NO863837L - PROCEDURE FOR THE PREPARATION OF 2-OXO-1 - (((SUBSTITUTED SULPHONYL) AMINO) CARBONYL) AZETIDINES. - Google Patents

Description

Connections with the formula

and pharmaceutically acceptable salts thereof, have antibacterial action. In formula I and throughout the present description, the symbols have the following meanings:

Ri is an acyl group which is written from a carboxylic acid;

R.2 and R3 are the same or different and are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, substituted phenyl or a 4-, 5-, 6- or 7-membered heterocyclic ring (hereinafter referred to as Rx), or one of R2 and R3 are hydrogen and the other is azido,

important information

For archival reasons, the Norwegian Patent Office only has access to documents for this generally available patent application that contain handwritten notes, comments or crossing outs, or that may be stamped "Expired" or the like. We have therefore had to use these documents for scanning to create an electronic edition.

Handwritten remarks or comments have been part of the proceedings, and must not be used to interpret the content of the document.

Cross-outs and stampings with "Expired" etc. indicates that newer documents have been received during the proceedings to replace the earlier document. Such crossing out or stamping must not be understood as meaning that the relevant part of the document does not apply.

Please ignore handwritten remarks, comments or crossing outs, as well as any stamps with "Expired" etc. which have the same meaning. halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethenyl, 2-phenylethynyl, carboxyl, -CH2Xi [where Xi is azido, amino (-NH2), hydroxy, carboxyl, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted phenyl, cyano,

. substituted phenyl)alkyl, alkanoyl, phenylalkanoyl, (substituted phenyl)alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl or heteroarylcarbonyl], or [wherein one of X3 and Xi is hydrogen and the other is hydrogen or alkyl, or X3 and X4 together the carbon atom to which they are attached forms a cycloalkyl group; and Xs is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl or cyano (-C=N)] or [wherein A is -CH =CH-, -(CH2)»-, -(CH2)m-0-, - (CH2 )m-NH-, or -CH2-S-CH2-, m is 0, 1 or 2, and X6 and X7 are equal or different and constitute hydrogen, alkyl, phenyl or substituted phenyl, or X6 is hydrogen and X7 is amino, substituted amino, alkanoylamino or alkoxy, or X6 and X7 together with the nitrogen atom to which they are attached form a 4-, 5-, 6- or 7 -membered heterocyclic ring]; Ai is a single bond,

, -NH- or A2 is a single bond, -NH-, -CH2-CH2-NH- or A3 is -(CHz)p- where p is 0 or 1,

, -NH-CH2-, -0-CH2-,

or A4 is -NH-, -(CH2),»-, -(CH2)y-NH-,

where X is hydrogen, carboxyl or carbamoyl and p is 0 or 1, and y is 2, 3 or 4;

A5 is a single bond, -CH2-, -NH-CH2-, -N=CH-, or

where q is 0 or 1;

A6 is a single bond, -CH=CH- or -(CH2)t- where t is 1, 2, 3 or 4.

The symbols given above (eg Ai, A2, A3, A4, As and Ae) are used for groups consisting of several atoms. These groups are entered into the structural formulas shown in the order in which they are presented (ie from left to right). Is e.g. R

and Ai is , the R group will be not

In what follows, definitions of various terms used to describe β-lactams produced according to the invention are given. These definitions apply to the designations in the form they are used in the present description (if they are not limited in certain situations (either individually or as part of a larger group.

The terms "alkyl" and "alkoxy" refer to both straight chain and branched groups. Groups with 1-10 carbon atoms are preferred.

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

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

The terms "alkanoyl", "alkenyl" and "alkynyl" refer to both straight chain and branched groups. Groups with 2-10 carbon atoms are preferred.

The term "halogen" includes fluorine, chlorine, bromine and iodine.

The term "substituted phenyl" refers to a phenyl group substituted with 1, 2 or 3 amino (-NH2), halogen, hydroxyl, trifluoromethyl, alkyl (of 1-4 carbon atoms), alkoxy (of 1-4 carbon atoms), alkanoyloxy, aminocarbonyl or carboxyl groups.

The term "a 4-, 5-, 6- or 7-membered heterocyclic ring"

(referred to as "Rx") refers to substituted and unsubstituted aromatic and non-aromatic groups containing one or more (preferably 1, 2 or 3) nitrogen, oxygen or sulfur atoms. The substituents can e.g. be oxo(=0), halogen, hydroxy, nitro, amino, cyano, trifluoromethyl, alkyl with 1-4

carbon atoms, alkoxy with 1-4 carbon atoms, alkylsulfonyl, phenyl substituted phenyl

2-Furfurylideneamino

, benzylideneamino and

substituted alkyl groups (where the alkyl group has 1-4 carbon atoms). A type of "4-, 5-, 6-, or 7-membered heterocyclic ring"

is the "heteroaryl" group. The term "heteroaryl" refers to the 4-, 5-, 6- or 7-membered heterocyclic rings that are aromatic.

Examples of heteroaryl groups can be mentioned substituted and unsubstituted pyridinyl, furanyl, pyrrolyl, thienyl, 1,2,3-triazolyl, 1,2,4-triazolyl, imidazolyl, thiazolyl, thiadiazolyl, pyrimidinyl, oxazoyyl, triazinyl and tetrazolyl. Examples of non-aromatic heterocycles (ie fully or partially saturated heterocyclic groups) are substituted and unsubstituted azetidinyl, oxetanyl, thietanyl, piperidinyl, piperazinyl, imidazolidinyl, oxazolidinyl, pyrrolidinyl, tetrahydropyrimidiyl, dihydrothiazolyl and hexahydroazepinyl. Examples of substituted 4-, 5-, 6- or 7-

fused heterocyclic rings are l-alkyl-3-azetidinyl, 2-oxo-l-imidazolidinyl, 3-alkylsulfonyl-2-oxo-l-imidazolidinyl, 3-benzylideneamino-2-oxo-l-imidazolidinyl, 3-alkyl-2- oxo-l-imidazolidinyl, 3-phenyl-(or substituted phenyl)-2-oxo-l-imidazolidinyl, 3-benzyl-2-oxo-l-imidazolidinyl, 3-(2-aminoethyl)-2-oxo-l- imidazolidinyl, 3-amino-2-oxo-l-imidazolidinyl, 3-[(Alkoxycarbonyl)amino]-2-oxo-l-imidazolidinyl, 3-[2-[(Alkoxycarbonyl)amino]ethyl]-2-oxo-l -imidazolidinyl, 2-oxo-1-pyrrolidinyl, 2-oxo-3-oxazolidinyl, 4-hydroxy-6-methyl-2-pyrimidinyl, 2-oxo-1-hexahydroazepinyl, 2-oxo-3-pyrrolidinyl, 2-oxo -3-tetrahydro-furanyl, 2,3-dioxo-l-piperazinyl, 2,5-dioxo-l-piperazinyl, 4-alkyl-2,3-dioxo-l-piperazinyl and 4-phenyl-2,3-dioxo -1-piperazinyl.

The term "substituted amino" refers to a group with

the formula -NXeX9 , where Xs is hydrogen, alkyl, phenyl, substituted phenyl, phenylalkyl or (substituted phenyl)alkyl and Xg is alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyDalkyl, hydroxy, cyano, alkoxy, phenylalkoxy or amino (- NH2).

The term "acyl" refers to all organic radicals which are formed from an organic acid (ie a carboxylic acid) by removal of the hydroxyl group. Certain acyl groups are of course preferred. Examples of acyl groups can be mentioned the groups that have been used in recent times to acylate (3-lactam antibiotics including 6-aminopenicillanic acid and its derivatives and 7-amino-cephalosporanic acid and its derivatives; see for example Cephalo-sporins and Penicillins, edited by Flynn, Academic Press

(1972), German Patent 2,716,677 (published October 10, 1978), Belgian Patent 867,994, (published December 11, 1978) US Patent 4,152,432 of May 1, 1979, US Patent 3,971,778 of 27 .July 1976, US Patent 4,172,199 dated October 23, 1979 and UK Patent I,348,894 dated March 27, 1974. The following list of acyl groups is presented to further exemplify the term "acyl" and is not to be considered a limitation of the designation:

(a) Aliphatic groups with the formula

wherein Ra is alkyl; cycloalkyl; alkoxy; alkenyi; cycloalkenyl; cyclohexadienyl; or alkyl or alkenyl substituted with one or more halogen, cyano, nitro, amino, mercapto, alkylthio or cyanomethylthio groups.

(b) Carbocyclic aromatic groups of the formula:

where n is 0. 1, 2 or 3; R b , R c o and R a independently of each other, are hydrogen, halogen, hydroxyl, ni tro, amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or air, inom, ethyl; and R" is amino, hydroxyl, a carboxyl salt,

protected carboxyl, formyloxy, a sulfo salt , a sulfonarr.ino salt, azido, halogen, hydrazino, alkylhydrazino,. phenylhydrazi.no or [(alkylthio)thioxomethyl]thio.

Preferred carbocyclic aromatic acyl groups include groups of the formula:

(Re is preferably a carboxyl salt or a sulfo salt) and

(Re is preferably a carboxyl salt or a sulfo salt) and

(c) Heteroaromatic groups of the formula:

where n is 0, 1, 2 or 3; Re is as stated above; and Rf is a substituted or unsubstituted 5-, 6- or 7-membered heterocyclic ring containing 1, 2, 3 or 4 (preferably 1 or 2) nitrogen, oxygen or sulfur atoms. Examples of heterocyclic rings include thienyl, furyl, pyrrolyl, pyridinyl, pyrazolyl, pyrazinyl, thiazolyl, pyrimidinyl, thiadiazolyl and tetrazolyl. Examples of substituents are halogen,

hydroxyl, nitro, amino, protected amino, cyano, trifluoromethyl, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms or

Preferred heteroaromatic acyl groups include the groups of the above formulas, where Rf is 2-amino-4-thiazolyl, 2-amino-5-halo-4-thiazolyl, 4-aminopyrimidin-2-yl, 5-amino-1,2, 4-thiadiazol-3-yl, 2-thienyl, 2-furanyl or 6-aminopyridin-2-yl. (d) [[(4-substituted-2,3-dioxo-1-piperazinyl)carbonyl]-amino]arylacetyl groups of the formula:

where Rg is an aromatic group (including aromatic carboxyl groups such as those of the formula:

and heteroaromatic groups according to the definition of Rf ); and Rh is alkyl, substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups), arylmethyleneamino, (ie -N=CH-Rg where Rg is as indicated above ), arylcarbonylamino (ie

where Rg is as stated above)

or alkylcarbonylamino.

Preferred [[(4-substituted-2,3-dioxo-1-piperazinyl)-carbonyl]amino]arylacetyl groups include those wherein Rh is ethyl, phenylmethyleneamino or 2-furylmethyleneamino.

(e) (Substituted oximino)arylacetyl groups of the formula

where Rg is as above and Ri is hydrogen, alkyl, cycloalkyl, 2-yl, 2-pyrrazolylmethyl, (2-oxo-3-pyrrolidinyl)methyl, alkylaminocarbonyl, arylaminocarbonyl (ie

where Rg is as stated above)

or substituted alkyl (wherein the alkyl group is substituted by one or more halogen, cyano, nitro, amino, mercapto, alkylthio, aromatic groups (as defined for Rg), carboxyl (including salts thereof), amido, alkoxycarbonyl, phenylmethoxycarbonyl, diphenylmethoxycarbonyl, hydroxyalkylphosphinyl, dihydroxy-phosphinyl, hydroxy(phenylmethoxy)phosphinyl, dialkoxyphosphinyl or tetrazolyl substituents).

Preferred (substituted oxyimino)arylacetyl groups include those where Rg is 2-amino-4-thiazolyl. Preferred are also those groups where R 1 is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 2,2,2-trifluoroethyl or 1-carboxycyclopropyl.

(f) (Acylamino)arylacetyl groups of the formula:

where Rg is as indicated above and Rj is amino, amido, alkylamido, (cyanoalkyl)amido,

Preferred (acylamino)arylacetyl groups of the above formula include those groups where Rj is amino or amido. Those groups where Rg is phenyl or 2-thienyl are also preferred. (g) [[[3-substituted-2-oxo-1-imidazolidinyl]carbonyl]-amino]arylacetyl groups of the formula:

where Rg is as stated above and R is hydrogen, alkylsulfonyl, arylmethyleneamino (ie -N=CH-Rg where Rg is as stated above),

(where Rra is hydrogen, alkyl or halogen substituted

alkyl), an aromatic group (as indicated above for Rg), alkyl or substituted alkyl (wherein the alkyl group is substituted with one or more halogen, cyano, nitro, amino or mercapto groups).

Preferred [[3-substituted-2-oxo-1-imidazolidinyl]carbonyl]amino]arylacetyl groups of the above formula include those wherein Rg is phenyl or 2-thienyl. Those groups where Ru is hydrogen, methylsulfonyl, phenylmethyleneamino or 2-furylmethyleneamino are also preferred.

The compounds produced according to the invention form basic salts with various inorganic and organic bases, and these are also to be covered by the invention. Such salts include ammonium salts, alkali metal salts, alkaline earth metal salts, salts with organic bases, e.g. dicyclohexylamine, benzathine, N-methyl-D-glucamine, hydrabamine and the like. Pharmaceutically acceptable salts are preferred although other salts are also useful, e.g. when isolating or cleaning the product.

Some of the compounds produced according to the invention can be crystallized or recrystallized from aqueous solvents. In this case, water of hydration may form. The invention shall therefore also encompass the preparation of stoichiometric hydrates and of compounds that contain varying amounts of water and can be formed by processes such as lyophilization.

The 3-lactams of formula I have at least one chiral center - the carbon atom in the 3-position of the 3-lactam iron to which the acylamino substituent ("Ri-NH-") is attached. The invention is also directed to the preparation of this type ( 3-lactams where the stereochemistry of the chiral center in the 3-position of the 3-lactam nucleus is the same as the configuration in the carbon atom in the 6-position of naturally occurring penicillins (e.g. penicillin G) and as the configuration in the 7-position of naturally occurring cefamycins (e.g. cefamycin C) The invention shall thus also include the production of racemic mixtures containing these 3-lactams.

The 3-lactams of formula I and pharmaceutically acceptable salts thereof are effective against gram-positive and gram-negative organisms

isms. The new compounds can therefore be used as agents to combat bacterial infections (including urinary tract and respiratory infections) in mammals, such as domestic animals (e.g. dogs, cats, cows, horses and the like) and humans.

To combat bacterial infections in mammals, a compound produced according to the invention can be given in an amount of approx. 1.4-350 mg/kg/day, preferably 14-100 mg/kg/day. All administration methods that have recently been used to deliver penicillins and cephalosporins to the site of infection can also be used for the new (3-lactams. Such administration methods include oral, intravenous and intramuscular administration as well as administration as a suppository.

(The 5-lactams of formula I can be prepared from a 3-protected amino-2-azetidinone of the formula:

In formula II and elsewhere in the specification, the symbol "R4" refers to an amino protecting group. These groups are well known in β-lactam chemistry, and which group is chosen is not of decisive importance. Benzyloxycarbonyl, trityl and t-butoxycarbonyl can for example be used as protecting groups. The reaction of a β-lactam II with an isocyanate of formula III where Y is a leaving group such as chlorine, leads to the corresponding compound with the formula: The reaction is preferably carried out in an inert organic solvent, e.g. ethyl acetate, tetrahydrofuran, dimethoxyethane, dichloromethane, acetonitrile or mixtures of these solvents. The displacement of the leaving group "Y" with the desired group "R" can be achieved by using a suitable nucleophile of formula optionally in the presence of a base (e.g. triethylamine), leading to the corresponding compound of formula:

The displacement of the leaving group can alternatively be carried out by reacting compound IV with a protected form of a compound of formula V. After the displacement reaction, the protecting group can be removed using known techniques, whereby a compound of formula VI is obtained.

Protected forms of a compound of formula V and of the reactants described herein which contain a 3-hydroxy-4-pyridone moiety include those compounds where the hydroxyl group is protected, those compounds where the hydroxyl group and the ring nitrogen are protected as well as compounds where both pyridone -the oxygen atoms are protected. Examples of protective groups include silyl (e.g. trimethylsilyl), benzyl and acyl (e.g. acetyl). If silyl is used, removal of the protecting group can be achieved by hydrolysis or cleavage using fluoride. If benzyl is used, later removal of the protecting group can be achieved by hydrogenolysis. If acyl is used, later cleavage of the protective group can take place by hydrolysis. Removal of the protecting group from a compound of formula VI by conventional techniques leads to the corresponding intermediate of the formula:

or a salt thereof. Which cleavage reaction is used obviously depends on the protecting group ("R4"). If R 4 is, for example, a t-butoxycarbonyl protecting group, the removal of the protecting group can be achieved by treating a compound of formula VI with acid (e.g. formic acid or trifluoroacetic acid). If R4 is, for example, a benzyloxycarbonyl protecting group, removal of the protecting group can be achieved by catalytic hydrogenation of a compound of formula VI. The protecting group R4 can alternatively be removed simultaneously with other pyridone protecting groups immediately after the above-mentioned displacement reaction.

Well-known acylation techniques can be used to convert an intermediate of formula VII into a corresponding product of formula I. As an example, reaction of a compound of formula VII with a carboxylic acid (Ri-OH) or corresponding carboxylic acid halide or carboxylic anhydride can be mentioned. The reaction with a carboxylic acid proceeds most easily in the presence of a carbodiimide, such as dicyclohexylcarbodiimide, and a compound capable of forming an active ester in situ, such as N-hydroxybenzotriazole. In cases where the acyl group Ri) contains reactive functional groups (such as amino or carboxyl groups), it may be necessary that these are first protected, after which the acylation reaction is carried out and the end product is finally freed of the protective group.

An alternative method for the preparation of compounds of formula I consists in first acylating (acylation techniques are described above)

a 3-amino-2-azetidinone of the formula:

which gives an intermediate with the formula:

Q

A -C-NH-SO2-R activating group can be introduced into the 1-position of a compound of formula IX (using the methods described above) to obtain the corresponding product of formula I. In those cases where the acyl side chain "Ri " contains reactive groups (such as amino groups), it may be necessary to protect these functional groups first and then place the activating group in the 1-position, whereupon the resulting product is finally freed of the protecting group.

A further synthetic method for compound I involves the use of 3-azido-2-azetidinone of the formula

An activating group can be introduced into the I-position of a compound of formula X (using the methods described above) to obtain the corresponding compound of formula:

Reduction of the intermediate XI leads to the corresponding intermediate with the formula:

The reduction can be achieved by catalytic (eg palladium-on-charcoal or platinum oxide) hydrogenation or with reducing agents such as zinc or triphenylphosphine. As described above, from these key products (compounds of formula VII) it is possible to prepare the products of formula I by means of conventional acylation techniques.

As an alternative, a 3-azido-2-azetidinone of formula X can be reduced to the corresponding 3-amino-2-azetidinone of the formula: The reduction can be carried out by catalytic hydrogenation (e.g. over palladium-on-charcoal or platinum oxide) or with reducing agents such as zinc or triphenylphosphine. A 3-amino-2-azetidinone of formula VIII can be reacted as described above (ie first acylation and then treatment as described above to introduce a

-R activating group in the 1-position) to give product-

one with formula I.

Another synthesis method for the preparation of the compounds of formula I where R2 and R3 are both hydrogen makes use of a 6-acylamino-penicillanic acid of the formula:

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

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

Replacement of the carboxyl group in a compound of formula XIII with an acetate group, followed by hydrolysis, leads to the corresponding 3-acylamino-2-azetidinone of the formula:

Treatment of a compound of formula XIII with copper (II) acetate and lead tetraacetate in an organic solvent (e.g. acetonitrile) results in the carboxyl group being replaced by an acetate group. Hydrolysis of the resulting compound can be achieved using potassium carbonate in the presence of sodium borohydride.

Q

A -C-NH-SO2-R activating group can be introduced in the 1-position in a compound of formula XIV (by which products of formula I where R2 and R3 are both hydrogen are obtained) by using the methods described above.

A further variant of the above-described synthetic method for preparing a compound of formula I, wherein R 2 and R 3 are both hydrogen, consists in first desulfurizing 6-aminopenicillanic acid, acylating the resulting compound to a compound of formula XIII and then proceeding as described above for first to obtain a 3-acylamino-2-azetidinone of formula XIV and then a product of formula I.

