GB2071664A

GB2071664A - Phosphonic acid derivatives of 7-((2-amino-4- thiazolyl)oximino)cephalosporins

Info

Publication number: GB2071664A
Application number: GB8106693A
Authority: GB
Original assignee: ER Squibb and Sons LLC
Current assignee: ER Squibb and Sons LLC
Priority date: 1980-03-14
Filing date: 1981-03-03
Publication date: 1981-09-23
Also published as: DE3109762A1; IT8120322A0; IT1167715B; JPS56142288A; GB2071664B; FR2485016A1

Abstract

Novel compounds having the general formula I, <IMAGE> wherein: the <IMAGE> group is in the syn or anti configuration; R represents hydrogen, sodium, potassium, benzyl, p-methoxybenzyl, diphenylmethyl, t-butyl, -CH2-O- lower alkyl, <IMAGE> or <IMAGE> R1 is in the a-configuration and represents hydrogen or methoxy; R2 and R3 independently represent hydrogen, methyl, ethyl, i-propyl or n- propyl; R4 and R%4 are the same and represent hydrogen, sodium, potassium, or lower alkyl, or one is hydrogen and the other is lower alkyl; R5 represents hydrogen or lower alkyl; n is 0, 1 or 2; X represents hydrogen, <IMAGE> R6 represents hydrogen or lower alkyl; R7 represents hydrogen, lower alkyl, -(CH2)m-N-(lower alkyl)2, -(CH2)m-COOR8 or -(CH2)m-SO3R8; R8 represents hydrogen, sodium, or potassium; m is 1, 2, 3 or 4, are useful as antibacterial agents.

Description

SPECIFICATION Phosphonic acid derivatives of 7(-(2-amino-4-thiazolyl)oximino)cephalosporins This invention relates to cephalosporins of the general formula 1,

wherein: the

group is in the syn or anti configuration; R represents hydrogen, sodium, potassium, benzyl, p-methoxybenzyl, diphenylmethyl, t-butyl, -CH2-O- lower alkyl.

R1 is in the a-configuration and represents hydrogen or methoxy; R2 represents hydrogen, methyl, ethyl, i-propyl or n-propyl; R3 represents hydrogen, methyl, ethyl, i-propyl or n-propyl; R4 and R4 are the same and represent hydrogen, sodium, potassium, or lower alkyl, or one is hydrogen and the other is lower alkyl; R5 represents hydrogen or lower alkyl; n isO, 1 or2; X represents hydrogen,

R represents hydrogen or lower alkyl; R7 represents hydrogen, lower alkyl, -(CH2)rn-N-(lower alkyl)2, -(CH2)m-COOR8 or -(CH2)m-SO3R8; R8 represents hydrogen, sodium, or potassium: m is 1,2,3 or 4.

The lower alkyl groups referred to throughout this specification include straight or branched chain hydrocarbon groups containing from 1 to 4 carbons, e.g., methyl, ethyl, -propyl, t-butyl, etc.

The compounds of formula I and their intermediates that are described below that have the 2amino-4-thiazolyl group as part of their structure are, of course, tautomeric and can also be structurally represented as containing a 2-imino group. Thus, the compounds of formula I can be represented as

The intermediate and final products are structurally represented and named throughout this specification as 2-amino-4-thiazoles, but it is to be understood that both forms are within the scope of the invention.

The compounds of formula I and the intermediates described below having the oximono substituent

can be obtained as the syn or anti isomer or as a mixture of these isomers. All of these isomeric forms are within the scope of this invention. However, in general, final products in the syn form are preferred since it is believed that isomeric form has the greatest activity.

