyimino) -4-thiazoleacetic acid, 2.14 ml (0.009 mol) of tributylamine was added at room temperature. The suspension was cooled to -30 ° C, at which point 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 - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] - 65 amino] -2-oxo-1-imidazolidinyl] sulfonyl] -2-oxo-1-azetidinecar-boxamide in 20 ml of ethyl acetate, 2.6 ml of bis- was added at room temperature trimethylsilylacetamide

Example 20

[3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3 - [[(1,4-di-hydro-5- hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l-imidazolidmyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic acid Disodium salt of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3- [ [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) carbonyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] -çarbonyl] -2-oxo-3-azétidinyI ] amino] -2-oxoethylidene] ami-no] oxy] -2-methylpropanoic acid (2.2 g; see Example 1) in 20 ml of a 1: 1 mixture of acetone and water, and adjusted the pH to 2 with 2N hydrochloric acid. Chromatography on a macroreticular copolymer of styrene and divinylbenzene gave 0.7 g of the title compound.

Example 21

[3S (Z)] monosodium salt - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1-

[[[[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -amino] -2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] -2- oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] -N-hydroxy-2-methylpropanamide 4.72 g of (Z) -2-amino-a acid was suspended - [[l , 1-dimethyl-2-oxo-2 - [(triphenylmethoxy) amino] ethoxy] imino] -4-thiazoleacetic in 65 ml of acetonitrile and, at -30 ° C, 3.72 ml of triethylamine was added. After stirring for 10 min, 1.97 ml of diphenyl chlorophosphate was poured in dropwise. Agitation was then continued for 90 min (solution A).

8.9 ml of (3S) -3-amino-N - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridi) was suspended in 70 ml of acetonitrile -nyl) -carbonyl] amino] -2-oxo-l-imidazolidinyl] sulfonyl] -2-oxo-l-azetidinecarboxamide, and 7.7 ml of bis-trimethylsilyl-acetamide was added. A clear solution was obtained after stirring for 1 h at -10 ° C and for 1.5 h at 0 ° C. The solvent and the trimethylsilyl ester of trifluoroacetic acid formed were evaporated in vacuo, and the remaining oil was dissolved in 70 ml ethyl acetate (solution B).

Solution A was then poured dropwise into the stirred solution B, at -20 ° C in 30 min. The reaction was completed by continuous stirring at -10 ° C for 1.5 h and at 0 ° C for 1 h.

The solvents were then removed by vacuum distillation and the oily residue was stirred with 300 ml of ice water, the pH of which had been adjusted to 4.0 with 10% phosphoric acid. The solid formed was then filtered off, washed with water and dried in vacuo overnight. Yield: 9 g of crude product.

4.5 g of this crude product were stirred with 45 ml of 98% formic acid and 4.5 ml of dichloromethane at 0 ° C for 1 h. 2.3 g of the title compound were obtained by precipitation with diethyl ether.

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40

Example 22

Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[2 - [[3 - [[(l , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-nyl] amino] -2-oxo-l-imidazolidinyl] carbonyl] -hydrazino] sulfo-nyl] amino] carbonyl] -2-oxo- 3-azetinyl] amino] -2-oxoethyhdene] -amino] oxy] -2-methylpropanoic A) 2 - [[(Phenylmethoxy) carbonyl] amino] -2-imidazolidinone We dissolved l-amino-2-imidazolidinone ( 26 g, 0.257 mol) in 200 ml of water. The solution was extracted with 200 ml of ethyl acetate, and 43.8 g (0.257 mole) of benzyl ester of chloroformic acid was poured into the mixture, with stirring, while maintaining the pH between 8 , 5 and 9 by addition of a saturated sodium bicarbonate solution. After stirring overnight at room temperature, the title compound was filtered off, washed first with water and then with ethyl acetate. Yield: 46.7 g, melting point 140-144 ° C.

B) l - [[(Phenylmethoxy) carbonyl] amino] -3- (chlorocarbonyl) -2-imidazolidinone To a suspension of 69.9 g (0.297 mol) of 2 - [[(phenylmethoxy) carbonyl] amino] - 2-imidazolidinone in 11 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. We have . the solvent was removed in vacuo and the remaining syrup was triturated with ether. Yield: 76.0 g, melting point 102-105 ° C.