Azetidinones of formula I can also be prepared from amino acids having the formula:

The amino group is first protected (with a protecting group "R4", eg t-butoxycarbonyl). The carboxyl group of the protected amino acid is then reacted with an amine of the formula: where Z is alkyl, benzyl or triphenylmethyl, in the presence of a carbodiimide to give a compound of the formula:

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

The fully protected compound of the formula: is cyclized by treatment with a base, e.g. potassium carbonate. The reaction is preferably carried out in an organic solvent, possibly in a mixture with water, under reflux conditions and leads to a compound with the formula:

The cyclization of a compound of formula XVII can alternatively be achieved without first converting the hydroxyl group into a leaving group. Treatment of a compound XVII with triphenylphosphine and diethyl azodicarboxylate thus leads to a compound of formula XIX.

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

(1982).

Both of the above-mentioned methods for cyclization of a compound of formula XVII result in inversion of the stereochemical relationships in the carbon atom that has the R2 and R3 substituents when R2 and R3 are different.

Removal of the protecting group from the 1-position in an azetidinone of formula XIX, when Z is alkyl, can occur via sodium reduction and leads to an intermediate of the formula:

(of which at least one of R2 and R3 is hydrogen). If Z is benzyl, catalytic hydrogenation (e.g. palladium-on-charcoal) will initially lead to the corresponding N-hydroxy compound which then leads to an intermediate of formula II when treated with titanium trichloride. If Z is triphenylmethyl, formic acid or 70% acetic acid/water will initially lead to the corresponding N-hydroxy compound.

0

A -C-NH-SO2-R activating group can be introduced into the 1-position of a compound of formula II using the methods described above, and the resulting compound can be deprotected and acylated.

Nucleophiles of formula V, where R is

and each of Ai and A2 constitute single bonds, can be produced by

react a silylated derivative of 2-imidazolidinone

or the anion of 2-imidazolidinone formed with a strong non-nucleophilic base, with an activated, suitably protected derivative of an acid of formula to, after being deprotected, obtain the corresponding compound of formula:

The reaction can be carried out in an inert organic solvent such as dimethylformamide, acetonitrile, dichloromethane or tetrahydrofuran. The acid XX can be activated with dicyclohexylcarbodiimide or with a combination of dicyclohexylcarbodiimide and hydroxybenzotriazole. An activated and suitably protected derivative of a compound of formula XX may also be the corresponding acid chloride (prepared with reagents such as phosphorus pentachloride, thionyl chloride, oxalyl chloride or triphenylphosphine/carbon tetrachloride) or a mixed anhydride (prepared with reagents such as diphenylphosphoryl chloride, pivaloyl chloride or isobutyl chloroformate) . Compounds of formula XX where A6 is a single bond can be prepared as described in the literature; see Heiv. Chem. Acta, 43, 469 (1960) and J. Med. Chem., 17, 1 (1974).

The compound of formula XX, where A6 is -CH=CH- can be formed by oxidizing

(suitably protected) to the corresponding aldehyde of formula: (suitably protected), reacting the aldehyde with a carboxyl-protected derivative and deprotecting this to obtain the Compounds of formula XX, where A6 is -(CH2)t- and t is 2, 3 or 4, can be formed by conjugation of a compound XXIII (suitably protected) with a Wittig reagent of formula (with suitably protected carboxyl group), subsequent hydrogenation of the resulting exocyclic double bond and removal of the protecting group to obtain

where t is 2, 3 or 4.

The compounds of formula XX, where A 6 is -(CH 2 )t - and t is 1, can be formed by reacting a suitably protected compound of formula

(where La is a leaving group, such as chloride, bromide, methanesulfonyloxy or toluenesulfonyloxy) with cyanide and subsequent hydrolysis and removal of the protecting group to give the compound of formula XXVII, where t is 1. A compound of formula XXVIII can be prepared from a compound of formula XXII (suitably protected) by known methods (such as reaction with thionyl chloride or methanesulfonyl chloride/triethylamine).

Nucleophiles of formula V, where R is

Ai is a single bond and A2 is -NH-, can be prepared by reacting an activated and possibly protected derivative of a compound XX with 1-amino-2-imidazolidinone which after removal of the protecting group leads to Nucleophiles of formula V, where R is

Ai is a single bond and

Aa is -CH2-CH2-NH- can be prepared by reacting an activated or optionally protected derivative of compound XX with l-(2-

aminoethyl)-2-imidazolidinone

which after removal of the protecting group gives Nucleophiles of formula V, where R is Ai is a single bond and A<2>er , can be prepared by reacting with a silylated form of 2-imidazolidinone, the anion of 2-imidazolidinone being formed with strong non- nucleophilic base, or with 2-imidazolidinone in the presence of an organic base, to obtain Catalytic hydrogenation of compound XXXII leads to the compound of formula which can be coupled with an activated and optionally protected derivative of a compound of formula XX which, after removal of the protecting group, gives Alternatively, the compound of formula XXXIII can be prepared by reacting l-chlorocarbonyl-2-imidazolidinone with t-butoxycarbonyl-protected hydrazine to give

and then cleaving the protecting group in compound XXXV.

Nucleophiles of formula V, where R is

Ai is and Az is a single bond, can be prepared by reacting a compound of formula (suitably protected) with hexamethyldisilazane which after hydrolysis and removal of the protecting group leads to a compound of formula

The compounds of formula XXXVI (suitably protected) can be prepared by reacting a silylated form of a compound 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 with subsequent hydrolysis of the resulting intermediate and removal of the protecting group.

Nucleophiles of formula V, where R is

Ai is and A2 is -NH-, can be prepared by reacting a silylated form of the compound where the symbol Prot can be an amino protecting group, such as t-butoxycarbonyl or benzyloxycarbonyl, with phosgene which can be reacted with hexamethylsilazane and after removal of the protecting group gives Reaction of the compound XL with an optionally protected activated form of a compound XX gives after removal of the protecting group

A compound of formula XL can also be prepared by reacting the compound of formula with chlorosulfonyl isocyanate which after hydrolysis gives

Treatment of this compound with an aqueous acid leads to a salt of the compound XL.

Nucleophiles of formula V, where R is

Ai is and A2 is -CH2-CH2-NH- can be prepared by first deprotecting 1-(aminocarbonyl)-3-[2-[[(t-butoxy)carbonyl]amino]ethyl]-2-imidazolidinone, after which the resulting compound is coupled with an activated form of a compound of formula XX (optionally protected) which, after removal of the protecting group, gives

Nucleophiles of formula V, where R is

Ai is , can be prepared by reacting a silylated form of a compound of formula XXXIV (optionally protected) with phosgene and then with hexamethyldisilazane which after hydrolysis and removal of the protecting group gives A compound of formula XLV can alternatively be prepared by reacting a protected form of a compound XXXIV with chlorosulfonyl isocyanate and subsequent hydrolysis of the resulting intermediate and removal of the protecting groups. Alternatively, compound XXXII can be reacted with chlorosulfonyl isocyanate, whereupon hydrolysis of the resulting intermediate yields

Removal of the protective group from XLVI by hydrogenolysis leads to which can be coupled with an activated and possibly protected derivative of a compound of formula XX which, after removal of the protective group, gives a compound of formula XLV.

Nucleophiles of formula V, where R is

Ai is -NH- and A2 is a single bond, can be prepared by coupling compound XXXVIII to an activated form of a compound of formula XX (optionally protected) and cleaving the protecting group to obtain

Nucleophiles of formula V, where R is Ai is -NH- and A2 is -NH-, can be prepared by coupling a mono-protected (preferably with t-butoxycarbonyl or benzyloxycarbonyl) derivative of 1,3-diamino-2-imidazolidinone with a activated form of a compound of formula XX (optionally protected), whereupon the resulting compound is deprotected to give

Alternatively, a compound of formula XLIX can be formed by nitrosation of a protected form of a compound of formula XXIX and subsequent reduction of the nitroso group and removal of the protecting groups.

Nucleophiles of formula V, where R is

Ai is -NH- and A2 is -CH2-CH2-NH-, can be prepared by nitrosation of a compound of formula XXX (suitably protected) to give a compound of formula

(suitably protected) and reduction and removal of the protecting group from this compound to obtain Nucleophiles of formula V, where R is Ai is -NH- and A2er , can be prepared by nitrosation, reduction and removal of the protecting groups in a protected derivative of a compound with formula XXXIV. The resulting compound has the formula

Alternatively, a compound of formula LII can be prepared by reacting a compound XXXVIII with phosgene to give which, after reaction with a mono-protected hydrazine in the presence of base, gives

(The two protection groups must be different).

Selective cleavage of the hydrazide protecting group leads to

Coupling of a compound of formula LV with an activated and optionally protected form of a compound XX and subsequent removal of the protecting group leads to a compound of formula LII.

Nucleophiles of formula V, where R is

Ai is and A2 is a single bond, can be prepared by reacting a compound XXXVI (preferably a protected derivative thereof) with hydrazine (preferably in mono-protected form) in the presence of a base, or with a silylated form of hydrazine or mono-protected hydrazine , whereby a protected derivative of is obtained

which can be freed from the protecting group in the conventional manner.

Alternatively, a compound of formula XXXV (either a silylated derivative or an anion thereof formed by reaction with a strong base) can be reacted with an activated form of compound XX (suitably protected) and deprotected to give a compound of formula LVI .

Nucleophiles of formula V, where R is

Ai is and A2 is -NH-, can be prepared by selective removal of protecting groups that do not protect the hydrazide group, in a compound LIV which is then coupled with an activated and optionally protected compound of formula XX and subsequent removal of the protecting group to give a compound of formula Nucleophiles of formula V, where R is Ai is and A2 is -CH2-CH2-NH-, can be prepared by successive reaction of a compound of formula XXX (or a protected derivative thereof) with phosgene and then with hydrazine (or a mono- protected derivative thereof) in the presence of a silylating agent, such as N-methyl-N-(trimethylsilyl)trifluoroacetamide which after removal of the protecting group gives

Alternatively, an amino-protected derivative of 1-(2-aminoethyl)-2-imidazolidinone (optionally silylated) can be reacted with phosgene and then with a mono-protected derivative of hydrazine in the presence of a base or a silylating agent (e.g. N-methyl-N-(trimethylsilyl)trifluoroacetamide or bis(trimethylsilyl)acetamide) to give a protected derivative of the compound

The groups used to protect the terminal amino groups in a compound LIX should be chosen so that the protecting group on the aminoethyl group can be selectively removed. The resulting compound where a protecting group has been cleaved off can be coupled with an activated form of an acid XX (or a protected derivative thereof) to obtain (after removal of the protecting group) a compound of formula LVIII.

Nucleophiles of formula V, where R is

Ai is , can be prepared by reacting the compound XXXII (optionally as a silylated derivative thereof) with phosgene to give a protected derivative of the compound of formula which can be coupled with a protected derivative of hydrazine to give a protected derivative of the Groups used for protecting the terminal amino groups in a compound of formula LXI should be chosen so that one of the protecting groups can be selectively removed. The resulting compound where one protecting group has been removed can be coupled with an optionally protected, activated form of an acid XX which (after removal of the protecting groups) gives a compound of formula Nucleophiles of formula V, where R is can be prepared using the technique above is described for the preparation of nucleophiles of formula V, where R is

with appropriate 2,3-piperazinedione reactants being used instead of the 2-imidazolidinone reactants.

Nucleophiles of formula V, where R is

Ai is a single bond and As is a single bond, can be prepared by using a suitable protected derivative of the compound A compound of formula can be prepared by converting a protected form of the compound of formula

to a protected form of the compound of formula LXIV according to K. Heyns et al., Chem. Ber., 1440 (1954) and subsequent removal of the protecting groups to obtain compound LXIV as such.

A compound of formula LXV may be prepared from a suitably protected form of a compound of formula LXIII by conversion to an ester (such as the ethyl or methyl ester), reaction with hydrazine and removal of the protecting group. Alternatively, a suitably protected, activated form of a compound LXIII can be reacted with a mono-protected hydrazine, whereby a compound of formula LXV is obtained after removal of the protecting group.

Reaction of the compound LXIV (or a suitably protected derivative thereof) with 2-(chloroethyl)isocyanate, optionally in the presence of a base (such as triethylamine), or a silylating agent leads, after removal of the protecting group, to the compound of formula

Treatment of LXVI (or a suitably protected derivative thereof) with base, after removal of the protecting group, leads to the compound

Nucleophiles of formula V, where R is

Ai is a single bond and As is -CH2- , can be prepared by reacting a compound of formula (or a derivative where the pyridone is suitably protected and the primary amine is unprotected) with 2-(chloroethyl)isocyanate to obtain the compound which after removal of the protecting group, has formula Treatment of LXIX (or a suitably protected derivative thereof) with base leads to the compound of formula

A compound of formula LXVIII can be prepared from a compound of formula XXVIII (suitably protected) by treatment with azide, reduction of the azide and removal of the protecting group.

Nucleophiles of formula V, where R is

Ai is a single bond and As is -N=CH- or -NH-CH2, can be prepared by condensing l-amino-2-imidazolidinone with the aldehyde XXIII (optionally protected) to obtain (after removal of the protecting group) the compound of formula Reduction of the compound of formula LXXI (optionally protected) by catalytic hydrogenation or using sodium cyanoborohydride gives the compound of formula

Nucleophiles of formula V, where R is

Ai is a single bond and A5er, can be prepared by reacting 1-chlorocarbonyl-2-imidazolidinone with a compound of formula (or a suitably protected derivative thereof) in the presence of a base, or with a silylated derivative of a compound of formula LXXIII, to obtain a compound which, after removal of the protecting group, has the formula Nucleophiles of formula V, where R is and Ai is , can be prepared by reacting a suitably protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII or LXXIV with phosgene for to give a protected derivative of which can be reacted with hexamethylsilazane to give, after deprotection and hydrolysis, to give Alternatively, nucleophiles of formula V, where R is and Ai are

, is produced by marketing a suitable

protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII or LXXIV with chlorosulfonyl isocyanate to obtain a compound which, after hydrolysis and removal of the protecting group, has formula LXXVI.

Nucleophiles of formula V, where R is

and hi is -NH- , can be prepared by nitrosating a suitable protected derivative of a compound of formula LXVII, LXX, LXXI, LXXII or LXXIV (with, for example, nitric acid), after which the resulting compound is reduced (for example, with zinc under acidic conditions) and deprotected to give Alternatively, the compounds of formula LXXVII, where As is can be prepared by reacting a compound XXXIX with an optionally protected form of a compound of formula LXIV or LXVIII in the presence of a base or a silylating agent, whereby that after removal of the protecting group is obtained

Alternatively, compounds of formula LXXVII where As is -N=CH- or -NH-CH2- can be prepared by reacting a mono-protected 1,3-diamino-2-imidazolidinone with a compound XXIII (or a protected derivative thereof) and removing the protecting group in the product whereby the derivative of formula LXXVII, where As is -N=CH-, is obtained. Reduction of this derivative leads to the compound of formula LXXVII where As is -NH-CH2-.

Nucleophiles of formula V, where R is

Ai er can be prepared by reacting a compound of formula LXXV (suitably protected) with a mono-protected hydrazine in the presence of a base or a silylating agent. After removal of the protective groups, the products have the formula Nucleophiles with formula V, where R is

Ai is a single bond and As is a single bond or -CH2-, can be prepared by reacting a compound of formula LXIV or LXVIII (or a suitably protected derivative thereof) with aziridine or an activated aziridine (activated with groups such as acyl or sulfonyl) to, after removal of the protecting groups, yield A compound of formula LXXX (or a suitably protected derivative thereof) can be converted to the desired piperazinedione of formula

by reaction with a dialkyl oxalate (and possible subsequent removal of the protecting groups).

Nucleophiles of formula V, where R is

Ai is a single bond and As is -N=CH- or -NHCH2-, can be prepared by using the technique described above for the preparation of nucleophiles of formula V, where R is

Ai is a single bond and As is -N=CH- or -NHCH2-, but use l-amino-2,3-piperazinedione instead of l-amino-2-imidazolidinone. The resulting compounds have the formulas Nucleophiles of formula V, where R is Ai is a single bond and As is , can be prepared by reacting an optionally protected derivative of with a compound of formula LXXIII (or a suitably protected derivative thereof) in the presence of a base or a silylating agent. The resulting intermediate can be deprotected to give Nucleophiles of formula V, where R is and Ai is -NH-, can be prepared by nitrosating a protected derivative of a compound of formula LXXXI, LXXXII, LXXXIII or LXXXV (with, for example , nitric acid), after which the resulting compound is reduced (for example, using zinc under acidic conditions) and deprotected to give

Alternatively, the compounds of formula LXXXVI where As is -N=CH- or -NH-CH2- can be prepared by reacting a mono-protected 1,4-diamino-2,3-piperazinedione with a compound XXIII (or a protected derivative thereof) and then remove the protecting group to obtain a compound of formula LXXXVI, where As is -N=CH- which can then be reduced to a compound of formula LXXXVI, where As is -NH-CH2-. Alternatively, the reduction of -N=CH- may precede removal of the protecting group.

Nucleophiles of formula V, where R is

and Al is , can be prepared by reacting a suitably protected derivative of a compound of formula LXXXI, LXXXII, LXXXIII or LXXXV with phosgene to give which can be reacted with hexamethyldisilazane to, after deprotection and hydrolysis, give Alternatively, nucleophiles can of formula V, where R is and Ai

, is produced by reacting a suitably protected

derivative of a compound of formula LXXXI, LXXXII, LXXXIII or LXXXV with chlorosulfonyl isocyanate to obtain a compound of formula LXXXVIII after hydrolysis and removal of the protecting group.

Nucleophiles of formula V, where R is

and A3er -(CH2)p- has been described previously; see formula LXIV and

LXVIII.

Nucleophiles of formula V, where R is

and A3s

, can be produced by

reacting a compound of formula XXXI with a compound of formula LXIV or LXVIII (optionally protected) in the presence of a base or a silylating agent and subsequent removal of any protecting groups.

Alternatively, nucleophiles of formula V, where R is

and A3s

, is produced from a

suitably protected form of a compound LXIV or LXVIII by reaction with phosgene and subsequent treatment with a mono-protected derivative of hydrazine in the presence of a base or a silylating agent and subsequent removal of the protecting group.

Nucleophiles of formula V, where R is

and A3s

, can be produced by

coupling an activated N-protected glycine derivative with a compound of formula LXIV or LXVIII (optionally protected) followed by removal of the protecting group.

Nucleophiles of formula V, where R is

and A3er -NH-CH2-, can be prepared by reacting an optionally protected derivative of the aldehyde XXIII with hydrazine or mono-protected hydrazine and subsequent reduction of the carbon-nitrogen double bond and removal of the protecting group.

Alternatively, a mono-protected hydrazine can be mono-alkylated at the free amino group with a compound XXVIII (suitably protected), after which the protecting group is removed to give a nucleophile of formula V, where R is

and A 3 is -NH-CH 2 - .

Nucleophiles of formula V, where R is

and A3er -O-CH2-, can be prepared by reacting an appropriate protected derivative of Formula XXII with N-hydroxyphthalimide under Mitsunobu conditions (presence of triphenylphosphine and diethylazodicarboxylate) to give a protected derivative of the compound which, after removal of the protecting group, gives the compound

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

Nucleophiles of formula V, where R is

and A4er -NH-, can be prepared by reacting a mono-protected hydrazine with an activated, optionally protected derivative of an acid of formula XX which, after removal of the protecting group, gives a compound of formula

Alternatively, the compounds of formula XCI can be prepared by reacting a carboxylic acid ester of a suitably protected derivative of a compound XX with hydrazine and subsequent removal of the protecting group.