The sulfoxides of formula I and in the various intermediates described below, i.e., n is one, can be in either the a- of p- configuration. When the sulfoxide is only in the ,B-configuration it will be represented as

and when it is only in the a:-configuration it will be represented as 0 The compounds of formula I can be prepared by various methods.For example, the compounds wherein X is hydrogen,

can be prepared by acylating the 7-aminocephalosporanic acid ester of the general formula lil,

wherein X is as defined above and R9 is a removable ester protecting group such as benzyl, diphenylmethyl,p-methoxybenzyl, and t-butyl; with an activated derivative of the acid of the general formula IV,

wherein both R4 and R4 are hydrogen or lower alkyl or one is hydrogen and the other is lower alkyl; in the presence of a coupling agent such as dicyclohexylcarbodiimide to yield the ester of the general formula V,

Removal of the ester protecting group such as by treatement with trifluoroacetic acid and anisole yields the corresponding trifluoroacetic acid salt which can then be converted into the acid, i.e. R is hydrogen, product of formula I.

The preferred activated derivative of the acid of formula IV is the N-hydroxybenzotriazole ester which is obtained by treating the acid of formula IV with N-hydroxybenzotriazole and dicyclohexylcarbodiimide.

The products of formula I wherein R1 is methoxy are preferably prepared by reacting the acid chloride derivative of formula IV with the ester of formula III.

The 7-amino caphalosporanic acid ester a- and -sulfoxides of formula III (n is one) are prepared by converting the 7-amino cephalosporanic acid starting material (n is zero) to the Schiff base ester of the formula

which is then oxidized with the percarboxylic acid such as m-chloroperbenzoic acid to yield a mixture of a and p-sulfoxide Schiff base cephalosporin esters. The Schiff base sidechain is cleaved by treatment with toluenesulfonic acid and the a- and p-sulfoxide 7-amino cephalosporanic acid esters are separated chromatographically. Further oxidation of the a-sulfoxide yields the corresponding sulfone (n is two) for formula lil.

The acid of formula IV wherein R4 and R4 are both lower alkyl is obtained by reacting the aminoalkoxyphosphonic acid diester of the formula

with the glyoxylic acid of the formula

at a pH of about 6 to about 6.5.

The acid of formula IV wherein R4 and R4 are both hydrogen is obtained by treating the diester of formula VII with acid or trimethylchlorosilane and sodium iodide to yield the acid of the formula

which is then reacted with the glyoxylic acid of formula Villi.

The diester of formula VII is prepared by reacting the phthalimide phosphonic acid diester of the formula

wherein R4 and R4 are both lower alkyl; with hydrazine.

The compound of formula X can be prepared in several ways. For example, following the general procedure set forth by Grochowski et al. (Synthesis 1976 p. 682), a phosphoric acid diester of the formula

is reacted with N-hydroxyphthalimide in the presence of the diethylazodicaboxylic and triphenylphosphine. Alternatively, the phosphonic acid diester of formula XI can be reacted with a sulfonic acid chloride of the formula R10-SO2Cl to yield the intermediate of the formula

wherein R10 is methyl or tolyl. The intermediate of formula XII is then reacted with a compound of the formula

wherein R11 is an alkali metal ion such as sodium or potassium; to yield the phosphonic acid diester of formula X.

The phosphonic acid diester starting materials of formula Xl can be prepared according to the procedure of Abramov (Chem. Abst., Vol. 47, p. 5341 e).

The acid of formula IV wherein one of R4 and R4 is hydrogen and the other is lower alkyl is prepared by reacting the phosphonic acid monoester of the formula

with the glyoxylic acid of formula VIII at a pH of about 2.5.

The monoester of formula XIV can be prepared by various procedures. One procedure is to react the phosphonic acid of formula IX with o-chlorobenzaldehyde to yield

which is reacted with an alcohol, HO-lower alkyl, to yield the monoester of formula XIV along with the corresponding diester. Another procedure is to treat phosphonic acid of the formula

with carbonylbisimidazole and then the alcohol HO-lower alkyl.

The compounds of formula li can be prepared by reacting a compound of formula I wherein R is hydrogen and X is

with pyridine or carbamoyl substituted pyridine in a polar solvent such as water and in the presence of a catalyst such as an alkali metal thiocyanate according to the procedures taught in.US. Patent 3,792,047 and German Offenlegungsschrift 2,234, 280.