C) 2 - [(1,1-dimethylethoxy) carbonyl] hydrazide of acid 3 - [[(phenylmethoxy) carbonyl] amino] -2-oxo-l-imidazolidinecar-boxylic

1- [[(phenylmethoxy) carbonyl] amino] -3- (chlorocarbonyl) -2-imidazolidinone (76 g, 0.255 mol) was added at room temperature to 1.51 ethyl acetate. After cooling to 0-5 ° C., a solution of 39.6 g (60.9 mol) of N- (t-butoxycarbonyl) hydrazide and 41.8 ml (39.6 g (60.9 mol)) was poured in dropwise over 30 min. 0.3 mol) of triethylamine 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. Yield: 71.2 g, melting point 195-198 ° C.

D) 1,1-Dimethylethyl ester of 2 - [[3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2-oxo- acid l-

imidazolidinyl] carbonyl] hydrazinecarboxylic acid acid 2 - [(1,1-dimethylethoxy) carbonyl] hydrazide 3 - [[(phenylmethoxy) carbonyl] amino] -2-oxo-l-imidazoli-dinecarboxylic acid (31.5 g , 0.08 mole) in 400 ml of dimethylformamide, 16 g of 10% palladium on carbon were added, and hydrogen was passed through the stirred reaction mixture. After one hour, the catalyst was filtered off. To the filtrate were added 19.62 g (0.08 mole) of O-benzylcomena-mica acid, 0.48 g of dimethylaminopyridine and 0.64 g of N-hydroxy-benzotriazole. The mixture was stirred for 1 h at room temperature. A solution of 18.13 g (0.088 mole) of dicyclohexylcarbodiimide was added at room temperature, and the mixture was stirred overnight. The precipitate of dicyclohexylurea was filtered, 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) Acid hydrazide 3 - [[[1,4-dihydro-4-oxo-5- (phenylmeth-oxy) -2-pyridinyl] carbonyl] amino] -2-oxo-l-imidazolidinecarb-

oxylic

36 g of 1,1-dimethylethyl ester of 2 - [[3 - [[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] -amino] acid were added -2-oxo-1-imidazolidinyl] carbonyl] hydrazinecarboxylic at -10 ° C with stirring, to 300 ml of trifluoroacetic acid. The mixture was stirred at 0 ° C for 1 h, the trifluoroacetic acid was removed in vacuo and the residue was triturated with ether to obtain 41 g of the trifluoroacetate of the title compound. This trifluoroacetate was suspended in water, cooling, and the pH was adjusted to 7 by adding 2N sodium hydroxide. The precipitated io was separated by filtration to obtain 21.9 g of the title compound.

F) Acid hydrazide 3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyri-dinyl) -carbonyl] amino] -2-oxo-l-imidazolidinecarboxylic acid Suspended in 250 ml of acetonitrile 21.9 g of acid hydrazide 3 - [[[[1,4-dihydro-4-oxo-5- (phenylmethoxy) -2-pyridinyl] carbonyl] amino] -2-oxo -l-imidazolidinecarboxyli-qüe. To the suspension was added 75 ml of bis-trimethylsilylacet-amide, and the mixture was stirred to form a solution. To this solution was added 10 g of 10% palladium on charcoal and hydrogen was passed through the vigorously stirred mixture. 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 crude product was stirred with 150 ml of ethanol to obtain 8.8 g of the title compound, melting point <205 ° C, decomposition.

G) Phenylmethyl ester of acid (S) - [l - [[[[2 - [[3 - [[(1,4-di-30 hydro-5-hydroxy-4-oxo-2-pyridinyl) - carbonyl] amino] -2-oxo-l-

imidazolidinyl] carbonyl] hydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] carbamic A suspension of 5.9 g (0.02 mole) of acid hydrazide 3 - [[(1,4 -dihydro-5-hydroxy-4-oxo-2-pyridinyl) -carbonyl] amino] -2-35 oxo-l-imidazolidinecarboxylic crude, 14.9 ml (0.08 mol) of N-methyl-N- were added (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) -3 - [[(phenyl-methoxy) carbonyl] amino] -2-azetidinone in 160 ml of ethyl acetate was added 1.76 ml of chlorosulfonyl isocyanate at room temperature. The mixture was stirred for 1 h (solution B).

Solution A was added, while cooling in ice, to solutionB. After stirring for 1 h, 2.8 ml (0.02 "mole) of triethylamine was added to the mixture, which was then stirred overnight at room temperature. Another 2.8 ml (0.02 mole) of triethylamine was added, followed by ice water. The mixture was stirred thoroughly for one hour and the layers were separated. The aqueous phase was acidified to pH 3 and the precipitated so was isolated by filtration. Yield: 5.3 g of the title compound in the raw state.