Nucleophiles of formula V, where R is

and Ai is -(CH2>p- and p is 0, can be prepared by reacting ammonium hydroxide or hexamethylenedisilazane with an activated, optionally protected derivative of an acid XX which, after removal of the protecting group, gives a compound of formula Nucleophiles of formula V, where R er and A4er -(CH2)p- and p is 1, can be prepared by treating an appropriately protected, activated derivative of a compound XX with diazomethane and then with hydrochloric acid to give a protected derivative of a compound of formula

where "Lb" is chlorine. A compound of formula XCIII, wherein Lb is chlorine, can then be treated with an iodide or bromide salt (such as sodium iodide or lithium bromide) to obtain a protected derivative of a compound XCIII, wherein Lb is bromine or iodine. Displacement of the leaving group "Lb" (where Lb is chlorine, bromine

or iodine) with azide followed by reduction and removal of the protecting group, leads to

Nucleophiles of formula V, where R is and Å4 is -(CH2)y-NH-, can be prepared by reacting an (optionally mono-protected) compound of formula with an activated, optionally protected derivative of an acid XX, whereby after removal of the protecting group, a compound of formula is obtained

Nucleophiles of formula V, where R is

and A4er, can be prepared by reacting a compound of formula XCI (suitably protected) with a compound of formula

in the presence of a silylating agent, after which the protecting groups are removed.

Nucleophiles of formula V, where R is

and A4er , can be prepared by reacting (in the presence of a base or a silylating agent) with an activated, optionally protected derivative of compound XX, whereby, after removal of the protecting group, a compound of formula is obtained

Nucleophiles of formula V, where R is

and A4s can be prepared by reacting an optionally protected hydrazine derivative of formula with an activated, optionally protected derivative of an acid XX, whereby, after removal of the protecting group, a compound of formula is obtained

Alternatively, compounds of formula C, where X is hydrogen, can be prepared by reacting methylhydrazine with a carboxylic acid ester derivative of the acid XX (or a suitably protected derivative thereof).

The compounds of formula I where R is

is preferred. Most preferred are the compounds of formula I, where R is Other preferred compounds are compounds of formula I, where Ri is and Ry is 2-amino-4-thiazolyl and Ri is methyl, ethyl, carboxymethyl, 1-carboxy-1-methylethyl, 1-carboxy-1-ethyl

where s is 1, 2 or 3. The use of these preferred

Ri acyl groups lead to a product that occurs as syn- or anti-isomer or as an isomeric mixture. The syn isomers have greater activity than the anti isomers.

Example 1

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[l-[[[[3-[[(i,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl)carbonyl]-amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2 -methylpropanoic acid, disodium salt

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

69 g (3 mol) of sodium were dissolved in 5 liters of methanol. The solution was then added 425.3 g (3 mol) of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one and stirred at 30°C until a clear solution was obtained. 595 g (3.5 mol) of benzyl bromide was then added and stirred for 1 hour under reflux. The hot and very dark colored solution was poured into 15 liters of ice water. The product crystallized immediately. The crystals were filtered off and washed with 8 liters of water and then twice with 2.5 liters of ether. The product was allowed to stand overnight and was finally dried at 50°C for 16 hours. Yield: 646 g = 92.6%.

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

232 g (1 mol) of 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one was placed in a 10 liter stirring flask containing 6.6 liters of acetone and 400 ml of water. The clear solution was cooled to 5°C using an ice bath. While the temperature was maintained at 5-10°C, 640 ml of Jones reagent was added dropwise over the course of 1 hour

(202 g Cr0 3 , 600 ml water, 174 ml H 2 SCm). Stirring was continued for 2 hours without cooling, after which the reaction mixture was filtered through a glass frit and the dark green residue washed with 500 ml of acetone. The filtrate was then evaporated until all acetone was removed. To the aqueous, partially crystalline product was added 1.2 liters of methanol, and this mixture was then heated to the boiling point. The resulting clear, dark green solution was placed in an ice bath where the product was allowed to crystallize. The crystalline product was filtered off and washed with 500 ml of a cold mixture of 250 ml of methanol and 250 ml of water, and finally dried. Yield: 195 g = 79%. A further 5% of the product could be isolated from the mother liquor.

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

300 g (1.22 mol) of 4-oxo-5-(phenylmethoxy)-4H-pyran-2-carboxylic acid was placed in a flask and, while stirring, carefully added 5 liters of 33% NHtOH. The reaction mixture was then stirred under reflux and after 3 hours a further 1 liter of 33% NEU OH was slowly added. Stirring was continued for a further 2 hours under reflux. The reaction solution was then evaporated until the product crystallized. The product was returned to the reaction flask and water was added until a clear solution was formed (about 5 liters, pH 6.38). The solution was vigorously stirred while adding concentrated hydrochloric acid dropwise to pH = 3. The precipitated white product was filtered off, thoroughly washed with water and dried. Yield: 273 g (1.12 mol) = 91.8%.

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

1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid (12.26 g, 0.05 mol) and 1-amino-2-imidazolidinone (5.56 g, 0.055 mol) were suspended in 120 ml of dimethylformamide. 0.3 g of dimethylaminopyridine and 0.4 g of N-hydroxybenzotriazole were added to the suspension. After stirring for 30 minutes at room temperature, a solution of 11.35 g of dicyclohexylcarbodiimide (0.055 mol) in 50 ml of dimethylformamide was added dropwise and the mixture was stirred overnight at room temperature. The precipitate (dicyclohexylurea) was filtered off and the filtrate evaporated in vacuo. The remaining syrup crystallized on treatment with aqueous sodium bicarbonate to give 11.7 g

of the title compound, mp 158-160°C. A further fraction of 0.8 g of the product melting at 162-164°C crystallized from the aqueous filtrate.

E) 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)-2-pyridinecarboxamide

To a suspension of 12 g (0.0365 mol) of 1,4-dihydro-4-oxo-N-(2-oxo-1-imidazolidinyl)-5-(phenylmethoxy)-2-pyridinecarboxamide in 150 ml of acetonitrile was added 36 .1 ml (0.146 mol) of bis(trimethylsilyl)acetamide to give a slightly cloudy solution. After filtration, 6 g of 10% palladium on charcoal were added and hydrogen introduced through the reaction mixture while stirring. After hydrogenation for 60 minutes, the catalyst was filtered off and 15 ml of methanol and 2 ml of acetic acid were added. Stirring was continued overnight, whereupon the title compound crystallized to give 6.6 g of melting point 270-275°C.

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

To a suspension of 13.8 g of (S)-3-[[(phenylmethoxy)carbonyl]-amino]-2-azetidinone in 500 ml of ethyl acetate was added 5.63 ml (0.0626 mol) of chlorosulfonyl isocyanate. The mixture was stirred for 1 hour at room temperature to form a solution of (S)-1-[[(chlorosulfonyl)amino]carbonyl]-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The solution was cooled to 0°C and at this temperature a solution of silylated 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)-2-pyridinecarboxamide (prepared from a suspension of 14.9 g (0.0626 mol) of 1,4-dihydro-5-hydroxy-4-oxo-N-(2-oxo-1-imidazolidinyl)-2-pyridinecarboxamide in 500 ml of ethyl acetate by adding 46.4 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide (0.25 mol) and stirring for 30 minutes) slowly added. Then 150 ml of dichloromethane was added and the mixture was stirred at room temperature overnight. To the clear solution was added 26.2 ml of triethylamine (0.188 mol), followed by 300 g of ice and 200 ml of water. pH was 6.5. After stirring for 1.5 hours, the phases were separated and the aqueous phase washed with three 200 ml portions of ethyl acetate. After removal of residual ethyl acetate in vacuo, the pH of the aqueous phase was adjusted to 2 by slow addition of 2N hydrochloric acid (47 mL) with cooling. The crystals were filtered off, suspended in 200 ml of ethyl acetate and stirred for 1 hour. Then the crystals were filtered off again, washed twice with 30 ml of ethyl acetate and twice with 50 ml of petroleum ether and dried in vacuo to give 28.6 g of the title compound, melting point 190-200°C (decomp.).

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

At room temperature, 4 g (0.00713 mol) ( 3S)-[1-[ [ [ [3-[[(1,4-dihydro-5-hydroxy~4-oxo-2-pyridinyl)carbonyl]amino]- 2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester added to a mixture of 15 ml of trifluoroacetic acid and 3.5 ml of thioanisole at 10°C. The clear solution was stirred overnight at 10°C. After evaporation in vacuo at room temperature, the remaining syrup was treated with ether to give the title compound as a yellowish solid. The yield was almost quantitative.

H) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2- [[l-[[[[3-[[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxo-ethylidene]amino]oxy ]-2-methylpropanoic acid, diphenyl methyl ester

To a solution of 3.08 g (0.007 mol) (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid in 70 ml of dimethylformamide 2.9 ml (0.021 mol) of triethylamine was added and then, after cooling to -30°C under nitrogen, 1.55 ml (0.007 mol) of diphenylchlorophosphate. The mixture was stirred for 1 hour at -30°C. Then 1.95 ml of triethylamine (0.014 mol) and then 0.007 mol of (3S)-3-amino-N-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl) carbonyl]amino]-2-oxo-1-imidazolidinyl]-sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate (1:2) salt added. The reaction mixture was stirred at -10°C for 2 hours and at 0°C for 1 hour. The solvent was removed in vacuo. Treatment of the residue with water and ethyl acetate led to an insoluble product which turned into solid form on treatment with ether and gave 8.0 g of crude product.

I) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl]carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxo-ethylidene]amino]oxy ]-2-methylpropanoic acid, d inadium salt

Crude [3S (Z)]-2 - [ [[1-(2-amino-4-thiazolyl)-2-[ [ 1- [ [[[3-[[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2 -methylpropanoic acid, diphenyl methyl ester (8 g) was suspended in 15 ml of anisole. After cooling to -10°C, 80 ml of trifluoroacetic acid was added dropwise and the mixture was stirred at -10°C for 1 hour. Addition of ether at 0°C resulted in precipitation of the trifluoroacetate salt of the free acid of the product (4.1 g crude). The raw material was suspended in water, pH adjusted to 5.5 by addition of sodium bicarbonate solution and the resulting solution freeze-dried. The crude sodium salt was then purified by chromatography on HP-20<*>.<1>The product was eluted with water to give 0.52 g of product.

NMR (DMSO-de): δ = 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 (broad s, 1H).

Example 2

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

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

1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid (61.3 g, 0.25 mol) was suspended in 500 ml of dimethylformamide at room temperature and then 39.65 g (0.3 mol) N-(t-butoxycarbonyl)hydrazine, 1.5 g of dimethylaminopyridine and 2.0 g of N-hydroxybenzotriazole, after which the mixture was stirred for 30 minutes at room temperature. 57.7 g (0.28 mol) of dicyclohexylcarbodiimide

<1>HP-20: a macroreticular styrene-divinylbenzene copolymer resin from Mitsubishi Chemical Industries Ltd.

dissolved in 100 ml of dimethylformamide was then added dropwise with stirring for 30 minutes, after which the mixture was stirred at room temperature overnight. The precipitate (dicyclohexylurea) was filtered off and the filtrate evaporated in vacuo. The remaining syrup crystallized on treatment with dilute sodium bicarbonate solution. The dried crude product was recrystallized from 2 liters of ethyl acetate to give 69.5 g of the title compound melting at 173-175°C. Another fraction was obtained by evaporation of the mother liquor; 3.2 g, melting point 160-165°C.

B) 1,4-dihydro-5-hydroxy-4-oxo-2-pyridine-carboxylic acid, hydrazide

1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 2-[(1,1-dimethylethoxy)carbonyl]hydrazide (69 g, 0.191 mol) was added at 0°C to 370 mL of trifluoroacetic acid . The mixture was stirred for 1 hour at room temperature and then evaporated. The remaining syrup was treated with ether to give 68.2 g of crude 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, hydrazide, trifluoroacetate (1:2) salt as a solid.

The crude 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, hydrazide, trifluoroacetate (1:2) salt was dissolved in 250 ml of acetonitrile and stirred under cooling for 1 hour. The crystals were then filtered off and resuspended in 600 ml of acetonitrile. Bis(trimethylsilyl)acetamide (135 mL) and then 28 g of 10% palladium on charcoal were added, after which hydrogen was passed through the stirred solution. The hydrogenation was complete after 90 minutes. After filtration, 70 ml of methanol and 2 ml of acetic acid were added. After stirring overnight, crystals formed which were filtered off and constituted 19.4 g of the title compound, melting point 290-340°C (decomp.).

C) (3S)-[1-[[[[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo- 3-a Zetidinyl]carbamic acid, phenyl methyl ester

2.05 g (0 .0236 mol) chlorosulfonyl isocyanate. The mixture was stirred for 1 hour at room temperature to give a solution of (S)-1-[[(chlorosulfonyl)-amino]carbonyl]-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone. The solution was cooled to 0°C, 80 ml of dichloromethane was added and then 9.9 ml (0.0707 mol) of triethylamine and a solution of silylated 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, hydrazide ( obtained from a suspension of 3.99 g (0.0236 mol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, hydrazide in 50 ml of ethyl acetate and 8.75 ml of N-methyl-N-( trimethylsilyl)trifluoroacetamide (8.75 ml = 0.0472 mol)). The mixture was stirred at room temperature overnight, then ice water was added, whereupon stirring was continued for an additional 30 minutes. The aqueous phase was decanted with ethyl acetate and acidified to pH 2.5. The precipitate crystallized after stirring for 1 hour and gave 6.6 g of the title compound.

Evaporation of the ethyl acetate phase and treatment with petroleum ether led to a further fraction of 1.4 g of the title compound. D) (3S)-3-amino-N-[[2-(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate (1:2) salt

(3S)-[1-[[[[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3- azetidinyl]carbamic acid, phenylmethyl ester (6.6 g, 0.0133 mol) was added to a stirred mixture of 22 mL of trifluoroacetic acid and 5.3 mL of thioanisole at room temperature and stirred overnight at this temperature. The trifluoroacetic acid was removed in vacuo and the remaining syrup treated with ether to give the title compound in quantitative yield.

E) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[2-[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)carbonyl]hydrazino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]- 2- methylpropanoic acid, diphenylmethyl ester

To a solution of 5.84 g (0.0133 mol) (Z)-2-amino-oc-[ [ 2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid in 135 ml of dimethylformamide, 5.6 ml of triethylamine and (after cooling to -30°C) 3.57 g (0.0133 mol) of diphenylchlorophosphate were added. The mixture was stirred for 1 hour at -30°C and then 3.72 ml of triethylamine was added followed by 0.0133 mol of (3S)-3-amino-N-[[2-[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)-carbonyl]hydrazino]sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate (1:2) salt.

The mixture was stirred at -10°C for 2 hours and at 0°C for 1 hour, after which the solvent was removed in vacuo and the remaining syrup treated with 150 ml of ethyl acetate and 70 ml of ice water, which was then adjusted to pH 1.5- 2 by adding 2N hydrochloric acid. The insoluble material was filtered off and triturated with ether to give 5.3 g of crude product.

F) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[ [ [ [2- [ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)carbonyl]hydrazino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]-2-methylpropanoic acid, disodium salt

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

The raw material was dissolved in a mixture of 100 ml of water and

50 ml of acetone. The pH was adjusted to 5-5.5 and the acetone removed in vacuo. The remaining aqueous solution was lyophilized to give 8.1 g of crude product which was purified by HP-20 chromatography eluting with water. Chromatography gave 1.05 g of product. NNMR (DMSO-de): 5-1.40 (s, 3H); 1.42 (2.3H); 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

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2- [[l-[[[[3-[[(1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]- 2-oxo-ethylidene]amino]oxy]- 2- acetic acid, disodium salt A) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[ [1- [ [[ [3- [ [ (1,4- dihydro-5-hydroxy-4~oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]- 2- oxo - ethylidene] amino] oxy]- 2- acetic acid, diphenyl methyl ester

To a solution of 2.06 g (0.005 mol) (Z)-2-amino-α-[[2-(diphenylmethoxy)-2-oxoethoxy]imino]-4-thiazoleacetic acid in 100 ml of dimethylformamide was added 2.1 ml ((0.015 mol) of triethylamine. The mixture was cooled to -30°C and, with stirring, 1.1 ml of diphenylchlorophosphate (0.005 mol) was added. After stirring for 1 hour at -30°C, a further 1.4 ml of triethylamine (0, 1 mol) added at -30°C, followed by 2.7 g of (3S)-3-amino-N-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl )carbonyl]amino]-2-oxo-1-imidazolidinyl]-sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate (1:2) salt.

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

B) [3S(Z)]-2-[[ [1-(2-amino-4-thiazolyl)-2-[[l-[[[[3-[[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]- 2-oxo-ethylidene]amino]oxy ]- 2- acetic acid, disodium salt

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

Example 4

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[(1,4-dihydro-5-hydroxy-4-oxo- 2-pyridinyl)methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]-2-methyl-propanoic acid A) 2-(hydroxymethyl) - 5-(phenylmethoxy)-4-(1H)-pyridinone

A mixture of 2-(hydroxymethyl)-5-(phenylmethoxy)-4H-pyran-4-one (9.65 g, 41.59 mol), 95 mL of concentrated ammonium hydroxide, and 20 mL of ethanol was heated under reflux overnight,< A further 75 ml of ammonium hydroxide was added and the mixture was then refluxed for 2 hours and cooled. The resulting brown solid was filtered off and washed with water until the wash water was neutral. The crude product was suspended in ethanol, filtered, washed with ethanol and hexane and dried in vacuo. The yield of the title compound was 7.61 g.

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

A suspension of 2-(hydroxymethyl)-5-(phenylmethoxy)-4(1H)-pyridinone (3 g, 12.99 mmol) in chloroform (15 mL) was cooled to 0 °C under argon and treated with thionyl chloride (6 .1 ml, 83.62 mmol). Within a few minutes, a homogeneous solution was obtained. After stirring for a further 5 minutes, a creamy yellow solid precipitated. The cooling bath was removed and the mixture heated under reflux for 45 minutes. The mixture was cooled to 0°C and the white precipitate was filtered off, washed with chloroform and hexane and dried in vacuo. The yield of the title compound was 3.65 g.

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

A mixture of 2-(chloromethyl)-5-(phenylmethoxy)-4(1H)-pyridinone, monohydrochloride (3.59 g, 12.54 mmol), sodium azide (4.08 g,

62.7 mmol) and diisopropylethylamine (2.19 mL, 12.54 mmol) in 70 mL of dimethylformamide was stirred at room temperature under argon for 3.5 days. An additional 4.08 g of sodium azide was added and the mixture heated to 45-50°C for 2 hours. After cooling, the reaction mixture was poured into 500 ml of water, resulting in an insoluble solid. The pH of the supernatant was lowered from 8.5 to 7.5

with dilute hydrochloric acid and the white solid filtered off.

After washing with water, acetone and hexane, the solid was dried

in vacuum. The yield of the title compound was 2.81 g.

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

A mixture of 2-(azidomethyl)-5-(phenylmethoxy)-4(1H)-pyridinone (2.03 g, 7.93 mmol) and platinum oxide (200 mg) in 100 mL of dimethylformamide was stirred for 6 h at room temperature under 1

atm. hydrogen. The catalyst was filtered off and the solution concentrated in vacuo to give 1.5 g (82% yield) of the title compound as a gray powder.

E) (3S)-[1-[[[[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]methyl]amino]sulfonyl]amino]carbonyl]-2-oxo- 3-az etidinyl] carbamic acid, phenyl methyl ester

To a stirred suspension of 2-(aminomethyl)-5-(phenylmethoxy)-4(1H)-pyridinone (2.330 g, 10.13 mmol) in 60 mL of ethyl acetate was added N-methyl-N-(trimethylsilyl)trifluoroacetamide ( 3.76 ml,

20.26 mmol). The resulting solution was stirred for 30 minutes at room temperature and then cooled to 0°C. At the same time, chlorosulfonyl isocyanate (882 µl, 10.13 mmol). The resulting solution was stirred for 30 minutes at room temperature, cooled to 0°C and finally treated with triethylamine (4.23 mL 30.39 mmol) and then with the above described solution of silylated 2-(aminomethyl)-5-(phenylmethoxy) )-4(1H)-pyridinone. The mixture was stirred for 2 days at room temperature.

The mixture was concentrated in vacuo, the residue dissolved in CH 3 CN-water (40-60) and the pH lowered to 2.9, whereby a thick oil separated. On cooling to 5°C, the oil turned into solid form. The solid was separated, washed four times with water and then dried in vacuo to give 3.4 g of crude product. The crude product was dissolved in a minimal volume of dimethylformamide and applied to a column (1 liter) of HP-20 resin. The column was eluted with an acetone-water gradient. The desired material eluted with approx. 65% acetone. Relevant fractions were combined and lyophilized to give 2.69 g of the title compound.

F) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1- [ [[[[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl)methyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester (as a mixture of monopotassium and monotriethylammonium salts)

A mixture of (3S)-[1-[[[[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]methyl]amino]sulfonyl]amino]carbonyl]-2-oxo -3-azetidinyl]carbamic acid, phenylmethyl ester (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 was stirred under 1 atm. hydrogen until 3.28 mmol (73 ml) of hydrogen had been consumed (about 3 hours).

To a stirred solution of (Z)-2-amino-α-[[2-(diphenylmethyloxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (846 mg, 1.804 mmol) in 16 ml of dimethylformamide, diphenylchlorophosphate (374 µl, 1.804 mmol) and then triethylamine (450 µl, 3.28 mmol) were added at -20°C. The solution was stirred for 1 hour at -20°C, after which the above-described mixture of hydrogenolyzed (3S)-[1-[ [ [ [ t[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2- pyridinyl]methyl]-amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was added. The resulting mixture was stirred at -20°C for 1 hour and then at 5°C overnight. The catalyst was filtered off, volatile compounds removed in vacuo and the resulting oil dissolved in a minimal volume of acetone-water (75-25, pH 5.2) and added dropwise to a stirred suspension of 20 ml of Dowex 50 x 2-400<*2 >(K<+>) in acetone-water 35-65. After 40 minutes, the mixture was filtered and the filtrate lyophilized to give 2.1 g of solid. The solid was dissolved in a minimal amount of acetonitrile-water (40-60, pH 5.6) and applied to a column (800 ml) of HP-20 resin under stepwise elution with an acetonitrile-water gradient. The desired material was eluted with approx. 30% acetonitrile. Relevant fractions were combined and lyophilized to give the title compound (254) mg in crude form.

<2>styrene-divinylbenzene copolymer gel with attached -SH3 groups from Dow Chemical Company

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

Trifluoroacetic acid (4.7 mL) was added dropwise to a stirred suspension of the above-mentioned impure [3S(Z)]-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-methylpropanoic acid, diphenylmethyl ester (mixture of monopotassium and monotriethylammonium salts) (131 mg) in 3 ml of dichloromethane and 0.31 ml of anisole at 0°C. After stirring for 45 minutes at 5°C, 2 ml of toluene was added and the volatile compounds were removed in vacuo. The resulting oil was washed with hexane (3x4 mL) and triturated with 10 mL of ether to give a solid. The solid was washed once with ether (10 mL) and dried in vacuo. The above reaction and work-up was repeated with 166 mg of [ 3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[1,4-dihydro -5-hydroxy-4-oxo-2-pyridinyl)-methyl]amino]sulfonyl]amino]-carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenyl methyl ester (mixture of monopotassium and monotriethylammonium salts). The crude products were combined, dissolved in 2 ml CH 3 CN-water 40-60 (pH 2.5) and chromatographed on a column (200 ml) HP-20 resin using an acetonitrile-water gradient. The desired material was eluted by CH 3 CN-water 20-80. Relevant fractions were combined and lyophilized to give 103 mg of [3S(Z)]-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-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid as a white solid.

Example 5

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-f[1-[[[[2-[[(2-[(1,4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxo-ethylidene]amino]oxy]- 2-methylpropanoic acid, disodium salt

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

A solution of 4.54 g (0.022 mol) of dicyclohexylcarbodiimide in 25 ml of dry dimethyl formate was added to a stirred suspension of 4.90 g (0.020 mol) of 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2- pyridinecarboxylic acid, 4.50 g (0.022 mol) 4-methoxybenzylcarbamate, 0.12 g (1.0 mmol) 4-dimethylaminopyridine and 0.155 g (1.0 mmol) 1-hydroxybenzotriazole hydrate in 25 ml dry dimethylformamide at room temperature and the stirring continued overnight. The precipitate was filtered off and the filtrate evaporated in vacuo. The residue turned into a solid by stirring with ether and aqueous sodium bicarbonate, and the solid was collected, washed with water and finally dried in a vacuum. The crude material (8.14 g) was extracted in a soxhlet apparatus with 800 ml CHCl 3 (7 hours). 5.70 g (67%) of pure 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 2-[[(4-methoxyphenyl)-methoxy]carbonyl]hydrazide crystallized directly from the cold CHCl3 -extract, and a further fraction of impure title compound (1.5 g, 18%) could be obtained by evaporation of the CHCl 3 solution in vacuo; melting point 174.5-178°C.

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

A -10°C solution of 3.81 ml (35.04 mmol) anisole in 38 ml trifluoroacetic acid was added to an ice-cold suspension of 3.71 g (8.76 mmol) 1,4-dihydro-4-oxo-5 -(phenylmethoxy)-1-pyridinecarboxylic acid, 2-[[(4-methoxyphenyl)methoxy]carbonyl]hydrazide in 15 ml of dry dichloromethane. After stirring at 0°C for 20 minutes, the solution was evaporated in vacuo to leave the title compound as a solid which was stirred with a few ml of dry ether, filtered off under suction and dried in vacuo. Yield: 3.25 g (99%); melting point 173-175°C (decomp.).

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

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

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

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

Q

stirred solution of 4.57 g (0.020 mol) PhCH20CNHNHC0C1 (J. Gante, Chem. Ber. 97, 2551 (1964) in 60 ml of dichloromethane at 0-5°C. After stirring at this temperature for 2.5 hours, the solution was evaporated in vacuo and the solid foam redissolved in 20 mL methanol. Evaporation in vacuo afforded the title compound as a solid foam which crystallized upon stirring with dry ether. Yield: 8.87 g (98%); mp >120°C (decomp.).

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

A solution of 4.02 g (8.9 mmol) of 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 2-[[2-(phenylmethoxy)carbonyl]hydrazino]carbonyl]hydrazide in 50 mL of methanol containing 2.94 mL (35.6 mmol) of concentrated hydrochloric acid was hydrogenated in the presence of 0.4 g of palladium (10%) on charcoal for 10 min. The catalyst was filtered off and the solvent distilled off in vacuo, whereby

the title compound remained as a solid (2.58 g) which was stirred with a few ml of dry ether and then filtered off under suction

and dried in vacuum. Yield: 2.47 g (92%); melting point 235-236°C (decomp.).

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

4.86 ml (25.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 1.5 g (5.0 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid , 2-(hydrazinocarbonyl)-hydrazide, dihydrochloride in 20 ml of dry acetonitrile. After stirring for 45 minutes at room temperature, the clear solution was evaporated in vacuo and the residue dissolved in 20 ml of dry ethyl acetate (solution A).

0.45 ml (5, 0 mmol) of chlorosulfonyl isocyanate, and the mixture was then stirred for 1 hour at room temperature and then cooled to 0°C. After addition of 10 ml of dry dichloromethane and 2.09 ml (15.0 mmol) of triethylamine, solution A was stirred in at 0°C. After stirring overnight at 0°C, the reaction mixture was poured into ice water and the organic layer separated. Acidification of the aqueous phase to pH 2 by addition of 1N hydrochloric acid gave the title compound as a sticky precipitate which was filtered off under suction, washed with water and dried in vacuo. Yield: 1.76 g (64%).

G) (3S)-3-amino-N-[[2-[[2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl]carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl] -2-oxo-1- azetidine arboxamide, trifluoroacetate (1:2) salt

At 0°C, 1.73 g (3.1 mmol) of (3S)-[1-[ [ [ [2-[[2-[(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl)carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester added 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 stirred with dry dichloromethane. The precipitate was filtered off under suction, washed with dichloromethane and dried in vacuo to give 1.78 g (88%) of the title compound.

H) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[ [ [[2 - [ [2-[ (1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2- methyl propanoic acid, diphenyl methyl ester

In a -30° C. solution of 1.10 g (2.5 mmol) (Z)-2-amino-oc-[(2-diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4- thiazoleacetic acid in 22 ml of dry dimethylformamide, 1.05 ml (7.5 mmol) of triethylamine was added followed by 0.53 ml (2.5 mmol) of diphenylchlorophosphate. After stirring at -30°C for 1 hour, 1.05 ml (7.5 mmol) of triethylamine was added. The addition was followed by 1.62 g (2.5 mmol) of (3S)-3-amino-N-[[2-[[2-[(1,4-dihydro-5-hydroxy-4-oxo-2- pyridinyl]carbonyl]hydrazino]carbonyl]-hydrazino]sulfonyl]-2-oxo-i-azetidinecarboxamide, trifluoroacetate (1:2) salt The mixture was stirred for 2 hours at -10°C and then another 1 hour at 0°C The solvent was removed in vacuo and the residue taken up in

a few ml of ethyl acetate and ice water. The pH of the mixture was adjusted to 2 by adding dilute hydrochloric acid. The insoluble material was filtered off under suction and stirred with a few ml of ethyl acetate until it assumed crystalline form and after drying in vacuo gave 1.72 g (82%) of the title compound.

I) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[!-[[[[2-[[2-[(1,4-dihydro- 5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2- methylpropanoic acid, disodium salt

To a suspension of 1.68 g (2.0 mmol) of crude [3S(Z)]-2-[ [ [1-(2-amino-4-thiazolyl)-2-[[l-[[[[ 2-[[2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]carbonyl]hydrazino]sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl] amino]-2-oxoethylidene]-amino]oxy]-2-methylpropanoic acid, diphenyl methyl ester in 3 ml of dry dichloromethane, 2.0 ml of anisole was added, followed by 20 ml of trifluoroacetic acid at -10°C. After stirring at 0°C for 10 minutes, the solvent was removed in vacuo at 0-5°C. The residue was taken up in ice water and ether and the pH adjusted to 6.0 by adding dilute sodium hydroxide (1%). The organic phase and undissolved material (0.38 g) were separated and the aqueous phase freeze-dried

(2.66 g). The residue from the lyophilization was purified on an XAD-2<*><3>resin (elution with water) to obtain after lyophilization

0.25 g (17%) of the title compound as a colorless powder; melting point >213°C (decomp.).

Example 6

[3S - [3a (Z) , 4(3] ] -2- [ [ [1-(2-amino-4-thiazolyl)-2- [[l-[[[[2-[(l,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]-sulfonyl]amino]carbonyl]-4-methyl-2-oxo-3-azetidinyi]amino]-2-oxoethylidene]amino]oxy] - 2-methylpropionic acid, disodium salt A) (3S-trans)-[1-[[[[2-[[1,4-dihydro-4-oxo-5-hydroxy-2-pyridinyl]carbonyl]hydrazino]sulfonyl] amino]carbonyl]-4-methyl-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester

To a suspension of 2.34 g of (3S-trans)-4-methyl-2-oxo-3-azetidinyl)carbamic acid, phenyl methyl ester in 50 ml of dry ethyl acetate was added 1.41 g of chlorosulfonyl isocyanate. After stirring for 1 hour at room temperature, a clear solution 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 was added 6 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide. After stirring at 50° C. for 1 hour, a clear solution (solution B) formed.

After cooling to -10°C, solution B was added to solution A, after which the mixture was stirred overnight at room temperature. The mixture was then cooled to -15°C and 3 g of triethylamine and then 150 ml of ice water were added. After stirring for 1 hour at 0°C, the organic phase was washed with 50 ml of water. The combined aqueous phases were adjusted to pH 2 with 1N HCl and extracted three times with 100 mL ethyl acetate. The combined organic phases were dried and the solvent evaporated to give 3.64 g of the title compound.

B) (3S-trans)-3-amino-N-[[2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]-4-methyl-2 -oxo-1-azetidine carboxamide, trifluoroacetate (1:2) salt

<3>macroreticular styrene-divinylbenzene

To 3.5 g of (3S-trans)-[1-[[[[2-[[1,4-dihydro-4-oxo-5-hydroxy-2-pyridinyl]carbonyl]hydrazino]sulfonyl]amino]carbonyl] -4-methyl-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester in 20 ml of thioanisole, 50 ml of trifluoroacetic acid was added at room temperature, after which the reaction mixture was stirred for 13 hours. After adding 100 ml of ether, 3.2 g of precipitate was obtained. This crude product was then stirred for 1 hour with 50 ml of isopropanol/methylene chloride (1:1) to give 2.21 g of the title compound.

C) [3S-[3a(Z) ,43]]-2-[[[1-(2-amino-4-thiazolyl)-2-[ [1-[[ [ [2-[(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]amino]carbonyl]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy ]- 2- methylpropionic acid, diphenyl methyl ester

To a solution of 1.8 g of (Z)-2-amino-α-[[2-diphenyl-methoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid and 1.2 g of triethylamine in 2.1 g of diphenylchlorophosphate was added to 30 ml of dimethylformamide at -30°C. After stirring at -30°C for 45 minutes, 1.95 g of (3S-trans)-3-amino-N-[[2-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl )carbonyl]hydrazino]sulfonyl]-4-methyl-2-oxo-i-azetidinecarboxamide, trifluoroacetate (1:2) salt in 10 ml of dimethylformamide and then 0.8 g of triethylamine added. After stirring at -10°C for 2 hours and at 0°C for 1 hour, the dimethylformamide was removed in vacuo, and the residue was stirred with 250 ml of ethyl acetate and 400 ml of ice water. The aqueous phase was adjusted to pH 1.5 with 2N HCl and extracted twice with 200 mL portions of ethyl acetate. The organic phase was dried over sodium sulfate and evaporated to give 1.3 g of the crude title compound. D) [3S-[3a(Z),43]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[2-[(1,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]amino]carbonyl]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]- 2-methylpropionic acid,

disodium salt

To a solution of 1.2 g of [3S-[ 3a(Z) ,43]]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[2- [(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]amino]carbonyl]-4-methyl-2-oxo-3-azetidinyl]amino]-2-oxoethylidene] amino]oxy]-2-methylpropionic acid, diphenylmethyl ester in a mixture of 10 ml of methylene chloride and 15 ml of anisole, 30 ml of trifluoroacetic acid was added at -5°C. After stirring for 30 minutes, 100 ml of ether was added to give 0.8 g of precipitate. The precipitate was suspended in 20 ml of water and the pH adjusted to 6.5 with sodium bicarbonate. The clear solution was chromatographed on XAD-2 with water as eluent to give 0.28 g of pure title compound.

Example 7

[3S(Z)-1-[[[1-(2-amino-4-thiazolyl)-2-[[l-[[[[3-[[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]cyclopentanecarboxylic acid, disodium salt

A) [3S(Z)]-1-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]cyclopentanecarboxylic acid , diphenyl methyl ester

To a suspension of 3.9 g (8.3 mmol) (Z)-2-amino-α-[[[1-(diphenylmethoxy)carbonyl]cyclopentyl]oxy]imino]-4-thiazoleacetic acid in 100 ml of dry acetonitrile was 3.5 ml (25 mmol) of triethylamine was added, which gave a clear solution. After cooling to -30°C, 1.8 ml (8.3 mmol) of diphenylchlorophosphate was added, after which the mixture was stirred at -30°C for 1 hour (solution A).

At the same time, 4.5 g (8.3 mmol) of (3S)-3-amino-N-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino ]-2-oxo-1-imidazolidinyl]sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate (1:2) salt suspended in 100 ml of dry ethyl acetate. Then 7.2 ml of bis(trimethylsilyl)acetamide was added at room temperature, and within 5 minutes a clear solution was obtained. After stirring for 1 hour, the solution was cooled to 0°C (solution B).

Solution B was added dropwise to solution A at -30°C during 10 minutes with stirring. The mixture was stirred for 1 hour at -10°C and 1.5 hours at 0°C. Volatile compounds were evaporated and the residue triturated with water. The residue assumed solid form and the solid was collected and resuspended in water that held approx. pH 2. After stirring for 30 minutes, the solid was collected and dried to give 12.0 g of the crude title compound.

B) [3S(Z)]-1-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxo-ethylidene]amino]oxy ]cyclopentanecarboxylic acid, d inadium salt

Crude [3S(Z)]-1-[[[1-(2-amino-4-thiazolyl)-2-[ [1-[[ [ [3- [ [ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxo-ethylidene]amino]oxy] cyclopentanecarboxylic acid, diphenyl methyl ester (12 g) was suspended in 20 ml of anisole and after cooling to -10°C added 100 ml of trifluoroacetic acid. The mixture was stirred at -10°C for 1 hour and then 300 ml of ether was added at -10°C which led to a precipitate. After stirring for 1 hour, the precipitate was filtered off to give 5.7 g of material. This was dissolved in a mixture of 30 ml of water and 60 ml of acetone, after which the pH of the solution was adjusted to 5.5 by adding 0.1N NaOH at 0°C with stirring. The acetone was removed in vacuo and the aqueous solution freeze-dried to give 5.7 g of solid residue. The residue was chromatographed on HP-20 (elution with water) to give 1.69 g (27%) of pure title compound.

1 H NMR (DMSO-d 6 + CF 3 COOH): δ = 1.67 (s, 4H); 2.07 (2.4H); 3.65 (t, 2H); 3.75 (dd, 1H); 3.97 (dd, 1H), 4.07 (t, 2H); 5.07 (dd, 1H); 7.00 (p, 1H); 7.67 (s, 1H); 8.07 (s, 1H), ppm.

Example 8

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[l-[[[[3-[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]- 2- methylpropanoic acid, disodium salt A) 2-(azidomethyl)-5-(phenylmethoxy)-1-(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 was added 3.9 g (60 mmol ) sodium azide and 0.1 g of 18-crown-6, and the mixture was heated to the boiling point for 4 hours. The salts were filtered off under suction and the filtrate evaporated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate methanol 8:2), which gave 1.86 g of the title compound melting at 120°C.

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 minutes, and the catalyst was then filtered off under suction through Hyflo. The filtrate was evaporated in vacuo and the oily residue triturated with ether to give the crystalline title compound (0.89 g), mp 207°C.

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

To a suspension of 48.0 g (0.15 mol) 2-(aminomethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone in 1.5 liters of ethyl acetate was added 12.8 ml (0.15 mol) of 2-chloroethylisocyanate. The mixture was stirred overnight at room temperature, the product filtered off under suction, washed with ethyl acetate and dried in vacuo, whereby 59.6 g of the title compound which melted at 130°C was obtained.

D) 2-[(2-oxo-1-imidazolidinyl)methyl]-5-(phenymethoxy)-1-(phenyl-methyl)-4-(1H)-pyridinone

A solution of 7.29 g (0.13 mol) of potassium hydroxide in 500 ml of ethanol was added dropwise to a mixture of 60.8 g (0.13 mol) of 2-[[[[(2-chloroethyl)amino]carbonyl] amino]methyl]-5-(phenylmethoxy)-2-(phenylmethyl)-4-(1H)-pyridinone and 1.3 liters of ethanol. The reaction mixture was heated to the boiling point for 3 hours and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and methanol (7:3) as eluent, whereby 23.1 g of product was obtained which was further purified by recrystallization from acetonitrile to give 17.0 g of the title compound, m.p. 190°C (decomp.).

E) 5-hydroxy-2-[(2-oxo-1-imidazolidinyl)methyl]-4(1H)-pyridinone, p-toluenesulfonate salt

To a solution of 2-[(2-oxo-1-imidazolidinyl)methyl]-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone (4.98 g, 12.8 mmol)

in dimethylformamide (90 ml) was added p-toluenesulfonic acid

monohydrate (4.86 g, 25.6 mmol) and palladium on charcoal (1.0 g), after which hydrogen was bubbled through the mixture for 30 min. The catalyst was filtered off under suction and the filtrate evaporated in vacuo. The residue was triturated with dichloromethane and ether and the product filtered off under suction, whereby 4.12 g of the title compound with a melting point of 195°C were obtained.

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

5-Hydroxy-2-[(2-oxo-1-imidazolidinyl)methyl]-4(1H)-pyridinone, p-toluenesulfonate salt (4.0 g, 10.5 mmol) was dissolved in water (50 mL) and The pH was adjusted to 6.5 by adding 2N sodium hydroxide. The precipitate was filtered off under suction, washed with water and dried in vacuo, yielding 1.5 g of the title compound, melting point 280°C (decomp.).

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

1.10 g (5 mmol) of {S)-3-[t(phenylmethoxy)carbonyl]amino]-2-azetidinone was suspended in 20 ml of dry ethyl acetate and 0.44 ml (5 mmol) of chlorosulfonyl isocyanate was added. The mixture was stirred at room temperature for 1 hour (solution a).