Also, the compounds of the formula I wherein X is heterothio (i.e.

can be prepared by reacting the compound of formula I wherein R is hydrogen and X is

with a mercaptan of the formula hetero-S-H (XVI I) or an alkali metal (preferably sodium) mercaptan salt of the formula hetero-S-alkali metal (XVIII) Such methods of introducing a heterothio group in the 3-position are disclosed in various U.S. Patents including 3,955,213 4,066,762, etc.

The p-sulfoxide compounds of formula I (n is one) can also be prepared by the direct oxidation of the corresponding sulfide compound (n is zero). Suitable oxidizing agents are percarboxylic acids such as m-chloroperbenzoic acid, peracetic acid, etc., and this reaction can be performed at from about 0 to about 250.

Also, the sulfone compounds of formula I (n is two) can be prepared by the direct oxidation of the corresponding a-sulfoxide compound (n is one). Again, percarboxylic acids such as m-chloroperbenzoic acid and peracetic acid are the preferred oxidizing agents.

The compounds of formula I wherein R, R4, R4, and R8 are sodium or potassium are prepared by exchanging the proton of the corresponding free acid of formula I (R, R4, F4,, and R8 are hydrogen) with the appropriate salt forming ion.

The compounds of formula I wherein R is

can be obtained by treating the corresponding'free acid of formula I with one or two miles of a compound of the formula

wherein halo is chlorine or bromine in an inert solvent such as dimethylformamide at or below ambient temperature.

Similarly, the compounds of formula I wherein R is

are prepared by treating free acid compound of formula I with a compound of the formula

wherein L is hydroxy or Br as taught in U.S. Patents 3,860,579, 3,951,954, and 4,072,677.

Preferred compounds of this invention are those of formula I wherein R is hydrogen, sodium or potassium; Ra, R2, and F3 are hydrogen; n is zero or one and when n is one the sulfoxide is in the ,B- configuration; R4 and R4 are both hydrogen, sodium, potassium, methyl, or ethyl; X is hydrogen,

R7 is hydrogen, methyl, -CH2-000R8,

or-(CH2)2-N(CH3)2; and R8 is hydrogen, sodium or potassium.

Most preferred are the above compounds wherein R4 and R4 are both hydrogen, sodium, or potassium and X is

The compounds of formula I are useful antibacterial agents possessing activity against various gram negative organisms including Klebsiella, Proteus, and Enterobacter species. These compounds are also active against strains of Escherichia coli, Serratia marcescens, Salmonella typhosa, Shigella sonnei, Citrobacterfreundii, etc. They-may be used-as antibacterial agents to combat infections due to organisms such as those named above, and in general may be utilized in a manner similar to other gram-negative antibacterial agents.For example, a compound of formula I or a physiologically acceptable salt thereof may be used in various animal species in an amount of about 1 to 100 mg./kg., daily in parenteral form, in single or two to four divided doses to treat infections of bacterial origin, e.g., 5.0 mg./kg. in mice.

Up to about 600 mg. of an acid compound of formula I or a physiologically acceptable salt or ester thereof may be incorporated in an injectable form prepared according to conventional pharmaceutical practice.

In particular, those most preferred compounds as defined above in addition to their broad spectrum of antimicrobial activity, also exhibit exceptional activity against a range of gram-negative microorganisms, e.g., Serratia sp., indole positive Proteus sp., Enterobacter sp., and strains of Klebsiella pneumoniae. These compounds show a high degree of stability to p-lactamases from both grampositive and gram-negative bacteria.

Illustrative process details are in the examples for the various reactions. All temperatures are on the centigrade scale.