This crude product was dissolved in a mixture of acetone and water and the pH of the solution was adjusted to 6.5 by adding 2N sodium hydroxide thereto. After removing the acetone under vacuum, it was filtered the solution and lyophilized to obtain 5.5 g of the crude sodium salt of the title compound. By chromatography of this crude sodium salt on a macroreticular copolymer of styrene and divinylbenzene, 0.64 g of purified product was obtained. This was dissolved in water and acidified with 2N hydrochloric acid to precipitate the title compound. Yield: 0.5 g.

H) (S) -N- [3 - [[2 - [[[((3-Amino-2-oxo-1-azetidinyl) carbonyl] ami-no] sulfonyl] hydrazino] carbonyl] -2-oxo-l- imidazolidinyl] -l, 4-di-

65 hydro-5-hydroxy-4-oxo-2-pyridinecarboxamide

0.5 g of phenylmethyl ester of (S) acid - [1 - [[[[2 - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-) was added pyridinyl) -carbonyl] -amino] -2-oxo-l-imidazolidinyl] carbonyl] hydrazino] sulfonyl] -

41

670,828

amino] carbonyl] -2-oxo-3-azetidinyl] carbamic in a mixture of 0.5 ml of thioanisole and 2 ml of trifluoroacetic acid. The mixture was stirred overnight at room temperature and evaporated in vacuo. The residue was triturated with ethyl acetate to obtain the title compound with a 5

quantitative yield.

I) [3S (Z)] diphenylmethyl ester - 2 - [[[l- [2-amino-4-thiazolyl] -2 - [[l - [[[[2 - [[3 - [[ 1,4-dihydro-5-hydroxy-4-oxo-2-pyri-dinyl) -carbonyl] amino] -2-oxo-l-imidazolidinyl] carbonyl] hydra- io zino] sulfonyl] amino] carbonyl] -2- oxo-3-azetidinyl] amino] -2-

oxoethylidene] amino] oxy] -2-methylpropanoic A solution of 0.35 g (0.0008 mole) of (Z) -2-amino-a acid - [[2- (diphenylmethoxy) -l, l-dimethyl- 2-oxoethoxy] imino] -4-thiazoleacetic in 10 ml of acetonitrile, 0.34 ml of triethylamine is 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- [3 - [[2 - [[[(3-amino-2-oxo-1-azetidinyl) carbonyl] amino] sulfonyl] hydrazino] carbonyl] -2 -oxo-1-imidazolidinyl] -1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide in 6 ml of ethyl acetate, 0.7 ml of bis-trimethylsilylacetamide (solution B) was added.

Solution B was added to Solution A at -30 ° C. The mixture was stirred at-10 ° C for 2 h and at 0 ° C for 1 h, then evaporated in vacuo. After treating the residue with water, 0.7 g of the title compound in the raw state was obtained, melting point 155 ° C, decomposition.

J) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2-30 [[l - [[[[2 - [[3- [ [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbo-nyl] amino] -2-oxo-l-imidazolidinyl] carbonyl] hydrazino] sulfo-nyl] amino] carbonyl] -2- oxo-3-azetidinyl] amino] -2-oxoethyli-

dene] amino] oxy] -2-methylpropanoic A suspension of 0.7 g (0.00077 mole) of [3S (Z)] diphenylmethyl-35-ester - 2 - [[[1-- [2- amino-4-thiazolyl] -2 - [[l - [[[[2 - [[3 - [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -amino] - 2-oxo-1-imidazolidinyl] carbonyl] hydrazino] sulfonyl] -amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] -amino] oxy] -2-methylpropanoic acid in 1 ml of anisole , 6 ml of trifluoroacetic acid was added at -10 ° C. The mixture was kept at -10 ° C for one hour. At -10 ° C, ether was added to precipitate the trifluoroacetate from the free acid of the starting material, yield 0.5 g.

The precipitate was suspended in water at 45

cooling, and the pH was adjusted to 5.5 by addition of 2N sodium hydroxide. By lyophilization, 0.55 g of crude product was obtained. This crude product was purified by chromatography on a macroreticular copolymer of styrene and divinylbenzene to obtain 0.1 g of the purified title compound.

so

Example 23

Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2- 55 [[l - [[[[2 - [(1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -2-methylhydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -

amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic A) 1-Methylhydrazide of 1,4-dihydro-4-oxo-5- (phenyl-methoxy) -l- (phenylmethyl) -2- pyridinecarboxylic 60 On friends in suspension 0.15 mole of N, 0-dibenzylcomenamyl chloride in 150 ml of dichloromethane, cooling in ice. To the suspension was added 26.2 ml (0.5 mole) demethylhydrazine, then 150 ml of acetonitrile. The mixture was stirred for one night at room temperature. The cloudy solution was evaporated in vacuo and triturated with 300 ml of water. The solid obtained was filtered and dried to obtain 26.3 g of crude product. By recrystallization of this crude product from water, 12.7 g of the title compound were obtained in the pure state, melting point 138-142 ° C.