To a solution 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 was added 3.70 ml (20 mmol) of N-methyl-N-(trimethylsilyl)-trifluoroacetamide and the mixture heated to 60°C. The resulting clear solution was evaporated in vacuo at 60°C, whereupon the residue was dissolved in 10 ml of dry ethyl acetate (solution b).

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

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

(S)-[1-[[[[3-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-methyl]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl ]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (0.50 g, 0.93 mmol) was added to a mixture of 0.5 mL of thioanisole and 2 mL of trifluoro-

acetic acid. The solution was stirred overnight at room temperature and evaporated in vacuo. The residue was triturated with ether, filtered off under suction and dried in vacuo to give 0.49 g of the title compound, mp 155°C.

I) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[ [1-[[ [ [3- [ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid , diphenyl methyl ester

To a suspension of 0.41 g (0.93 mmol) (Z)-2-amino-or-[ [ 2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid 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 hour at -30°C (solution a).

(S)-3-amino-N-[[3-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridiny1)methyl]-2-oxo-1-imidazolidinyl]sulfonyl]-2- Oxo-1-azetidinecarboxamide, trifluoroacetate salt (0.48 g, 0.93 mmol) was suspended in 20 mL of dry acetonitrile and 0.78 mL (3.2 mmol) of bistrimethylsilyl acetamide added. The suspension was stirred for 30 minutes at room temperature and then added to solution (a).

The reaction mixture was stirred for 1 hour at -10° C. and

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

J) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxo-ethylidene]amino]oxy]-2 -methylpropanoic acid, dina triium salt

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[!-[[[[3-[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl)methyl]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxo-ethylidene]amino]oxy]-2-methylpropanoic acid , diphenyl methyl ester (0.7 g, 0.85 mmol) was suspended in 1.4 mL of anisole and cooled to -10°C. Trifluoroacetic acid was added and the solution was stirred for 1 hour at -10°C. Ether (100 ml) was added and the precipitate was filtered off under suction, washed with ether and dried in vacuo.

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

Example 9

[3S(Z)]-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-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]- 2 - methyl propanoic acid, disodium salt 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 was cooled to 0°C and 4.65 ml (64 mmol) thionyl chloride added dropwise. The mixture was stirred for 10 minutes at 0°C and then heated to reflux for 1 hour. The solvent was evaporated in vacuo and the residue washed with petroleum ether and dried in vacuo to give 3.66 g of the title compound, mp 85°C (decomp.).

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

2-(Chloromethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone hydrochloride (3.5 g, 9.3 mmol) was dissolved in a mixture of water/ethyl acetate and the layers separated. The organic phase was washed twice with water, dried over magnesium sulfate and evaporated in vacuo. The residue was rubbed with petroleum ether, filtered off below

suction and dried in vacuo to give 2.27 g of the title compound, mp 115-120°C (decomp.).

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

A mixture of 2,3-piperazinedione (11.4 g, 100 mmol), bistrimethylsilylacetamide (55.7 g, 270 mmol) and 150 mL of acetonitrile was heated under reflux for 1 hour. Over 30 minutes, triphenylmethyl chloride (22.2 g, 80 mmol) was added dropwise, after which the mixture was again refluxed for 2 hours. 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 concentrated in vacuo. The residue was triturated with water and dried to give 25.5 g of crude title compound which was recrystallized from ethanol. Yield of pure product: 12.19 g, melting point 230-235°C.

D) 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-4-(triphenylmethyl)-2, 3- piperazinedione

To a solution of N-(triphenylmethyl)piperazine-2,3-dione (4.19 g, 11.77 mmol) in 95 ml of dry dimethylformamide was added 0.35 g (11.77 mmol) of sodium hydride (80% oil ). After hydrogen evolution had ceased, a solution of 2-(chloromethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)-pyridinone (4.0 g, 11.77 mmol) in 25 mL of dry dimethylformamide added to the thick suspension which then turned into a clear solution. After 1 hour of stirring at room temperature, precipitation began. After 2 hours, the crystals were filtered off, washed and dried in vacuum, whereby 5.13 g of the title compound with melting point 165-168°C were obtained.

E) 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridiny1] methyl]- 2, 3- piperazinedione

To a solution of 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-4-(triphenylmethyl)-2,3-piperazinedione (8 .77 g, 13.23 mmol) in 65 ml of dichloromethane, 65 ml of formic acid was added dropwise at room temperature. After stirring for 3 days, volatile compounds were distilled off in vacuo and the residue triturated twice with ether to give 5.24 g of 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl) -2-pyridinyl]-methyl]-2,3-piperazinedione, melting point 260-265°C.

F) (S)-[1-[[[[4-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-2,3- dioxo-1-piperazinyl]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester

To a solution of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (0.44 g, 2.0 mmol) in 25 ml of dry ethyl acetate was added 0.28 g (2.0 mmol) of chlorosulfonyl isocyanate and the solution was stirred for 30 minutes at room temperature. To it was then added 12 ml of dichloromethane, 0.61 g (6 mmol) of triethylamine and a previously stirred (3 h) mixture of 1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-1- (phenylmethyl)-2-pyridiny1]methyl]-2,3-piperazinedione (0.83 g, 2.0 mmol) and N-methyl-N-(trimethylsilyl)trifluoroacetamide (1.59 g, 8.0 mmol) in 25 ml dry ethyl acetate. After stirring for 3 days at room temperature, ice water was added and the pH adjusted to 1 with hydrochloric acid. The insoluble residue was filtered off and dried in vacuo to give 1.15 g of the title compound in 72% purity.

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

To a solution of (S)-[1-[[[[4-[ [1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinyl]methyl]-2, 3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (0.98 g, 1.32 mmol) in 20 ml of dimethylformamide was added 0.5 g ( 2.64 mmol) p-toluenesulfonic acid and 0.5 g palladium on charcoal (10%). Hydrogen was then bubbled through the mixture for 1 hour. The catalyst was filtered off, the solvent distilled off in vacuo and the residue triturated with dichloromethane to give, after drying, 0.82 g of the title compound, mp 160-185°C (decomp.).

H) [3S(Z)]-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-azetidinyl]amino]-2-oxoethylidene]-amino]oxy]- 2 - methylpropanoic acid, diphenyl methyl ester

To a solution of (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (0.57 g, 1.3 mmol)

triethylamine (0.39 g, 3.9 mmol) and triphenylchlorophosphate (0.31 g, 1.3 mmol) were added to 30 ml of dimethylformamide at -30° C. After stirring for 1 hour, triethylamine (0.39 g, 3.9 mmol) and

(S)-3-amino-N-[[4-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-methyl]-2,3-dioxo-1-piperazinyl]sulfonyl] -2-oxo-1-azetidinecarboxamide, 4-methylbenzenesulfonic acid salt (0.98 g, 1.3 mmol) added. The mixture was stirred for 2 hours at -10°C and for 1.5 hours at 0°C. Water and ethyl acetate were added and the pH was brought to 1 with 3N hydrochloric acid. The precipitate was filtered off, washed with ethyl acetate and dried in vacuo, whereby 0.86 g of the title compound, with a melting point of 130-190°C (decomp.) was obtained.

I) [3S(Z)]-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-azetidinyl]amino]-2-oxoethylidene]amino]oxy]- 2 - methylpropanoic acid, disodium salt

To a suspension of [ 3S (Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[l-[[[[4-[(i,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl)methyl]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]- 2-Methylpropanoic acid, diphenylmethyl ester (0.8 g, 0.94 mmol) in 1.4 ml of anisole, 7 ml of trifluoroacetic acid was added at -10°C. After stirring for 1 hour, 30 ml of ether was added and the resulting precipitate was filtered off and dried in vacuo. The trifluoroacetic acid salt was suspended in water and the pH adjusted to 6.5 with 2N sodium hydroxide. Freeze drying of the solution gave 0.66 g of crude product which was chromatographed together with a new portion of sample prepared in the same manner (total 1.55 g) on macroreticular styrene-divinylbenzene copolymer under MPLC conditions, whereby 0.34 g of the title compound was obtained. A second round of column chromatography on macroreticular styrene-divinylbenzene copolymer gave 0.18 g of the title compound, mp 242-270°C.

Example 10

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl)methylene]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2- methylpropanoic acid, disodium salt

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

21.5 g (156 mmol) of potassium carbonate was added to a suspension of 29.4 g (120 mmol) of O-benzylcomenamic acid in 350 ml of dimethylformamide and stirred for 1 hour at room temperature. Benzyl bromide (31 ml,

264 mmol) was added and the mixture was heated to 100°C with stirring for 25 hours. After cooling to room temperature, the dimethylformamide was distilled off in vacuo and the residue triturated with ethyl acetate while briefly heating to 60°C. 40 g of inorganic salts were filtered off, the filtrate concentrated to approx. 75 ml and chromatographed on silica gel with ethyl acetate:petroleum ether (90:10) as eluent, whereby 35.5 g of the title compound, with a melting point of 116.7°C, were obtained.

B) 4,5-bis(phenylmethoxy)-2-pyridinemethanoi

To a suspension of 95 mg (25 mmol) of lithium aluminum hydride in 10 ml of ether and 10 ml of tetrahydrofuran was added 1.06 g (25 mmol) of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, phenyl methyl ester in three portions at 0° C. After stirring for 20 minutes at 0°C, 0.2 ml of saturated sodium bicarbonate solution, 0.2 ml of 10% potassium hydroxide solution and more saturated sodium bicarbonate solution were added until the inorganic precipitate clumped together. The clear organic phase was decanted and evaporated in vacuo to give an oil which slowly crystallized. Dividend:

0.6 g, melting point 96.6°C.

C) 4 f 5-bis(phenylmethoxy)-2-pyridinecarboxaldehyde

To a solution of 0.54 g (1.7 mmol) of 4,5-bis(phenylmethoxy)-2-pyridinemethanol in 15 ml of acetone was added 1.5 mg (17 mmol) of manganese dioxide and the mixture was stirred overnight at room temperature . The mixture was then filtered over a silica gel column (70-250 mesh) and the aldehyde eluted with acetone. Evaporation of the eluate and trituration of the residue with petroleum ether gave 0.3 g of the title compound, mp 104.3°C.

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

To a solution of 4,5-bis(phenylmethoxy)-2-pyridinecarboxaldehyde (1.9 g, 6.0 mmol) in 25 ml of dry dimethylformamide was added 0.2 g of palladium on charcoal catalyst, after which hydrogen was bubbled through the mixture for 3 hours. The catalyst was filtered off, the solvent distilled off in vacuo and the residue triturated with ether to give 0.64 g of the title compound, mp 174-177°C (decomp.). E) [3S (Z)]-2- [ [[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)methylene]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy] -2-methylpropanoic acid,

disodium salt

To a solution of [3S (Z)]-2-[[[2-[[I-[[[(3-amino-2-oxo-1-imidazolidinyl)sulfonyl]amino]carbonyl]-2-oxo-3 -azetidinyl]-amino]-1-(2-amino-4-thiazolyl)-2-oxoethylidene]amino]oxy]-2-propanoic acid, monosodium salt (0.64 g, 1.1 mmol) in 15 mL of dry dimethylformamide was 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxaldehyde (0.18 g, 1.3 mmol) was added, and after stirring for 4.5 h, a further 0.02 g (0.14 mmol ) of 4 added. After stirring overnight at room temperature, the solvent was evaporated in vacuo, the residue taken up in 30 ml of water and filtered, after which the solution was freeze-dried. The raw material (0.82 g) was dissolved in 5 ml of water and chromatographed on macroreticular styrene-divinylbenzene copolymer resin with water as eluent, whereby 0.22 g of pure product, melting point 248°C (decomp.) was obtained.

Example 11

[3S (Z)]-2- [ [ [1-(2-amino-4-thiazolyl)-2-[[1-[[[[4-[[(1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl)carbonyl]amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2- oxoethylidene]amino]oxy]- 2 - methylpropanoic acid, disodium salt A) 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid

16 ml of water and 35 ml of 1N potassium hydroxide were added to a solution of 11.8 g (28 mmol) of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid, phenylmethyl ester in 115 ml of tetrahydrofuran. After stirring overnight at room temperature, 115 ml of water was added and the pH adjusted to 2.5 with 1N hydrochloric acid. The acid was filtered off, washed with water and dried in vacuo to give 8.6 g of the title compound, mp 203.6°C.

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

To a suspension of 4,5-bis(phenylmethoxy)-2-pyridinecarboxylic acid (7.1 g, 21.17 mmol), hydroxybenzotriazole (0.29 g, 2.12 mmol) and N-aminopiperazine-2,3-dione (2.73 g, 21.17 mmol) in 140 ml of dry dimethylformamide, after 15 minutes of stirring, 4.80 g (23.3 mmol) of dicyclohexylcarbodiimide was added. After stirring for 21 hours at room temperature, dicyclohexylurea was filtered off (4.0 g) and the solvent evaporated in vacuo. The solid residue was triturated for 40 minutes with 240 ml of tetrahydrofuran, filtered, washed with tetrahydrofuran and dried in vacuo to give 7.76 g of the title compound, mp 231.1°C.

C) (S)-[1-[[[[4-[[[4,5-bis(phenylmethoxy)-2-pyridinyl]carbonyl]-amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino ]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenyl methyl ester

To a suspension of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (2.02 g, 9.18 mmol) in 130 ml of ethyl acetate was added chlorosulfonyl isocyanate (1.43 g, 10 mmol ) and after stirring for 1 hour, triethylamine (279 g, 27.54 mmol) at 0°C. To the mixture was added a previously stirred solution of (1.5 h) N-(2,3-dioxo-1-piperazinyl)-4,5-bis(phenylmethoxy)-2-pyridinecarboxamide (4.10 g, 9.18 mmol) and N-methyl-N-(trimethylsilyl)trifluoroacetamide (5.4 g, 27.54 mmol) in 150 mL ethyl acetate added. After stirring overnight at room temperature, 220 ml of ice water was added and the pK was adjusted to 2 (from 10.3) with 3N hydrochloric acid. When treating the separated organic phase with salt water, the title compound is precipitated. It was filtered off, washed with water and dried in vacuo and amounted to 5.35 g. After rubbing 2.5 g of the material for 1 hour 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 obtained.

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

To a solution of (S)-[ 1-[[[[4-[[[4,5-bis(phenylmethoxy)-2-pyridinyl]carbonyl]amino]-2,3-dioxo-1-piperazinyl]sulfonyl] - amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (1.54 g, 2 mmol) in 30 ml of dimethylformamide, 0.77 g of palladium on charcoal was added and the mixture was hydrogenolyzed for 45 minutes. The catalyst was filtered off over Hyflo and the resulting solution used in the next step without isolation of the title compound.

E) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2 - [[!-[[[[4-[[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)carbonyl]amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy ]-2-methylpropanoic acid, diphenyl methyl ester

To a solution of (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (0.88 g, 2.0 mmol)

triethylamine (0.60 g,

6.0 mmol) and at -30°C under nitrogen, triphenylchlorophosphate (0.54 g, 2.0 mmol). After stirring for 1 hour at -30°C, triethylamine (0.20 g, 2 mmol) and the dimethylformamide solution of (S)-N-[4-[[[(3-amino-2-oxo-1-azetidinyl) carbonyl]amino]sulfonyl]-2,3-dioxo-1-piperazinyl]-1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide added dropwise. The mixture was stirred for 2 hours at -10°C and for 17 hours at 0°C. The solvent was distilled off under vacuum and the residue distributed between 40 ml of ethyl acetate and 20 ml of ice water. On adjusting the pH to 1.5 with dilute hydrochloric acid, an oil separated from the solvent and dried in vacuo yielded 1.35 g of the title compound.

F) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[ [1- [ [ [ [4- [[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)carbonyl]amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxo-ethylidene]amino ]oxy]-2-methylpropanoic acid, disodium salt

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2- [ [1- [ [ [ [4- [ [ (1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2,3-dioxo-1-piperazinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl ] -amino]-2-oxo-ethylidene]amino]oxy]-2-methylpropanoic acid, diphenyl methyl ester (1.3 g, 1.48 mmol) added at -10°C and the mixture stirred for 2 hours at 0°C. The volatile compounds were distilled off in vacuo and the residue triturated with ether, whereby after drying 1.0 g of trifluoroacetic acid salt was obtained. The trifluoroacetic acid salt was suspended in 20 ml of water and pH adjusted to 6.5 with 1N sodium hydroxide. The freeze-dried solution gave 1.10 g of crude product which was chromatographed on a macroreticular styrene-divinylbenzene copolymer under MPLC conditions with water as eluent. Yield: 0.48 g. This material was chromatographed twice more along with other similarly prepared samples. Column chromatography no. 2 was carried out on macroreticular styrene-divinylbenzene copolymer and the 3rd on Organogen, in both cases with water as eluent. Final yield 0.10 g, melting point >300°C.

Example 12

[3S(Z)]-3-[[(2-amino-4-thiazolyl)[(2-fluoroethoxy)imino]acetyl]-amino]-N-[[3-[[(1,4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl)-carbonyl]amino]-2-oxo-l-imidazolidinyl]sulfonyl]-2-oxo-l-azetylcarboxamide, ethyldiisopropylamine salt

N-hydroxybenzotriazole (0 .19 g, 1.4 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 stirred for 1 hour. A solution of (3S)-3-amino-N-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazoiidinyl ]sulfonyl]-2-oxo-1-azetidinecarboxamide, trifluoroacetate (1:2) salt (0.87 g, 1.6 mmol; see Example 1G) and N-ethyldiisopropylamine (0.41 g, 3.2 mmol) in 3 ml of dry dimethylformamide added and after stirring for 2 hours at 0°C, the mixture was stirred for a further 16 hours at room temperature. Dicyclohexylurea was filtered off and the solvent distilled off in vacuo. The remaining oil was triturated with water until complete crystallization. The solvent (0.82 g) was filtered off, the filtrate brought to pH 6.1 and freeze-dried. The solid was suspended in 40 ml of water and the pH adjusted to 6.0 with 0.25N sodium hydroxide. Undissolved material was filtered off and the filtrate freeze-dried. Two portions of freeze-dried material were combined (approx. 0.6 g) and chromatographed on macroreticular styrene-divinylbenzene copolymer with water and water:acetonitrile (95:5) as eluent. After freeze-drying, the relevant fractions gave 0.22 g of the title compound with a melting point of 163-165°C.

Example 13

[3S(Z)]-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- methylpropanoic acid, trisodium salt A) N,O-dibenzylcomenamyl chloride, hydrochloride

In a suspension of 16.77 g (50.0 mmol) of N,O-dibenzylcomeneamic acid in 360 ml of dry dichloromethane, 11.45 g (55.0 mmol) of phosphorus pentachloride were added in portions at 0-5°C. The stirring continued for one hour at room temperature, after which the precipitate was collected under suction, washed with 20 ml of dry dichloromethane and dried in vacuum. 15.02 g of the title compound were then obtained, melting point 126-127°C (decomp.).

B) [2-[(phenylmethoxy)carbonyl]hydrazino]acetic acid, 1, 1- dimethyl ethyl ester

To a stirred solution of 6.65 g (0.040 mol) of N-[(phenylmethoxy)carbonyl] hydrazine in 40 ml of dimethylformamide was added dropwise a solution of 8.58 g (0.044 mol) of t-butylbromoacetate in 20 ml of dimethylformamide followed by a solution of 8.2 ml (0.048 mol) of N,N-diisopropylethylamine in 8 ml of dimethylformamide. After the mixture had been stirred at room temperature for 1 day, the solvent was distilled off in vacuo and the residue taken up in ether and water. The organic layer was washed three times with water, dried (magnesium sulfate) and evaporated in vacuo, whereupon the remaining oil (10.6 g) was purified by column chromatography on silica gel eluting with ethyl acetate/toluene (1:1). The relevant fractions were evaporated in vacuo and the residue stirred with petroleum ether, whereby 6.0 g of the title compound, melting point 61-62°C, were obtained.

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

15.6 ml (80.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a solution of 11.2 g (40.0 mmol) of [2-[(phenylmethoxy)carbonyl]hydrazino]acetic acid, 1,1- dimethyl ethyl ester in 60 ml of dry acetonitrile. After stirring for 30 minutes at room temperature, the clear solution was evaporated in vacuo and the residue dissolved in 45 ml of dry dichloromethane. The solution was dropped into a suspension of 15.61 g of N,O-dibenzyl-comenamyl-

chloride, hydrochloride in 60 ml of dry dichloromethane at room temperature. After stirring overnight, the reaction mixture was evaporated in vacuo. The residue was stirred with 10 ml of methanol, evaporated in vacuo again and then chromatographed on silica gel eluting with ethyl acetate and ethyl acetate/methanol (10:1). After evaporation in vacuo, the relevant fractions gave a solid foam which became crystalline on stirring with ether. Yield: 12.7 g; melting point 177-178° C (decomp.) .

D) [1-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-hydrazino] acetic acid, 1, 1- dimethylethyl ester

A suspension of 7.17 g (12.0 mmol) [1-[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]-2[(phenylmethoxy)carbonyl]-hydrazino ]acetic acid, 1,1-dimethylethyl ester in 400 ml of methanol was hydrogenated in the presence of 1.6 g of palladium on charcoal (10%) for 40 minutes. The catalyst and the precipitated product were filtered off and washed thoroughly with 300 ml of dry dimethylformamide to dissolve the precipitated product. From the combined filtrates, the solvents were removed in vacuo, whereupon the residue was crystallized while stirring with ether (1.68 g; melting point 221°C, decomp.). Recrystallization from methanol gave the pure compound. Yield: 1.26 g; melting point 225°C, sintering 229°C (decomp.).

E) (3S)-[1-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-carbonyl]-2-[[[[2-oxo-3-[[(phenylmethoxy) carbonyl]amino]-1-azetidinyl]carbonyl]amino]sulfonyl]hydrazino]acetic acid, i, 1-dimethylethyl ester

9.0 ml (46.2 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 3.2 g (11.0 mmol) [1-[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl)carbonyl]hydrazino]acetic acid, 1,1-dimethylethyl ester in 120 ml of dry ethyl acetate. Stirring was continued for 1 hour at room temperature to give a clear solution (solution A).

To a suspension of 2.42 g (11.0 mmol) (S)-3-[[(phenylmethoxy)carbonyl ] amino]-2-azetidinone in 80 ml of dry ethyl acetate was added 0.99 ml (11.0 mmol) of chlorosulfonyl isocyanate added while stirring. The mixture was stirred for 1 hour at room temperature and then cooled to 0°C. Solution A was added dropwise at 0°C and stirring continued overnight at room temperature. After adding 4 ml of triethylamine, the mixture was evaporated in vacuo. The residue was dissolved in 10 ml of methanol-water (4:1). This solution was dropped into a mixture of 30 ml of methanol/water maintained at pH 2 to give a residue (10.25 g) which crystallized on stirring with a few ml of water and methanol. The precipitate was purified by successive washing (stirring) with isopropanol/water (4:1), methanol, methanol/ether (1:1) and ether. Yield after drying in vacuum: 2.39 g.

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

At 0°C, 2.39 g (3.9 mmol) of (3S)-[1-[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]-2-[[[ [2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]amino]sulfonyl]-hydrazino]acetic acid, 1,1-dimethylethyl ester added to a mixture of 7.0 ml of trifluoroacetic acid and 1, 66 ml of thioanisole. After stirring overnight at room temperature, the solution was evaporated in vacuo. The residue was successively washed (stirred) with ethyl acetate, ethyl acetate/petroleum ether (1:1), petroleum ether and dichloromethane and then dried in vacuo. The crude salt was used in the next step without any further purification. Yield 2.15 g.

G) [3S(Z)]-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-oxo- ethylidenej amino]oxy]- 2- methyl propanoic acid, diphenyl methyl ester

0.70 ml (3.24 mmol) of diphenylchlorophosphate was dropped into a -30°C cold mixture of 1.42 g (3.24 mmol) of (Z)-2-amino-α-[[2-(diphenylImethoxy) -1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid and 1.81 ml (12.96 mmol) of triethylamine in 30 ml of dry acetonitrile (solution A).

3.27 mL (12.96 mmol) of bistrimethylsilylacetamide was added

to a suspension of 2.13 g (ca. 3.3 mmol) of crude (S)-3-amino-1-[[ [[2-(carboxymethyl)-2-[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-azetidinone, trifluoroacetate salt in 30 ml of dry ethyl acetate at room temperature. After stirring for 1 hour, the clear solution was cooled and dropped into the -30°C cold solution A. The mixture was stirred for 1 hour at -10°C and then for an additional 1.5 hours at 0°C, after which it was evaporating vacuum. The residue was stirred with a few

ml of water that had been adjusted to pH 2 by adding dilute hydrochloric acid. The precipitate was filtered off, washed with water, redissolved in water/acetone at pH 5.5-6.0 (addition of dilute sodium hydroxide) and purified by MPLC on macroreticular styrene-divinylbenzene copolymer eluting with a water-methanol gradient (0 -100%). Freeze drying of the appropriate fractions gave 270 mg of the purified product. A suspension of the salt in a few ml of cold water was acidified with dilute hydrochloric acid to pH 2 to precipitate the free acid which was then filtered off under suction and dried in vacuo; yield 0.19 g; melting point >180°C (decomp.). H) [3S(Z)]-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-oxo-ethylidene]amino]oxy]-2- methylpropanoic acid,

trifluoroacetic acid salt

0.17 g (0.2 mmol) [ 3S(Z)]-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-oxo-ethylidene] amino]oxy]-2-methylpropanoic acid, diphenyl methyl ester was slowly added to a -10°C cold, stirred solution of 0.62 ml (8.0 mmol) trifluoroacetic acid and 0.087 ml (0.8 mmol) thioanisole. Stirring was continued for 15 minutes at 0°C. The suspension was evaporated in vacuo at 0-5°C and the residue stirred with dry ether, filtered off under suction, washed with dry ether and dried in vacuum, whereby 0.14 g; m.p. >230°C (decomp.) was obtained.

I) [3S(Z)]-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-oxo-ethylidene]amino]oxy]- 2- methylpropanoic acid, trisodium salt

115 mg (0.146 mmol) [3S(Z)]-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 -methylpropanoic acid, trifluoroacetic acid salt was suspended in 1.5 ml of water and pH adjusted to 5.5 by dropwise addition of dilute sodium hydroxide. The solution was passed through two columns containing, respectively, macroreticular styrene-divinylbenzene copolymer (0.05-

0.1 mm) and cross-linked dextran gel (25-100 µm) while eluting with water. Appropriate fractions were combined and lyophilized to give 100 mg of the title compound.

Example 14

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl)acetyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2- methylpropanoic acid,

disodium salt

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

3.9 g (60 mmol) potassium cyanide and 0.1 g 18-crown-6; whereupon the mixture was heated to the boiling point for 2.5 hours. The salts were filtered off under suction and the filtrate evaporated in

vacuum. The resulting residue was purified by column chromatography on silica gel using ethyl acetate/methanol (8:2) as eluent; which gave 0.55 g of the title compound, mp 175-180°C.

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

A mixture of 2.45 g (7.16 mmol) of 2-(cyanomethyl)-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)pyridinone and 40 ml of concentrated hydrochloric acid (37%) was stirred for 4 hours at 70°C and then evaporated in vacuo. The residue was suspended in 15 ml of ice-cold water and the pK adjusted to 2.0 by the addition of 5N sodium hydroxide. The precipitate was filtered off, washed with ice water and ether and dried in vacuo (1.71 g). The crude acid was dissolved in 20 ml of 0.5N sodium hydroxide, precipitated again by acidification (pH 1.8) with 2N hydrochloric acid, filtered off under 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)-1-(phenylmethyl)-2-pyridineacetamide

4.99 ml (35.83 mmol) of triethylamine was added to a suspension of 9.29 g (35.83 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-1-(phenylmethyl)-2-pyridineacetic acid , 0.28 g (1.79 mmol) 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 evaporated in vacuo to a residue which became crystalline on stirring with 110 ml of dichloromethane. The precipitate was filtered off under suction and dried in vacuum. To a suspension of this raw material in 65 ml of dry acetonitrile was added 14.0 ml (71.6 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide. After stirring for 30 minutes at room temperature, the undissolved dicyclohexylurea was filtered off and the filtrate evaporated in vacuo. The oily residue was boiled in 70 ml of methanol for 15 minutes and then cooled. The precipitate was filtered off under suction, washed successively with methanol, methanol/ether (1:1) and ether and dried in vacuum. Yield: 8.7 g; sintering at 242°C, melting point 260-265°C (decomp.)

D) (S)-[1-[[[[3-[[[1,4-dihydro-5-hydroxy-4-oxo-1-(phenyl-methyl)-2-pyridiny1]acetyl]amino]-2 -oxo-1-imidazolidinyl]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenyime tyleste r_, monosodium salt

5.86 ml (30.0 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide was added to a suspension of 3.42 g (10.0 mmol) of 1,4-dihydro-5-hydroxy-4-oxo-N-( 2-oxo-1-imidazolidinyl)-1-(phenylmethyl)-2-pyridineacetamide in 50 ml of dry ethyl acetate and the stirring continued for 1 hour at room temperature (solution A).

From a solution of 2.20 g (10.0 mmol) of (S)-3-[[(phenylmethoxy ) carbonyl ] amino]-2-azetidinone in 50 ml of dry ethyl acetate, 0.90 ml (10.0 mmol) chlorosulfonyl isocyanate added with stirring and the mixture was stirred for 1 hour at room temperature and then cooled to 0°C. Solution A was added dropwise with stirring at 0°C. After stirring overnight at room temperature, the mixture was evaporated in vacuo and the residue taken up in a few ml of methanol and water. The pH was adjusted to 5.5 by adding dilute sodium hydroxide and the filtered solution was then freeze-dried. MPLC on macroreticular styrene-divinylbenzene copolymer eluting with water/acetone (8:1) and freeze-drying relevant pure fractions gave 0.40 g of the title compound. The impure fractions were purified by repeated 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- 5-Hydroxy-4-oxo-2- pyridineacet amide, trifluoroacetate salt

A solution of 0.90 g (1.3 mmol) of (S)-[1-[ [ [ [ 3-[[[1,4-dihydro-5-hydroxy-4-oxo-1-(phenylmethyl)-2 -pyridiny1]acetyl]-amino]-2-oxo-i-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyi]carbamic acid, phenylmethyl ester, monosodium salt in 13 ml of dry dimethylformamide containing 0.50 ml (6, 5 mmol) of trifluoroacetic acid was hydrogenated in the presence of 0.15 g of palladium on charcoal (10%) for 20 minutes. The catalyst was filtered off and washed with a few ml of dimethylformamide. Evaporation of the filtrate in vacuo gave an oily residue which became crystalline on stirring with a few ml of ethyl acetate. Yield: 0.675 g; melting point >150°C (decomp.)

Simple stirring of this crude title compound in dry ethyl acetate for 1 hour followed by filtration, washing with ethyl acetate and drying in vacuo improved the purity; yield: 80%, melting point

>165° C (decomp.) .

F) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)acetyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxo-ethylidene]amino]oxy ]-2-methylpropanoic acid, diphenylmethyl ester

1.1 ml (4.45 mmol) of bistrimethylsilylacetamide was added to a suspension of 0.75 g (1.35 mmol) of (S)-N-[3-[[[(3-amino-2-oxo-1- azetidinyl)carbonyl]amino]sulfonyl]-2-oxo-1-imidazolidinyl]-1,4-dihydro-5-hydroxy-4-oxo-2-pyridineacetamide, trifluoroacetate salt in 12 ml of dry ethyl acetate. After stirring for 1 hour at room temperature, the clear solution was evaporated in vacuo and the oily residue dissolved in 12 ml of dry ethyl acetate (solution

A).

To a -30°C cold suspension of 0.60 g (1.35 mmol) (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]- 4-thiazoleacetic acid in 12 ml of dry acetonitrile, 0.57 ml (5.4 mmol) of triethylamine and then 0.29 ml (1.35 mmol) of diphenylchlorophosphate were added. Stirring was continued for 1 hour at -30°C and for a further 1 hour at 0°C. The solvent was removed in vacuo and the residue precipitated by stirring with a few ml of water (0°C). The precipitate was filtered off under suction, washed with cold water, suspended in water at pH 2 (addition of a few drops of dilute hydrochloric acid), filtered off, washed successively with water, methanol and ether and dried in vacuo. Yield: 1.07 g; melting point

>180°C (decomp.). This raw material was used in the next step without further purification.

G) [3S(Z)j-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3 - [ [ (1, 4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)acetyl]amino]-2-oxo-l-imidazolidinyl] sulfonyl] amino] carbonyl] - 2-oxo-3-azetidi nyt-arn ino]-2-oxoethylidene] am i no] ok sy]-2-methylpropanoic acid, disodium salt

1.01 g (1.17 mmol) crude [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[l-[[[[3-[[( 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)acetyl]-amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]- 2-Oxoethylidene]amino]oxy]-2-methylpropanoic acid, diphenylmethyl ester was added to a -10°C solution of 2.0 ml of anisole in 10 ml of trifluoroacetic acid. After stirring for 20 minutes at -10°C, the solvent was removed in vacuo at +10°C. The residue was stirred with a few ml of dichloromethane, filtered off, stirred once more with a few ml of dichloromethane, filtered off under suction, washed with hexane and dried in vacuo. The crude product (1.06 g) was suspended in a few ml of water/acetonitrile and then dissolved by adjusting the pH to 6.0 by adding 1N sodium hydroxide. After concentration in vacuo, the aqueous solution was chromatographed (MPLC) on macroreticular styrene-divinylbenzene copolymer eluting with water. Appropriate fractions were combined and freeze-dried. Yield: 0.10 g, melting point >255°C.

Example 15

[3S(Z)]-2- [ [[1-(2-amino-4-thiazolyl)-2-[[1-[[[[3-[[3-(1,4-dihydro-5-hydroxy -4-oxo-2-pyridinyl)-1-oxo-2-propenyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2- oxoethylidene]amino]oxy]-2-methylpropanoic acid, di sodium salt

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

9.0 g of 2-(hydroxymethyl)-5-(phenylmethoxy)-4(1H)-pyridinone and 26 g of manganese dioxide (activated) were stirred overnight at room temperature in 100 ml of methanol. Crystals of the product formed below. After boiling the reaction mixture for 10 minutes and subsequent hot filtration through Hyflo, washing the filter cake with two portions of 50 ml of boiling methanol, the combined filtrates were evaporated and the residue stirred with 50 ml of ethyl acetate. White crystals of the product formed. Yield: 9.7 g, melting point 156°C (decomp.).

B) 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridiny1]-2-propenoic acid, ethyl ester

0.5 g of p-toluenesulfonic acid, 6.26 g of 2-(1-hydroxy-1-methoxy-methyl)-5-(phenylmethoxy)-4(1H)-pyridinone and 8.35 g of carbethoxy-methylenetriphenylphosphorane were stirred in 100 ml of dioxane at 70°C for 3 hours. A clear, dark colored solution resulted. Evaporation of the solvent in vacuo gave an oily residue of the title compound and triphenylphosphine oxide. The residue was dissolved in 30 ml of isopropanol, whereby separation of product crystals started. After standing in a refrigerator overnight, the crystals were filtered off, washed with ether and recrystallized from isopropanol. Yield: 5.72 g, melting point 188°C.

C) 3-[1,4~dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid

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

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

3 - [1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid (10.85 g), 1 g of N-hydroxybenzotriazole, 0.01 g of N,N-dimethylaminopyridine and 8.24 g of dicyclohexylcarbodiimide was stirred for 30 minutes in 100 ml of dimethylformamide. After cooling to 0°C, 4 g of N-aminoimidazolidinone were added and stirring continued for 1 hour at 0°C and 10 hours at room temperature. The resulting suspension was then heated to 60°C and filtered. The filter cake is again suspended in 50 ml of dimethylformamide and heated to 60°C and filtered again. The combined filtrates were evaporated at 40°C (oil pump 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.

12.3 g of solid was obtained after drying. It was stirred together with 80 g of p-toluenesulfonic acid in 100 ml of dichloromethane for 1 hour. Filtration afforded 12.98 g of a white solid. This material was suspended in water. Recrystallization from water/dimethylformamide gave 8.49 g of the title compound, mp 271°C.

E) (3S)-[1-[[[[3-[[3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl)-1-oxo-2-propenyl]amino ]-2-oxo-1-imidazolidinyl]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester

3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-N-(2-oxo-1-imidazolidinyl)-2-propenamide (3.55 g) was suspended in 100 ml ethyl acetate and 6.3 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide added. After stirring for 1 hour, a clear solution was obtained. The solution was then added over 10 minutes to a cooled solution (0°C) of 3.3 g of (S)-i-[[(chlorosulfonyl)-amino]carbonyl]-3-[[(phenylmethoxy)carbonyl]amino ]-2-azetidinone in 50 ml of ethyl acetate. After stirring overnight, the solvent and the oily residue were stirred for 1 hour with 50 ml of isopropanol. The resulting precipitate was filtered off and washed with isopropanol and ether. Yield: 5.91 g.

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

(3S)-[1-[[[[3-[[3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-1-oxo-2-propenyl]amino]- 2-oxo-1-imidazolidinyl]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (6.8 g) was stirred at room temperature overnight in 60 mL of trifluoroacetic acid/thioanisole (3:1) . After evaporation of the resulting solution to 1/3 of the original volume, 50 ml of isopropanol and 10 ml of ether were added. (3S)-3-amino-N-[[3-[[(1,4-dihydro-5~hydroxy-4-oxo-2-pyridinyl]-1-oxo-2-propenyl]-

amino]-2-oxo-1-imidazolidinyl]sulfonyl]-1-azetidinecarboxamide, trifluoroacetate salt was obtained as a white precipitate. It was washed several times with ether and dried. Yield: 4.30 g.

G) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[!-[[[[3-[[3-(1,4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl)-1-oxo-2-propenyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2 -oxoethylidene]amino]oxy]-2-methylpropanoic acid, disodium salt

(Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxo-ethoxy]imino]-4-thioazoleacetic acid (2.2 g) and 1.5 g of triethylamine were dissolved in 150 ml of acetonitrile. At -30°C, 1.4 g of diphenylchlorophosphate was added dropwise and the mixture was stirred for 1 hour.

(3S)-3-amino-N-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl]-1-oxo-2-propenyl]amino]-2-oxo -1-imidazolidinyl]-sulfonyl]-1-azetidinecarboxamide, 2.0 trifluoroacetate salt (3.3 g) suspended in 100 mL of ethyl acetate was treated with 6 mL of N-methyl-N-(trimethylsilyl)trifluoroacetamide and stirred for 1 hour at room temperature . The solution was added dropwise to the activated acid at -30°C (15 minutes). It was then stirred for 1 hour at -10°C and for 30 minutes at 0°C. The solvent was evaporated in vacuo and the remaining oil stirred with ice water at pH 2 (2N phosphoric acid). The ice water was discarded and the residue washed with ice water again and then dissolved in 100 ml tetrahydrofuran. The solution was dried over sodium sulfate and the filtrate evaporated. The diphenylmethyl ester of the title compound was isolated as a solid foam, 1, 81 g.

1.5 g of the material was stirred in 30 ml of trifluoroacetic acid/anisole at 0° C. for 30 minutes and after the addition of 100 ml of ether, 1.7 g of the trifluoroacetic acid salt of the title compound was filtered off. The compound was dissolved in 10 ml of water and sodium bicarbonate was added until pH 5.5. The filtered solution was chromatographed on macroreticular styrene-divinylbenzene copolymer (400 g) using water as eluent. The respective fractions contained 0.64 g of the product. Bioautography showed the presence of a minor bioactive by-product. The material was subjected to new chromatography on Merck Lobar C with water as eluent. Current fractions contained 0.17 g of the title compound.

Example 16

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[l-[[[[2-[3-(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)-1-oxo-2-propenyl]hydrazino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]- 2- methylpropanoic acid, disodium salt A) 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridiny1]-2-propenoic acid, 2-[(1,1-dimethylethoxy)carbonyl]hydrazide

3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid (1.36 g), 0.75 g N-hydroxybenzotriazole, 0.01 g N,N- Dimethylaminopyridine and 1.06 g of dicyclohexylcarbodiimide were stirred in 1 20 ml of dimethylformamide at 0°C for 20 minutes. 0.66 g of N-(t-butoxycarbonyl)hydrazine was added. After stirring overnight, the dicyclohexylurea formed was filtered off and the filtrate washed with 10 ml of dimethylformamide. The filtrate was evaporated to dryness and the residue suspended in 30 ml of water, 1 g of sodium bicarbonate added and stirred, after which the title compound was filtered off. Recrystallization from dimethylformamide/water gave white crystals. Yield: 1.47 g, melting point 141°C.