B) 1-Methyl-2 - [[[[[2-oxo-3 - [[(phenylmethoxy) carbonyl] amino] -1-azetidinyl] carbonyl] amino] sulfonyl] hydrazide of acid (S) -

1,4-dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyri-dinecarboxylic

1,4-Dihydro-4-oxo-5- (phenylmethoxy) -1- (phenylmethyl) -2-pyridi-necarboxylic acid (1.82 g, 0.005 mole) was suspended in 1-methylhydrazide acid ml of ethyl acetate. At room temperature, a total of 1.85 ml (0.01 mole) of N-methyl-N- (trimethylsilyl) trifluoroacetamide was added. The mixture was stirred for 4 h at 60 ° C (suspension A).

(S) -3 - [[(phenylmethoxy) carbo-nyl] amino] -2-azetidinone (1.1 g, 0.005 mole) was 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 1 h to form a solution (solution B).

To solution B was added 1.2 ml of triethylamine (while cooling in ice), then 20 ml of dichloromethane and suspension A. The resulting suspension was stirred overnight at room temperature. The slightly cloudy solution , 30 ml of dichloromethane and 20 ml of water were added and the mixture was stirred for 1 h at room temperature.

LepH of the aqueous phase was 6.5-7. 60 ml of ethyl acetate were added, the organic layer was separated and the aqueous phase was washed twice with a 1: 3 mixture of dichloromethane and ethyl acetate. The organic phases were dried over magnesium sulfate and evaporated to give 4.5 g of a syrup, which crystallized on standing for two days. After treatment with ether, 2.6 g of the title compound in the raw state were obtained.

C) Trifluoroacetate du2 - [[[((3-amino-2-oxo-1-azetidinyl) carbo-nyl] amino] sulfonyl] -1-methylhydrazide of 1,4-dihydro-5- acid

hydroxy-4-oxo-2-pyridinecarboxyIique

To a solution of 2 g of 1-methyl-2 - [[[[2-oxo-3 - [[(phenyl-methoxy) carbonyl] amino] -1-azetidinyl] carbonyl] amino] sulfo-nyl] hydrazide (S) -1,4-dihydro-4-oxo-5- (phenylme-thoxy) -1- (phenylmethyl) -2-pyridinecarboxylic acid in 60 ml of dimethylformamide, 1.1 ml of trifluoroacetic acid was added, then 1 g of 10% palladium on charcoal. After purging with nitrogen, hydrogen was passed through the solution for 60 min with stirring, the catalyst was filtered off, the filtrate was evaporated in vacuo and the residue was triturated with ether to obtain 1.1 g of the title compound in the raw state. Yield: 86.6%.

D) [3S (Z)] diphenylmethyl ester - 2 - [[[l- (2-amino-4-thiazolyl) -2 - [[l - [[[[2 - [(l, 4- dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) carbonyl] -2-methylhydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] amino] oxy] - 2-methyl-propanoic

To a suspension of 0.88 g (0.002 mole) of (Z) -2-amino-a - [[2- (diphenylmethoxy) -1,-dimethyl-2-oxoethoxy] imino] -4-thiazoleacetic acid in 30 ml of acetonitrile, 0.7 ml (0.005 mole) of triethylamine was added, then, at -30 ° C., 0.44 ml (0.002 mole) of diphenyl chlorophosphate. The mixture was stirred at -30 ° C for 1 h (solution A).

To a suspension of 1.2 g (0.002 mole) of 2 - [[[((3-amino-2-oxo-1-azetidinyl) carbonyl] amino] sulfonyl] -l-methylhydrazide 1,4-dihydro trifluoroacetate -5-hydroxy-4-oxo-4-pyridi-necarboxylic acid in 30 ml of ethyl acetate, 2 ml (approximately 0.008 mole) of bis-trimethylsilylacetamide were added at room temperature to form, after 30 min , a clear solution (solution B).

670,828

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At -30 ° C, solution B was added dropwise to solution A (about 10 min). The temperature was kept at -10 ° C for one hour and at 0 ° C for another 1 h. 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) Disodium salt of [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[2 - [(l, 4- dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -2-methylhydrazino] sulfonyl] amino] carbonyl] -2-oxo-3-azétidi-nyl] amino] -2-oxoethylidene] amino] oxy] - 2-methylpropanoic At-10 ° C, 2.4 g of diphenylmethyl ester of [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2- [ [l - [[[[2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -2-methylhydrazino] sulfo-nyl] amino] carbonyl] -2-oxo-3 -azetidinyl] amino] oxy] -2-methyl-propanoic crude to a mixture of 20 ml of trifluoroacetic acid and 4 ml of anisole. The mixture was stirred at-10 ° C for 1 h and the reaction product was precipitated by adding ether at-10 ° C. Yield: 1.12 g of the crude trifluoroacetate of the title compound.

This crude product was transformed into sodium sol by adding 2 N sodium hydroxide to a suspension in a mixture of acetone and water, and by lyophilizing. The sodium salt was purified by chromatography on a macroreticular copolymer of styrene and divinylbenzene, eluting with water. Yield: 0.25 g.

Example 24

[3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[[(1,4-dihy-dro-5-hydroxy-4 -oxo-2-pyridinyl) methyl] amino] sulfonyl] ami-no] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] ami-

no] oxy] -2-methylpropanoic A) 2- (Hydroxymethyl) -5- (phenylmethoxy) -4H-pyran-4-one A suspension of 5-hydroxy-2- (hydroxymethyl) -4H-pyran-4 was treated -one (56.8 g, 0.4 mole) in 400 ml of methanol with sodium hydroxide (16 g, 0.4 mole) in 200 ml of warm methanol, then with 50.6 g (46 ml, 0, 4 mol) of benzyl chloride. The mixture was heated to reflux for 3.5 h, cooled, and poured into 11 of water. The resulting solid was filtered and washed with about 1.51 of water, 200ml of ethanol and 400ml of hexane. After drying under high vacuum, the product weight was 55.7 g.

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

A mixture of 2-hydroxymethyl-5- (phenylmethoxy) -4H-pyran-4-one (9.65 g, 41.59 mmol), 95 ml of concentrated ammonia and 20 was heated to reflux overnight. ml of ethanol. A further 75 ml of ammonia was added, the mixture was heated under reflux for 2 h, then cooled. The resulting brown sodium was filtered and washed with water until the washings 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) hydrochloride beyond l- (chloromethyl) -1,4-dihydro-5-phe-

nylmethoxy) -4-pyridinone A suspension of 1,4-dihydro-2- (hydroxymethyl) -5- (phenylmethoxy) -4-pyridinone (3 g, 12.99 mmol) was cooled to 0 ° C under argon. ml of chloroform, and treated with dethionyl chloride (6.1 ml, 83.62 mmol). After several minutes, a homogeneous solution was obtained. After another 5 min of stirring, a cream-colored solid precipitated. The cooling bath was removed and the mixture was refluxed for 45 min. The mixture was cooled to 0 ° C and the white product in suspension 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-pyridi-

none

A mixture of 1- (chloromethyl) -1,4-dihy-5 dro-5- (phenylmethoxy) -4-pyridinone hydrochloride was stirred at room temperature for 3.5 days (3.59 g, 12 , 54mmol), sodium azide (4.08 g, 62.7 mmol) and diisopropylethylamine (2.19 ml, 12.54 mmol) in 70 ml of dimethylformamide. A further 4.08 g of sodium azide was added and the mixture was heated to 45-50 ° C for 2 h. After cooling, the reaction mixture was poured into 500 ml of water to give 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

A suspension of 2- (azidomethyl) -1,4-dihydro-5- (phenoxymethyl) -4-pyridinone (2.030 g, 7.93) was stirred for 6 h at room temperature under a hydrogen atmosphere. mmoles) and 200 mg of platinum oxide in 100 ml of dimethylformamide. The catalyst was filtered off and the solution was concentrated in vacuo to give 1.5 g of the title compound as a gray powder.

F) (3S) -1 - [[[[[1,4-Dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] -amino] sulfonyl] amino] carbonyl] -2-oxo-3- [ [(phenylmethoxy) -