B) 3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid, hydrazide

3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid, 2-[(1,1-dimethylethoxy)carbonyl]hydrazide (3.86 g) was stirred in 1/2 hour in 30 ml trifluoroacetic acid at 0-5°C. The trifluoroacetic acid salt of the title compound precipitated after addition of 50 ml of diethyl ether. The salt was suspended in 30 ml of water, stirred with 2 g of sodium bicarbonate for 20 minutes, after which the title compound was filtered off, washed with water and dried to a beige powder. Yield 2.75 g.

C) (3S)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 2 - [ [ [ [2-oxo-3-[[(phenylmethoxy)carbonyl]amino]-1- azetidinyl] carbonyl] amino] sulfonyl] hydrazide

3-[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-2-propenoic acid, hydrazide (2.86 g) and 8.1 g of N-methyl-N-(trimethylsilyl) trifluoroacetamide was stirred for 1 hour in 50 ml of ethyl acetate. To the resulting clear solution was added a solution of 3.27 g of (S)-1-[[(chlorosulfonyl)amino]carbonyl]-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone in 30 ml of ethyl acetate (addition over 10 minutes) at 0°C. After stirring overnight was

the solvent evaporated and the residue stirred with 50 ml of isopropanol and a drop of acid. The title compound was filtered off and washed with isopropanol and ether. Yield: 5.42 g.

D) (3S)-3-[1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl]-2-propenoic acid, 2-[[[(3-amino-2-oxo-1-azetidinyl) carbonyl]amino]-sulfonyl]hydrazide, trifluoroacetate salt

(3S)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinecarboxylic acid, 2-[[[[2~oxo-3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl] carbonyl]amino]sulfonyl]hydrazide (5.2 g) was stirred in 50 ml of trifluoroacetic acid/thioanisole (3:1) at room temperature overnight. A mixture of 100 ml of ether/isopropanol (8:2) was added to the clear solution. The resulting precipitate was filtered off and washed with ether. Yield: 4.01 g after drying.

E) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[ [1- [ [[[2-[3-(1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl)-1-oxo-2-propenyl]-hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]- 2 - methylpropanic acid, disodium salt

(Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxo-ethoxy]imino]-4-thiazoleacetic acid (1.5 g) and 1 g of triethylamine were dissolved in 100 ml of acetonitrile. At -30°C, 1 g of diphenylchlorophosphate was added dropwise and the mixture stirred for 1 hour.

(3S)-3-[1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl]-2-propenoic acid, 2-[[[(3-amino-2-oxo-1-azetidinyl)carbonyl] amino]-sulfonyl]hydrazide, trifluoroacetate salt (2.0 g) and 5.5 ml of N-methyl-N-(trimethylsilyl)trifluoroacetamide were stirred in 50 ml of ethyl acetate at room temperature for 1 hour. A clear solution was formed which, after cooling, was added dropwise to the activated acid at -30°C. The mixture was stirred for 1 hour at -30°C, 30 minutes at -10°C and 1 hour at 0°C. The solvents were then evaporated in vacuo and the residue stirred with 50 ml of isopropanol. A solid formed which was filtered off and stirred with 100 ml of ice water for 20 minutes at pH 2 (phosphoric acid). After filtration, the diphenylmethyl ester of the title compound was obtained. This was washed three times with 50 ml portions of ice water and dried (1.78 g). 1.5 g of the ester was stirred with 50 ml of trifluoroacetic acid/anisole (4:1) for 30 minutes at 0°C. After addition of 150 ml of ether, the trifluoroacetic acid salt of the free acid of the title compound was filtered off (1.65 g).

I g of this material was suspended in 5 ml of water and pH adjusted to 6.0 (sodium bicarbonate). The clear solution was then chromatographed on 400 g of macroreticular styrene-divinylbenzene copolymer using water as eluent to give 413 mg of the title compound. 400 mg of this material was rechromatographed on Merck Lobar C using water as eluent; yield: 160 mg.

Example 17

[3S(Z)]-2-[[ [1-(2-amino-4-thiazolyl)-2-[[1-[[[[[2-[[(1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)-carbonyl]amino]ethyl]amino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]- 2- methylpropanoic acid, disodium salt A) N-(4- methoxybenzyl)- Q- benzylcomenamic acid

O-benzylkoinic acid (10 g) and 10 ml of 4-methoxybenzylamine i

60 rnl of water was refluxed for 4 hours. Acidification of the reaction mixture at room temperature with 2N hydrochloric acid to pH 2 gave 15 g of crystals. Recrystallization from dioxane gave 12.3 g of the title compound, mp 175°C.

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

N-[(4-methoxyphenyl)methyl]-O-benzylcomenamic acid (3.69 g), 1.50 g of N-hydroxybenzotriazole and 2.05 g of dicyclohexycarbodiimide were stirred for 1 hour at room temperature in 50 ml of dioxane. A solution of 1.35 g of N-benzylethylenediamine in 5 ml of dioxane was then added dropwise. After stirring overnight, the dicyclohexylurea formed was filtered off and the dioxane in the filtrate evaporated. The residue (oil) was dissolved in 50 ml dichloromethane and extracted with two 50 ml portions of 10% sodium bicarbonate and then washed with water. After drying the dichloromethane solution over sodium sulfate and evaporation, the remaining solid was recrystallized from ethanol, whereby crystals (4.2 g) of the title compound, m.p. 112°C, were obtained.

C) N-(2-aminoethyl)-1,4-dihydro-5-hydroxy-4'-oxo-2-pyridine-carboxamide, p-toluenesulfonate salt

1,4-dihydro-1-[(4-methoxyphenyl)methyl]-4-oxo-5-(phenylmethoxy)-N- [2-[(phenylmethyl)amino]ethyl]-2-pyridinecarboxamide (9.95 g) and 7.7 g of p-toluenesulfonic acid in 100 ml of methanol was

treated with 3 g of palladium on charcoal (10%) and hydrogen was bubbled through the reaction mixture at 45-50°C for 6 hours. An argon stream was then bubbled through the reaction mixture for 10 minutes. Filtration and evaporation of the filtrate gave beige crystals of the title compound which were washed 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

N-(2-aminoethyl)-1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide, p-toluenesulfonate salt (5.42 g) was dissolved in 50 mL of formic acid and 7.5 mL of formic acid/hydrogen chloride gas ( 2.2 equivalents of hydrogen chloride) and then 150 ml of ether was added, whereby white crystals were obtained. Filtration and washing with 200 ml of ether gave 2.60 g of the title compound, melting point 287°C.

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

To 4.38 g of (S)-3-[[(phenylmethoxy)-carbonyl]amino]-2-azetidinone suspended in 50 ml of ethyl acetate was added 2.83 g of chlorosulfonyl isocyanate at room temperature. A clear solution was obtained after 30 minutes of stirring.

N-(2-aminoethyl)-1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxamide, dihydrochloride (5.40 g) in 50 mL of acetonitrile was stirred with 24 g (6 equivalents) of N-methyl -N-(trimethylsilyl)trifluoroacetamide at 50°C for 1 hour. The volatile compounds were then evaporated in vacuo. To the resulting oily residue was added 50 ml of ethyl acetate.

The solutions prepared above were cooled to 0°C and

the second solution added to the first with stirring. After stirring overnight at 0°C, 200 ml of isopropanol was added to obtain the title compound in the form of beige crystals. Yield: 8.77 g, melting point 145°C.

F) (3S)-N-[[[[(3-amino-2-oxo-1-azetidinyl)carbonyl]amino]-sulfonyl]amino]ethyl]-1,4-dihydro-5-hydroxy-4-oxo -2-pyridinecarboxamide, 2.0 trifluoroacetate salt

(3S)- [1-[ [ [[[2-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-carbonyl]amino]ethyl]amino]sulfonyl]amino]carbonyl] -2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (2 g) was stirred in 20 ml

thioanisole/40 ml trifluoroacetic acid at 0°C for 12 hours. After addition of 100 ml of ether, white crystals (fine) of the title compound were isolated by filtration. Washing with 50 ml of isopropanol and 100 ml of ether gave 2.12 g of the title compound, mp 136°C. (decomp.).

G) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[2-[[(1, 4-dihydro-5- hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]ethyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]- 2 - methylpropanoic acid, diphenyl methyl ester

(Z)-2-amino-cx-[[2-(diphenylmethoxy)-1,1-dimethyl 1-2-oxo-ethoxy]imino]-4-thiazoleacetic acid (4.40 g) and 3 g of triethylamine were dissolved in 150 ml of acetonitrile. At -30°C, 2.8 g of diphenylchlorophosphate was added dropwise and the mixture was stirred for 1 hour.

(3S)-N-[[[[(3-amino-2-oxo-1-azetidinyl)carbonyl]amino]-sulfonyl]amino]ethyl]-1,4-dihydro-5-hydroxy-4-oxo-2 -pyridinecarboxamide, 2.0 trifluoroacetate salt (6.13 g) and 17 g of N-methyl-N-(trimethylsilyl)trifluoroacetamide were stirred for 2 hours in 100 ml of ethyl acetate. The solvent of the clear solution was distilled off in vacuo and the remaining oil evaporated for 2 hours at 30°C (oil pump vacuum <0.01 mm). The residue was redissolved in 100 ml of ethyl acetate and added dropwise to the activated acid at -30°C (30 minutes). The mixture was stirred for 1 hour at -10°C and 1 hour at 0°C. The solvent was evaporated and the remaining oily residue stirred with ice water at pH 3 (2N phosphoric acid). The ice water was discarded and the residue washed with ice water and dried. Yield: 7.8 g of beige crystals.

H) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[ [ [[2 - [ [ (1,4-dihydro-5- hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]ethyl]amino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]- 2- methylpropanoic acid, disodium salt

[3S (Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[2-[[(1, 4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl)carbonyl]amino]ethyl]amino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo ethylidene]amino]oxy]-2-methylpropanoic acid, diphenyl methyl ester ( 3 g) was stirred in 30 ml of trifluoroacetic acid/anisole for 30 minutes. 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 pH adjusted to 6.0 with sodium bicarbonate. After

stirring for 1/2 hour, the suspension was filtered and the solution chromatographed on macroreticular styrene-divinylbenzene copolymer using water as eluent to give 0.24 g yield.

This material was chromatographed again on Merck Lobar C

column; yield: 0.078 g, melting point 275°C (decomp.).

Example 18

[2S [2a, 3(3 (Z) ] ] -2- [ [ [1- (2-amino-4-thiazolyl) - 2- [[l-[[[[3-[[(l,4- dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-methyl-4-oxo-3-azetidinylamino]-2-oxoethylidene ]amino]oxy]-2-methylpropanoic acid, disodium salt

A) (2S-trans)-[1-[[[[3-[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]amino]-2-oxo-i -imidazoiidinyl]sulfonyl]aminojcarbonyl]-2-methyl-4-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester

(3S-trans)-(4-methyl-2-oxo-3-azetidinyl)-carbamic acid, phenyl methyl ester (2.35 g) and 1.41 g of chlorosulfonyl isocyanate were stirred for 1 hour at 0-5°C in 50 ml of ethyl acetate . A clear solution was obtained (solution A). 1,4-dihydro-4-oxo-N-(2-oxo-1-imidazolidinyl)-5-(phenylmethoxy)-2-pyridinecarboxamide (3.28 g) and 6 g of N-methyl-N-(trimethylsilyl) trifluoroacetamide was stirred in 50 ml of ethyl acetate for 1 hour at 40°C (solution B).

To the cooled (0°C) solution A, solution B was added

during 30 minutes with stirring. After continuous stirring overnight, the solvent was evaporated and the residue (oily) stirred with 50 ml of isopropanol and one drop of acetic acid. The title compound was obtained as a beige precipitate; melting point 16 3° C (decomp.) ; 4.3g.

B) (2S-trans)-N-[3-[[[(3-amino-2-methyl-4-oxo-1-azetidinyl)-carbonyl]amino]sulfonyl]-2-oxo-1-imidazolidinyl]- 1,4-dihydro-5-hydroxy- 4- oxo- 2- pyrid incarboxamide, di-p-toluenesulfonate

(2S-trans)-[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 acid, phenylmethyl ester (5.9 g) in 50 ml of dimethylformamide and 3.8 g of hydrated p-toluenesulfonic acid and 2.5 g of palladium on charcoal (10%) was hydrogenated at room temperature for 1 hour. After filtration over Hyflo was

the dimethylformamide distilled off in vacuo. The oily residue was stirred with 100 ml of dichloromethane. The title compound (5.8 g) appeared immediately as a white crystalline material.

C) [2 3-[2a,33(Z)]]-2-[[[i-(2-amino-4-thiazolyl)-2-[[1- [ [ [[3-[[(1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino] 2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-methyl-4-oxo-3-azetidinyl]amino]- 2-Oxoethylidene]amino]oxy]-2-methylpropanoic acid, di sodium salt

(Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (4.40 g) and 3.0 g of triethylamine were dissolved in 150 ml of acetonitrile. At -30°C, 2.8 g of diphenylchlorophosphate was added dropwise and stirred for 1 hour.

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

The suspension and solution prepared above were combined at -30°C and stirred for 1 hour at this temperature, 1 hour at -10°C and overnight at 0-10°C. The solvents were then distilled off in vacuo and the residue stirred with 100 ml of ice water at pH 3 (phosphoric acid). The diphenylmethyl ester of the title compound was filtered off and washed with water. Yield: 6.13 g, beige powder. 2 g of the ester was stirred in 30 ml of trifluoroacetic acid/anisole (4:1) for 30 minutes at 0°C. By adding 100 ml of ether, the trifluoroacetate salt of the free acid is precipitated. This was suspended in 10 ml of water and the pH adjusted to 6.0. After filtration, the filtrate was passed through a macroreticular styrene-divinylbenzene copolymer column (water as eluent). Yield: 0.48 g.

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

Example 19

[3S(Z)]-2-amino-N-[1-[[[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]- 2-oxo-1-imidazolidinyl]sulfonyl]-amino]carbonyl]-2-oxo-3-azetidinyl]-α-(methoxyimino)-4-thiazole-acetamide, monopotassium salt

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

To a suspension of 1.62 g of (3S)-3-amino-N-[[3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2- oxo-1-imidazolidinyl]sulfonyl]-2-oxo-1-azetidinecarboxamide (0.003 mol) in 20 mL of ethyl acetate was added at room temperature to 2.6 mL of bis-trimethylsilylacetamide to form a clear brownish solution which was stirred for 1 hour at room temperature and then cooled to 0°C (solution B).

Solution B was added dropwise to mixture A with stirring while the temperature was maintained at -30°C (about 10 minutes) The mixture was stirred at -10°C for 1 hour and at 0°C for another 1 1/2 hours and then evaporated in vacuum. The remaining syrup was dissolved in 50 ml of acetone. To the solution was added 6 ml of 1-molar potassium ethyl hexanoate to precipitate 3.0 g of the crude product. Addition of ether to the filtrate gave an additional 0.2 g of crude material. Chromatography of the crude material on macroreticular styrene-divinylbenzene copolymer gave 1.85 g of the title compound.

Example 20

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

[3S(Z) ] -2-[[[1-(2-amino-4-thiazolyl)-2-[[l-[[[[3-[[(1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-2- methylpropanoic acid, disodium salt (2.2 g; see Example 1) was dissolved in 20 ml of acetone/water (1:1) and the pH was adjusted to 2 with 2N hydrochloric acid. Chromatography using macroreticular styrene-divinylbenzene copolymer afforded 0.7 g of the title compound.

Example 21

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[l-[[[[3-[[(1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]-N- hydroxy-2-methylpropanamide, monosodium salt

(Z)-2-amino-α-[[-1,1-dimethyl-2-oxo-2-[(triphenylmethoxy)-amino]ethoxy]imino]-4-thiazoleacetic acid (4.72 g) was suspended in 65 ml of acetonitrile and 3.72 ml of triethylamine were added at -30° C. After stirring for 10 minutes, 1.97 ml of diphenylchlorophosphate was added dropwise. Stirring was then continued for 90 minutes (solution A).

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

Solution A was then dripped into the stirred solution B at -20°C over 30 minutes. Continued stirring at -10°C for 1 1/2 hours and at 0°C for 1 hour completed the reaction.

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

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

Example 22

[3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2- [ [1- [ E [ [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-methyl-propanoic acid, disodium salt

A) 2-[[(phenylmethoxy)carbonyl]amino]-2-imidazolidinone 1-amino-2-imidazolidinone (26 g, 0.257 mol) was dissolved in 200 ml of water. The solution was decanted with 200 ml of ethyl acetate and 43.8 g of chloroformic acid, benzyl ester (0.257 moi) was dropped into the mixture with stirring while the pH was maintained at 8.5-9 by addition of saturated sodium bicarbonate solution. After stirring overnight at room temperature, the title compound was filtered off, washed with water and then with ethyl acetate. Yield: 46.7 g, melting point 140-144°C.

B) 1-[[(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 1 liter of dichloromethane was added a solution of 35 g of phosgene in 200 ml of dichloromethane. The mixture was stirred overnight at room temperature to form a clear solution. The solvent was removed in vacuo and the remaining syrup triturated with ether. Yield: 76.0 g, melting point 102-105° C.

C) 3-[[(phenylmethoxy)carbonyl]amino]-2-oxo-l-imidazolidine carboxylic acid, 2-[( 1,1- dimethylethoxy)carbonyl] hydrazide l-[[(phenylmethoxy)carbonyl]amino]-3 -(chlorocarbonyl)-2-imidazolidinone (76 g, 0.255 mol) was added at room temperature to 1.5 L of ethyl acetate. After cooling to 0-5°C, a solution of 39.6 g (0.9 mol) of N-(t-butoxycarbonyl)hydrazide and 41.8 ml of triethylamine (0.3 mol) in 150 ml of ethyl acetate was added dropwise into the of 30 minutes. The mixture was stirred overnight. The precipitate was filtered off, dried, stirred with 800 ml of water to remove triethylamine hydrochloride, filtered, washed with water and dried. Yield: 71.2 g, melting point 195-198°C.

D) 2-[[3-[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]carbonyl]amino]-2-oxo-1-imidazolidinyl]carbonyl]hydrazine carboxylic acid, 1, 1-dimethyl ethyl ester

3-[[ (phenylmethoxy)carbonyl]amino]-2-oxo-1-imidazolidine carboxylic acid, 2-[(1,1-dimethylethoxy)carbonyl]hydrazide (31.5 g, 0.08 mol) was dissolved in 400 ml of dimethylformamide, added 16 g of palladium on charcoal (10%), after which hydrogen was passed through the stirred reaction mixture. After 1 hour, the catalyst was filtered off and 19.62 g of O-benzylcomeneamic acid was added to the filtrate

(0.08 mol), 0.48 g of dimethylaminopyridine and 0.64 g of N-hydroxybenzotriazole. The mixture was stirred for 1 hour at room temperature. A solution of 18.13 g of dicyclohexylcarbodiimide (0.088 mol) was added at room temperature and the mixture stirred overnight. The precipitate (dicyclohexylurea) was filtered off, the filtrate evaporated in vacuo and the residue triturated with water to which sodium bicarbonate had been added to bring the pH to 7.5. The precipitate was filtered off to give 36 g of the title compound.

E) 3-[[[1,4-dihydro-4-oxo-5-{phenylmethoxy)-2-pyridinyl]-carbonyl] amino]- 2- oxo-1- imidazolidinecarboxylic acid, hydrazide 2 - [ [3 - [ [ [1,4-dihydro-4-oxo-5-phenylmethoxy)-2-pyridinyl]-carbonyl]amino]-2-oxo-1-imidazolidinyl]carbonyl]hydrazine carboxylic acid, 1,1-dimethylethyl ester (36 g ) was added at -10°C with stirring to 300 ml of trifluoroacetic acid. The mixture was stirred at 0°C for 1 hour, the trifluoroacetic acid removed in vacuo and the residue triturated with ether to give 41 g of the trifluoroacetate salt of the title compound. The trifluoroacetate salt was cooled and suspended in water and pH adjusted to 7 by addition of 2N sodium hydroxide. The precipitate was filtered off to give 21.9 g of the title compound.