30 carbonyl] amido] azetidine

To a stirred suspension of 2- (aminomethyl) -4-oxo-5- (phe-nylmethoxy) pyridine (2.330 g, 10.13 mmol) in 60 ml of ethyl acetate, N-methyl-N was added - (trimethylsilyl) trifluoracetamide (3.76 ml, 20.26 mmol). The resulting solution was stirred for 30 min at room temperature, then cooled to 0 ° C. In parallel, to a stirred suspension of (S) -3 - [[(phenylmethoxy) carbonyl] amino] -2-azetidinone (2.228 g, 10.13 mmol) in 60 ml of ethyl acetate, l 'chlorosulfonyl isocyanate (882 [xl, 10.13 mmol). The resulting solution was stirred for 30 min at room temperature, then cooled to 0 ° C and treated with triethylamine (4.23 ml, 30.39 mmol), then with silylated 2- (aminomethyl) -4-oxo-5- (phenylmethoxy) pyridine solution described above. The mixture was stirred for two 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, and a thick oil was then separated. By 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 title compound in the raw state. This crude product was dissolved in a minimum volume of dimethylformamide and loaded into a column of 11 of macroreticular copolymer of styrene and divinylbenzene. The column was eluted with a gradual gradient of azetone and water. The desired product was eluted with a mixture containing about 65% acetone. The fractions of interest were pooled and lyophilized to obtain 2.69 g of the title compound.

60

G) Diphenylmethyl ester of (3S) -2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[(1,4-dihydro-5-hydroxy) hydroxy -4-oxo-2-pyridinyl) -

methyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic 65 (3S) was stirred under a hydrogen atmosphere -1 - [[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] -sulfonyl] amino] carbonyl] -2-oxo - [[(phenylmethoxy) -carbonyl ] -aminojazetidine (912 mg, 1.64 mmol), p-toluenesulfo- acid

43

670,828

pic monohydrate (625 mg, 3.28 mmol) and 190 mg of 10% palladium on carbon, in 16 ml of dimethylformamide,

until 3.28 mmol (73 ml) of hydrogen has been consumed (approximately 3 h).

5

To a stirred solution of (Z) -2-amino-a - [[2- (diphenyl-methoxy) -1, l-dimethyl-2-oxoethoxy] imino] -4-thiazoleacetic acid (846 mg, 1.804 mmol) in 16 ml of dimethylformamide at -20 ° C., diphenyl chlorophosphate (374 µl, 1.804 mmol) was added, followed by triethylamine (450 (il, 3.28 mmol). The solution was stirred for one hour at -20 ° C., after which the above-described mixture of hydrogenolysed compound was added, and then triethylamine (921 µl, 6.6 mmol) was added. The resulting mixture was stirred at -20 ° C. hour, then at 5 ° C overnight. The catalyst was filtered off, the volatiles were removed in vacuo and the resulting oil was dissolved in a minimal volume of acetone and water (75- 25) (pH 5.2), and the solution was added dropwise to a stirred suspension of 20 ml of Dowex 50x2-400 (K +) in a 35-65 mixture of acetone and water. 40 min, the mixture was filtered and the filtrate was lyophilized to obtain 2.1 gd e solid. This solid was dissolved in a minimum quantity of a 40-60 mixture of acetonitrile and water (pH 5.6) and the solution was passed through a column of 800 ml of macroreticular copolymer of styrene and divinylbenzene, eluting with a gradual gradient of acetonitrile and water. The desired product was eluted with a mixture containing about 30% acetonitrile. The fractions of interest were pooled and lyophilized to obtain the title compound.

H) Acid (3S) -2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[(1,4-di-hydro-5-hydroxy-4- oxo-2-pyridinyl) methyl] aminojsulfonyl] ami-no] carbonyl] -2-oxo-3-azetidinyl] amino] -2-oxoethylidene] ami-no] oxy] -2-methylpropanoic shake was stirred 4, 7 ml trifluoroacetic acid to a stirred suspension of diphenylmethyl ester of (3S) acid -2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[[l , 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-aze-tidinyl] amino] -2-oxoethylidene] amino] oxy] - 2-methylpropanoï-que (131 mg, 0.113 mmol) in 3 ml of dichloromethane and 0.3 ml of anisole at 0 ° C. After stirring for 45 min at 5 ° C, 2 ml of toluene was added and the volatiles were removed in vacuo. The resulting oil was washed with three times 4 ml of hexane and triturated with 10 ml of ether until a solid was obtained. This solid was washed once with 10 ml of ether and dried in vacuo. The previous reaction and preparation was repeated on 0.166 mmol of diphenylmethyl ester of (3S) acid -2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1- - [[[ [[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridi-nyl) methyl] amino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidi-nyl] amino] -2-oxoethylidene ] amino] 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 the solution was chromatographed in a 200 ml column of macroreticular copolymer of styrene and divinylbenzene, using a gradient of acetonitrile and water. The desired product was eluted with a 20-80 mixture of acetonitrile and water. The fractions of interest were pooled and lyophilized to obtain 103 mg of the title compound as a white solid, melting point 180 ° C, decomposition.

m

Claims (26)

670,828 CLAIMS 1. Compound of formula R? I 2 I "CH- ' R ^ NH S jz ^ I -N-C-NH-S0o-R 4 optionally in the form of a pharmaceutically acceptable salt, formula in which R is V " 2 6 | H X5 is a formyl, alkanoyl, phenylcarbonyl (substituted phenyl) carbonyl, phenylalkylcarbonyl, (substituted phenyl) al-kylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino) carbonyl, or cyano radical; X6 and X7 are the same or different and are each a hydrogen atom, an alkyl radical, or an optionally substituted phenyl radical, or else X6 is a hydrogen atom and X7 is an optionally substituted amine, alkanoylamine or alkoxy radical, or Xf, and X7 form, with the nitrogen atom to which they are attached, a heterocycle with 4, 5, 6 or 7 members; A is -CH = CH-, - (CH2) m-, - (CH -,) m-0-, - (CH,) m-NH- or -CH2-S-CH2-; m is 0.1 or 2; Ai is a single bond or a radical of formula ^ S iiT0H i — i JUoa ^ F-Aj-C-Ag N, -Aj-N ^^ N-Ag "^ îjK 15 20 "^ O H 0 0 -NH-C-, -NH- or -NH-NH-C-; A2 is a single bond or a radical of formula 0 -NH-, -CH2-CH2 ~ NH-, OR -C-NH-NH-; A3est / \ il U -A.-N N-Ar ^ Nx, -NH-Ar ^ - ^ o5 AT OH \\ IT 0 h h il H H -NH-A.-C-Ar 4 6 â 25 30 - (ch2) -, -nh-c-nh-, -nh-c-nh-ch2 ", 0 -nh-ch2-, -0-ch2-, -ch2-c-nh-, o or -ch2-c-nh-ch2 "; A4 is Rt is an acyl radical derived from a carboxylic acid; 35 R2 and R3 are the same or different and are each a -NH-, - (CH2) -, - (CH2) -NH- atom, hydrogen, an alkyl, alkenyl, alkynyl, cycloalkyl, "^ orphenyl possibly substituted, or a heterocycle at 4,5,6 O O or 7 chains, or well R2 and R3 is hydrogen atom -NH-C-NH-NH- -C-NH-NH- or -N- and the other is an azide, halomethyl, dihalomethyl radical, 40 '■' trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenyl- ethynyl, carboxyl, A5 is a single bond or a radical of formula CH-X t ^ -ch2x. X, X. I 3 1 3 : lf -S-X2, -0-X2, -0-j: -X4, -S-Ç-X4 or 43 -ch2 ~, -nh-ch2-, -n = ch-, X ". X, - ^ -A-C1-nx6X7 ^ 50 or -C-NH- (CH-) -; 2 q- X, is an azide, amine, hydroxy, carboxyl, alkoxycarbonyl, alkanoylamine, phenylcarbonylamine radical (phenyl substi- A6 is a single bond or a radical of killed formula) carbonylamine, alkylsulfonyloxy, phenylsulfonyloxy, (phe -CH = CH- or - (CH2) t-; substituted nyl) sulfonyloxy, optionally substituted phenyl, p is 0 or 1; cyano, 55 y is 2, 3 or 4; O q is equal to 0 yes; -A — C — NX X —S-X, or —O-X- ^; t is 1, 2, 3 or 4; and • 6 7 '- ■ 2 2 X is a hydrogen atom or a carboxyl or carbamoyl group. X2 is an optionally substituted alkyl, optionally substituted phenyl 60, phenylalkyl, (substituted phenyl) al- 2. Compound according to claim 1, in the formula of which kyle, alkanoyl, phenylalkanoyl (substituted phenyl) alkanoyl, R is phenylcarbonyl (phenyl substituted jcarbonyl, or heteroarylcarn bonyl; one of X3 and X4 is a hydrogen atom and the other is a 65 1 1 9 f | H ^ hydrogen atom or an alkyl radical, or else X3 and Xt Jj-a -C-a'— n form, with the carbon atom to which they are attached, a radical 1 2 6 1 cycloalkyl; OH 3,670,828 3. Compound according to claim 1, in the formula of which methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 1-R is carboxy-1-ethyl or / \ jj JmT ° H 5 C? 2 ") 'CH2) S "1" nv. -C-COOH, where s is 1.2, or 3. 4. Compound according to claim 1, in the formula of which 14. Compound according to claim 1, in the formula of which Rest n io R! East O -C-C = N-0-R., i 1 15 R g 5. A compound according to claim 1, in the formula of which Rg is a 2-amino-4-thiazolyl radical and Rj is a radical r is O carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1-ethyl, or "„ CL-lŒj), / - \ n j - "" X'p's -A- ^ - y • -C-COOH, H where s is 1.2, or 3. where s is 1, 2, or 3. 15. Compound according to claim 2, in the formula of which 6. Compound according to claim 1, in the formula of which Ri is Rest O £ -C-C = N-0-Ri, -OH £ -NH-A5—. 30 9 'I Rg is a 2-amino-4-thiazolyl radical and Rj is a radical H 7. Compound according to claim 1, in the formula of which methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1-ethyl or Rest 35 CH _-. (CH0) 2s -C-COOH, where s is 1.2, or 3. 