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

3-[[[1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridinyl]-carbonyl]amino]-2-oxo-1-imidazolidinecarboxylic acid, hydrazide (21.9 g) was suspended in 250 ml of acetonitrile. To the suspension was added 75 ml of bis-trimethylsilylacetamide and the mixture was stirred until a solution was formed. To the solution was added 10 g of palladium on charcoal (10%) and hydrogen was passed through with vigorous stirring. The debenzylation was complete after 1 hour. After filtration, 15 ml of methanol and 10 drops of acetic acid were added to precipitate the title compound. Yield: 10.8 g. The crude material was stirred with 150 ml of ethanol to give 8.8 g of the title compound, mp <205°C (decomp.).

G) (S)-[1-[[[[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]carbamic acid, phenylmethyl ester

To a suspension of 5.9 g (0.02 mol) crude 3-[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)carbonyl]amino]-2-oxo-1-imidazolidine -carboxylic acid, hydrazide, 14.9 ml (0.08 mol) of N-methyl-N-(trimethylsilyl)trifluoroacetamide was added and the mixture was stirred at 50°C until a solution was formed (solution A).

To a suspension of 4.4 g of (S)-3-[[(phenylmethoxy)carbonyl]-amino]-2-azetidinone (0.02 mol) in 160 ml of ethyl acetate, 1.76 ml of chlorosulfonyl isocyanate was added at room temperature. The mixture was stirred for 1 hour (solution B).

Solution A was added (under cooling, ice) to solution 3. After stirring for 1 hour, 2.8 ml (0.02 mol) of triethylamine was added, after which the mixture was stirred overnight at room temperature. An additional 2.8 ml of triethylamine (0.02 mol) and then ice water were added. The mixture was stirred thoroughly for 1 hour and the layers separated. The aqueous phase was acidified to pH 3 and the precipitate filtered off. Yield: 5.3 g of the crude title compound.

The raw material was dissolved in acetone/water and the pK of the solution adjusted to 6.5 by crystallization of 2N sodium hydroxide. After removal of the acetone in vacuo, the aqueous solution was filtered and lyophilized to give 5.5 g of the crude sodium salt of the title compound. Chromatography of the crude sodium salt on macroreticular styrene-divinylbenzene copolymer gave 0.64 g of purified material. 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]-amino]sulfonyl]hydrazino]carbonyl]-2-oxo-1-imidazolidinyl ]-1,4-dihydro- 5- hydroxy- 4-oxo- 2- pyridinecarboxamide

0.5 g (S)-[1-[ [[[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]carbamic acid, phenyl methyl ester was added to 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 give the title compound in quantitative yield.

I) [3S(Z)]-2-[[[1-[2-amino-4-thiazolyl]-2-[[1-[[[[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-methyl-propanes yre, diphenylmethyl ester

To a solution of 0.35 g (0.0008 mol) (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid in 10 ml of acetonitrile, 0.34 ml of triethylamine was added. The mixture was cooled to -30°C and 0.17 ml of diphenyl chlorophosphate was added. The reaction mixture was stirred at -30°C for 1 hour (solution A).

To a suspension of 0.008 mol 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 was added 0.7 ml of bis-trimethylsilylacetamide (solution B).

Solution B was added to solution A at -30°C. The mixture was stirred at -10° C. for 2 hours and at 0° C. for 1 hour and then evaporated in vacuo. After treatment of the residue with water, 0.7 g of the crude title compound was obtained, m.p. 155°C (decomp.).

J) [3S(Z)]-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[ [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, disodium salt

To a suspension of 0.7 g of [ 3S ( Z )]-2-[[[1-[2-amino-4-thiazolyl]-2-[ [1-[[[[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, diphenyl methyl ester (0.00077 mol) in 1 ml of anisole was added 6 ml of trifluoroacetic acid at -10°C. The mixture was kept at -10°C for 1 hour. At -10°C ether was added to precipitate the trifluoroacetate of the free acid of the starting material, yield: 0.5 g.

The precipitate was suspended in water under cooling and the pH adjusted to 5.5 by adding 2N sodium hydroxide. Freeze-drying resulted in 0.55 g of crude material. The crude material was purified by chromatography on macroreticular styrene-divinylbenzene copolymer to give 0.1 g of purified title compound.

Example 23

[3S(Z)]-2-[[[i-(2-amino-4-thiazolyl)-2-[[1-[[[[2-[(1,4-dihydro-5-hydroxy-4- oxo-2-pyridinyl)carbonyl]-2-methylhydrazino3 sulfonyl3 - amino3carbonyl]-2-oxo-3-azetidinyl3 amino3-2-oxoethylidene3 amino]-oxy]-2- methylpropanoic acid, disodium salt A) 1,4-dihydro- 4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridine carboxylic acid, 1- methylhydrazide

N,O-dibenzylcomenamyl chloride (0.15 mol) was suspended in

150 ml dichloromethane under ice cooling. To the suspension was added 26.2 ml (0.5 mol) of methylhydrazine and then 150 ml of acetonitrile. The mixture was stirred overnight at room temperature. The cloudy solution was evaporated in vacuo and triturated with 300 ml of water. The solid material obtained was then filtered and dried to give 26.3 g of crude material. Recrystallization of the crude material from water led to 12.7 g of the pure title compound, mp 138-142°C.

B) (S)-1,4-dihydro-4-oxo-5-(phenylmethoxy)-1-(phenylmethyl)-2-pyridinecarboxylic acid, l-methyl-2-[[[[2-oxo-3-[[ (phenylmethoxy)-carbonyl] amino]-1- azetidinyl] carbonyl] amino] sulfonyl] hydrazide

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

(S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (1.1 g, 0.005 mol) 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 hour, thereby forming a solution (solution B).

To solution B, 1.2 ml of triethylamine (under ice-cooling) was

and then 20 ml of dichloromethane and suspension A added. The suspension was stirred overnight at room temperature. To the slightly cloudy solution, 30 ml of dichloromethane and 20 ml of water were added, after which the mixture was stirred for 1 hour at room temperature.

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

C) 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, 2-[ [ [ (3-amino-2-oxo-1-azetidinyl)carbonyl]amino]sulfonyl]-1-methylhydrazide, t rifluoroacetate salt

To a solution of 2 g of (S)-i,4-dihydro-4-oxo-5-(phenylmethoxy)-i-(phenylmethyl)-2-pyridinecarboxylic acid, 1-methyl-2-[[[[2-oxo- 3-[[(phenylmethoxy)carbonyl]amino]-1-azetidinyl]carbonyl]-amino]sulfonyl]hydrazide in 60 ml of dimethylformamide, 1.1 ml of trifluoroacetic acid and 1 g of palladium on charcoal (10%) were added. After purging with nitrogen, hydrogen was passed through the solution for 60 minutes with stirring, after which the catalyst was filtered off, the filtrate evaporated in vacuo and the residue triturated with ether to give 1.1 g of the crude title compound. Yield: 86.6%.

D) [3S(Z)]-2-[[ri-(2-amino-4-thiazolyl)-2-[[1- [ [[[2- [ (1,4-dihydro-5-hydroxy-4 -oxo-2-pyridinyl)carbonyl]-2-methyl-hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]- 2- methylpropanoic acid, diphenylmethyl ester

To a suspension of 0.88 g of (Z)-2-amino-α-[[2-(diphenyl-methoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid

(0.002 mol) in 30 ml of acetonitrile, 0.7 ml (0.005 mol) of triethylamine and then, at -30°C, 0.44 ml of diphenylchlorophosphate (0.002 mol) were added. The mixture was stirred at -30°C for 1 hour (solution A).

To a suspension of 1.2 g (0.002 mol) of 1,4-dihydro-5-hydroxy-4-oxo-2-pyridinecarboxylic acid, 2-[[[(3-amino-2-oxo-1-azetidinyl)carbonyl] amino]sulfonyl]-1-methylhydrazide, trifluoroacetate salt in 30 ml of ethyl acetate, 2 ml of bis-trimethylsilylacetamide (approx. 0.008 mol) was added at room temperature, whereby a clear solution was obtained after 30 minutes (solution B).

At -30°C, solution B was added dropwise to solution A (approx. 10 minutes). The temperature was maintained at -10°C for 1 hour and then at 0°C for a further 1 hour. The solvent was evaporated and the residue treated with water to give, after filtration and drying, 2.4 g of crude title compound.

E) [3S(Z)]-2-[[ [1-(2-amino-4-thiazolyl)-2-[[1-[[ [ [2- [ (1,4-dihydro-5-hydroxy- 4-oxo-2-pyridinyl)carbonyl]-2-methyl-hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]- 2- methylpropanoic acid, disodium salt

At -10°C, 2.4 g of crude [3S (Z)]-2-[ [ [1-(2-amino-4-thiazolyl)-2-[[l-[[[[2-[(l ,4-dihydro-5-hydroxy-4-oxo-2pyridinyl)carbonyl]-2-methylhydrazino]sulfonyl]amino]carbonyl]-2~oxo-3-azetidinyl]-amino]-2-oxoethylidene]amino]oxy]- 2-Methylpropanoic acid, diphenylmethyl ester added to a mixture of 20 ml of trifluoroacetic acid and 4 ml of anisole. The mixture was stirred at -10°C for 1 hour and the reaction product precipitated by the addition of ether at -10°C. Yield: 1.12 g of the crude trifluoroacetate of the title compound.

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

Example el 24

(3S)-2-[[[1-(2-amino-4-thiazolyl)-2-[[1-[[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyi )methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxoethylidene]amino]oxy]-2-methylpropanoic acid

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

A suspension of 5-hydroxy-2-(hydroxymethyl)-4H-pyran-4-one (56.8 g, 0.4 mol) in 400 mL of methanol was treated with sodium hydroxide (16 g, 0.4 mol) for 200 ml of hot methanol and then with 50.6 g (46 ml, 0.4 mol) of benzyl chloride. The mixture was heated to the boiling point for 3.5 hours, cooled and poured into 1 liter of water. The resulting solid was filtered off and washed with approx. 1.5 liters of water, 200 ml of ethanol and 400 ml of hexane. After drying under high vacuum, the weight of the product was 55.7 g.

B_)_ 1, 4- dihydro- 2-( hydroxymethyl) - 5-( phenylmethoxy) - 4- pyridinone

A mixture of 2-hydroxymethyl-5-(phenylmethoxy)-4H-pyran-4-one (9.65 g, 41.59 mmol), 95 mL of concentrated ammonium hydroxide, and 20 mL of ethanol was refluxed overnight. After addition of a further 75 ml of ammonium hydroxide, the mixture was refluxed for 2 hours and then cooled. The resulting brown solid was filtered off and washed with water until the washes were neutral. The crude product was suspended in ethanol, filtered, washed with ethanol and hexane and dried in vacuo. Yield of the title compound was 7.61 g.

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

A suspension of 1,4-dihydro-2-(hydroxymethyl)-5-(phenylmethoxy)-4-pyridinone (3 g, 12.99 mmol) in chloroform (15 mL) was cooled to 0 °C under argon and treated with thionyl chloride (6.1 mL, 83.62 mmol). Within a few minutes, a homogeneous solution was obtained. After stirring for a further 5 minutes, a creamy yellow solid precipitated. The cooling bath was removed and the mixture heated under reflux for 45 minutes. The mixture was cooled to 0°C, whereupon the white suspended material was filtered off, washed with chloroform and hexane and dried in vacuo. Yield of the title compound was 3.65 g. D) 2-(azidomethyi)-1,4-dihydro-5-(phenoxymethyl)-4-pyridinone

A mixture of 1-(chloromethyl)-1,4-dihydro-5-(phenylmethoxy)-4-pyridinone, hydrochloride (3.59 g, 12.54 mmol), sodium azide (4.08 g, 62.7 mmol) and diisopropylethylamine (2.19 mL, 12.54 mmol) in 70 mL of dimethylformamide was stirred at room temperature under argon for 3.5 days. A further addition of 4.08 g of sodium azide was made and the mixture was heated to 45-50°C for 2 hours. After cooling, the reaction mixture was poured into 500 ml of water, whereby an insoluble white solid was formed. The pH of the supernatant was lowered from 8.5 to 7.5 with dilute hydrochloric acid and the white solid filtered off. After washing with water, acetone and hexane, the solid was dried in vacuum. 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 mmol) and platinum oxide (200 mg) in 100 mL of dimethylformamide was stirred for 6 h at room temperature under 1 atm hydrogen The catalyst was filtered off and the solution concentrated in vacuo to give 1.5 g of the title compound as a gray powder.

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

To a stirred suspension of 2-(aminomethyl)-4-oxo-5-(phenylmethoxy)pyridine (2.330 g, 10.13 mmol) in 60 mL of ethyl acetate was added N-methyl-N-(trimethylsilyl)trifluoroacetamide (3, 76 ml,

20.26 mmol). The resulting solution was stirred for 30 minutes at room temperature and then cooled to 0°C. Simultaneously, to a stirred suspension of (S)-3-[[(phenylmethoxy)carbonyl]amino]-2-azetidinone (2.228 g, 10.13 mmol) in 60 ml of ethyl acetate was added chlorosulfonyl isocyanate (882 µl, 10.13 mmol). The resulting solution was stirred for 30 minutes at room temperature and then cooled to 0°C and treated with triethylamine (4.23 mL, 30.39 mmol) and then with the above-described solution of silylated 2-(aminomethyl)-4 -oxo-5-(phenylmethoxy)pyridine. The mixture was stirred for two days at room temperature.

The mixture was concentrated in vacuo, the residue dissolved in acetonitrile-water (40-60) and the pH lowered to 2.9, whereupon a thick oil separated. On cooling to 5°C, the oil went into solid form. The solid was separated, washed four times with water and dried in vacuo to give 3.4 g of crude title compound. The crude product was dissolved in a minimal volume of dimethylformamide and applied to a column (1 liter) of macroreticular styrene-divinylbenzene copolymer. The column bee eluted with a stepwise acetone-water gradient. Desired material eluted with approx. 65% acetone. Relevant fractions were combined and lyophilized to give 2.69 g of the title compound.

G) (3S)-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-methylpropanoic acid, diphenylmethyl ester

(3S)-1-[[[[[(1,4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)-methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-[[ (phenylmethoxy)-carbonyl]amino]azetidine (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 was stirred under 1 atm. hydrogen until 3.28 mmol (73 ml) of hydrogen had been consumed (about 3 hours).

To a stirred solution of (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid (846 mg, 1.804 mmol) in 16 ml of dimethylformamide at -20°C was added diphenylchlorophosphate (374 µl, 1.804 mmol) and then triethylamine (450 µl, 3.28 mmol). The solution was stirred for 1 hour at -20°C, after which the above-described mixture of hydrogenolyzed compound was added. Triethylamine (921 µl, 6.6 mmol) was then added. The resulting mixture was stirred at -20°C and then at 5°C overnight. The catalyst was filtered off, volatile compounds removed in vacuo and the resulting oil dissolved in a minimal volume of acetone-water (75-25) (pH 5.2) and added dropwise to a stirred suspension of 20 ml of Dowex 50 x 2-400 (K <+>) in acetone-water (35-65). After 40 minutes, the mixture was filtered and the filtrate lyophilized to give 2.1 g of solid. The solid was dissolved in a minimal amount of acetonitrile-water (40-60) (pH 5.6) and applied to a column (800 ml) of macroreticular styrene-divinylbenzene copolymer which was eluted with a stepwise acetonitrile-water gradient, the desired material was obtained with approx. 30% acetonitrile. Relevant fractions were combined and lyophilized to give the title compound.

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

Trifluoroacetic acid (4.7 mL) was added dropwise to a stirred suspension of (3S)-2-[[[ 1-(2-amino-4-thiazolyl)-2-[[1-[[[[[(1, 4-dihydro-5-hydroxy-4-oxo-2-pyridinyl)methyl]amino]-sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]- 2-Methylpropanoic acid, diphenyl methyl ester (131 mg, 0.113 mol) in 3 mL of dichloromethane and 0.3 mL of anisole at 0°C. After stirring for 45 minutes at 5° C., 2 ml of toluene was added and the volatile compounds were removed in vacuo. The resulting oil was washed with hexane (3 x 4 mL) and triturated with 10 mL of ether to give a solid. The solid was washed once with ether (10 mL) and dried in vacuo. The indicated reaction and work-up was repeated with 0.166 mmol of (3S)-2-[[[1-(2-amino-4-thiazolyl)-2-[[1- [ [[[[(1,4-dihydro-5 -hydroxy-4-oxo-2-pyridinyl)-methyl]amino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]amino]-2-oxo-ethylidene]amino]oxy]-2-methylpropanoic acid, diphenyl methyl ester . The solid crude products were combined, dissolved in 2 ml of acetonitrile-water (40-60) (pK 2.5) and chromatographed on a column (200 ml) of macroreticular styrene-divinylbenzene copolymer using an acetonitrile-water gradient. The desired material was eluted with acetonitrile-water (20-80). Relevant fractions were combined and lyophilized to give 103 mg of the title compound as a white solid, mp 180°C (decomp.).

Claims (1)

process for the preparation of a compound of formula': or a pharmaceutically acceptable salt thereof, wherein Ri is an acyl group which is written from a carboxylic acid; R 2 and R 3 are the same or different and are hydrogen; 1-a-l-kenyl,—alkynyl,—cycloalkyl,—f-onyl,—substituted" f-etryir—e±irer—a— 4-, 5-, 6- or 7-membered heterocyclic ring, or one of R2 and R3 is hydrogen and the other is azido, halomethyl, dihalomethyl, trihalomethyl, alkoxycarbonyl, 2-phenylethynyl, carboxyl Xii X3 2-phenylethynyl, -CH2 Xi , -S-X2 , -O-X2 , -O- Å - X* , -S-C-X4 or / Xs Xs Q -A-C-NXe X7 ; Xi is azido, amino, hydroxy, kai/boxyl, alkoxycarbonyl, alkanoylamino, phenylcarbonylamino, (Substituted phenyl)carbonylamino, alkylsulfonyloxy, phenylsulfonyloxy, (substituted phenyl)sulfonyloxy, phenyl, substituted f/enyl, cyano, Q -A-C-NXeX? , -S-X2 or -0-X2 ; X 2 is alkyl, substituted/alkyl, phenyl, substituted phenyl, phenylalkyl, (substituted f eny/1) alkyl, alkanoyl, f enyialkanoyi , (substituted phenyl)alkanoyl / phenylcarbonyl, (substituted phenyl)-carbonyl heteroarylcarbonyl; one of X3 and X4 is hydrogen and alkyl, or X3 and X4 together with the carbon atom to which they are attached form a cycloalkyl group; Xs is formyl, alkanoyl, phenylcarbonyl, (substituted phenyl)carbonyl, phenylalkylcarbonyl, (substituted phenyl)alkylcarbonyl, carboxyl, alkoxycarbonyl, aminocarbonyl, (substituted amino)carbonyl or cyano; Xe and X7 are the same or different and constitute hydrogen, alkyl, phenyl or substituted phenyl, or Xe is hydrogen and X7 is amino, substituted amino, alkanoylamino or alkoxy, or Xe and X7 together with the nitrogen atom to which they are attached form a 4-, 5-, &- or 7-membered heterocyclic ring; A is /cH=CH-, -(CH2 )m-, -(CH2 )m-O-, -(CH2 )m-NH- or -CH2 -S-CH4 - ; m dr 0, 1 ollor 2; | Q Q Ai is a single bond, | NH C ftt*~ -(or -NH-NH-C-; A2 is a single bondY^-NH-,' A4 is -NH-, I (CIL ) p—r)— (CH2 ) s<-NH- , .IMII C CH2X or -N-; .. A3 is bn widow 1 tbind-irftg-), -CH2 -"^y^NH-CHz - ; As is a single bond, -CH-CH- or -.^CH2 ; X is hydrogen Y-ifarboxyl^ jei ler carbamoylj, characterized by (1) acylation of a compound of formula: with an Ri acyl group obtained from an Ri carboxylic acid, or (2) introducing a -CO-NH-SO2 R activating group into a connection with formula: r A^ V cWcs i\\^ jTxxar4j^ ^-wj^s^sk «J^^e^o^c GOÅUr ^ V^-m^