16. A compound according to claim 2, in which the formula "o Rt is O tt ■ ** C ~ C = N O - * R 8. A compound according to claim 2, in the formula of which, i ' Ai is a single bond. R 9. Compound according to claim 2, in the formula of which “9 A2 is -NH-. Rg is a 2-amino-4-thiazolyl radical and R, is a radical 10. Compound according to claim 2, in the formula of which carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1-ethyl A6 is a single bond. or 11. Compound according to claim 1, in the formula of which CH., - (CH.,) Rest 50 q -C-COOH, L ^ where s is 1, 2 or 3. of which Ri is 1 1 Ì1 11 II - 17. Compound according to claim 11, in the formula -NOT. -N-NH-C — Nx 0 ^ 55 H —C ~ C = N O - R 12.According to the claim, in the form of which ■ ■ ■ i ' R2 and R3 are both hydrogen. R 13. A compound according to claim 1, in the formula of which 60 Ri is Rg is a 2-amino-4-thiazolyl radical and Rj is a radical 0 methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 1- -C-C = N-0-R carboxy-l-ethyl or R 65 CH_ - (CH_) g \ 2 y 2 S -C-COOH, and Rg is a 2-amino-4-thiazolyl radical and Rj is a radical where s is 1,2 or 3. 670,828 18. Compound according to claim 11, in the formula of which R! East O II -C-C = N-0-R., ■ •. - ■ i r g Rg is a 2-amino-4-thiazolyl radical and Rj is a carboxymethyl or 1-carboxy-1-methylethyl radical. 19. A compound according to claim 11, in the formula of which R2 and R3 are both hydrogen. 20. The compound according to claim 1, which is [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3- [ [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -amino] -2-oxo-l-imidazoli-dinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl ] amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic acid, or a pharmaceutically acceptable salt of this acid. 21. The compound according to claim 1, which is [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[2 - [( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] -hydrazino] sulfonyl] amino] carbo-nyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-methylpropanoic acid, or a pharmaceutically acceptable salt of this acid. 22. The compound according to claim 1, which is [3S (Z)] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3- [ [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l-imidizoli-dinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-acetic, or a pharmaceutically acceptable salt of this acid. 23. Compound according to claim 1, which is [3S (Z)] acid - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[[1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) methyl] amino] sulfonyl] amino] carbonyl] -2-oxo- 3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] -2-methylpro-panoic, or a pharmaceutically acceptable salt of this acid. 24. The compound according to claim 1, which is [3S (Z)] ~ 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[2- [ [2 - [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] carbonyl] hydra-zino] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -amino ] -2-oxoethylidene] amino] oxy] -2-methylpropanoic, or a pharmaceutically acceptable salt of this acid. 25. The compound according to claim 1, which is [3S- [3a (Z), 4ß]] - 2 - [[[1- (2-amino-4-thiazolyl) -2 - [[1 - [[[ [2 - [(1,4-dihy-dro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] hydrazino] sulfonyl] -amino] carbonyl] -4-methyl-2-oxo-3-azetidinyl] - amino] -2-oxo-ethylidene] amino] oxy] -2-methylpropionic, or a pharmaceutically acceptable salt of this acid. 26. The compound according to claim 1, which is [3S (Z)] - l - [[[1- (2-amino-4-thiazolyl) -2 - [[l - [[[[3- [ [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl] amino] -2-oxo-l-imidazoli-dinyl] sulfonyl] amino] carbonyl] -2-oxo-3-azetidinyl] -amino] -2-oxoethylidene] amino] oxy] cyclopentanecarboxylic acid, or a pharmaceutically acceptable salt of this acid. 27. A process for preparing the compounds according to claims 1 to 26, characterized in that a compound of formula is acylated R2 i z NH ' ch- --r- / ■ • n-c-nh-so2r & 28. Process for preparing the compounds according to claims 1 to 26, characterized in that an activator group -C0-NH-S02R is introduced into a compound of formula r1 ~ nh 10 15 20 25 30 ch 1 VS - R2 r i • é-i -nh