EXAMPLE 1 [6R-[6Kg,7p(Z)]]-3-[(AGetyloxy)methyl]-7-[[(2-amino-4-thiazolyi)[(phosphonomethoxy)imino]acetyl]- amino]-8 -oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trisodium salt a) [[(1,3-Dihydro- 1 ,3-dioxo-2-lsoindoIyl)oxo]methyll-phosphonic acid, diethyl ester Hydroxymethylphosphonic acid, diethyl ester (177.9 g), triphenylphosphine (277.2 g.) and Nhydroxyphthalimide (172.4 g.) are dissolved in 2 1. of dry tetrahydrofuran. The solution is cooled to about 100 and diethylazodicarboxylate (202.5 g.) dissolved in tetrahydrofuran (200 ml.) is added dropwise with cooling so that the temperature does not exceed 200. Stirring is continued at ambient temperature for 12 hours. The solution is evaporated to dryness and the oily residue dissolved in 700 ml. of diethyl ether.After cooling to OOC most of the triphenylphosphine oxide precipitates and is filtered off. The mother liquor is concentrated and distilled by a short-way distillation apparatus (b.p. 1 800/0.02 mm.). The oily crude product (410 g.) contains about 15% triphenylphosphine oxide. Purification by recrystallization from ether yields [[(1 ,3-dihydro-1 ,3-dioxo-2-isoindolyl)oxy]methyl]phosphonic acid, diethyl ester; m.p. 80--850.

b) ftAminooxy)methyl]phosphonic acid, diethyl ester The crude [[1 ,3-dihydro-1 ,3-dioxo-2-isoindolyl)-oxy]methyl]phosphonic acid, diethyl ester (208.4 g.) from part (a), is dissolved in 600 ml. of dry dichloromethane at 00. At this temperature, 44.8 g. of hydrazine are added dropwise with stirring. After 2.5 hours, the precipitate is filtered off and the mother liquor is evaporated to dryness. The residue is dissolved in 200 ml. of ether, filtered, and the solvent removed in vacuo. The oily residue is distilled, b.p. 1 500/0.003 mm., and yields 88.4 g. of [(aminooxy)methyl]phosphonic acid, diethyl ester.

c) [(Aminooxy)methyllphosphonic acid 30 g. of [(Aminooxy)methyl]phosphonic acid, diethyl ester, from part (b), are heated at reflux temperature in 200 ml. 25% aqueous hydrochloric acid for four hours. After evaporation of the solvent, the residue is treated with 20 ml. of water and filterd. The mother liquor is concentrated in vacuo and dissolved in 10 ml. of methanol. After cooling to 00, 1 6 g. of [(aminooxy)methyl]phosphonic acid precipitates; m.p. 161-163 (dec.).

d) 2-Amino-α-[(phosphonomethoxy)imino]-4-thiazole-acetic acid 2.1 g. of 2-Amino-a-oxo-4-thiazoleacetic acid are dissolved in 20 ml. of water at pH 6.5 by the addition of potassium carbonate. 1.3 g. of [(aminooxy)methyl]-phosphonic acid, from part (c), are added and the pH is maintained at 6 to 6.5 for 24 hours. After acidifying the solution with concentrated HCI to pH 1.5,2.1 g. of 2-amino-a-[(phosphonomethoxy)imino]-4-thiazoleacetic acid precipitates and is filtered off; m.p. 199-201 (dec.).

e) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]-4-thiazoleacetic amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 0.5 g. of 2-Amino-α-[(phosphonomethyl)imino acid, from part (d), 0.88 g. of 7aminocephalosporanic acid, diphenylmethyl ester and 0.26 g. of N-hydroxybenzotriazole are dissolved in 50 mi. of dimethyl sulfoxide and 10 ml. of acetonitrile. The solution is cooled to 0 and 0.52 g.

dicyclohexylcarbodiimide are added. The reaction mixture is stirred at 0 for 20 hours. After this time the insoluble urea is filtered off and the mother liquor poured into 200 ml. of ice-water. The precipitated compound is filtered off, washed with ice-water, dissolved in cold methyl ethyl ketone and extracted three times with ice-cold sodium bicarbonate solution. The bicarbonate layer is stirred with 200 ml. of methyl ethyl ketone at 0 while 2N phosphoric acid is added. The organic layer is separated and the aqueous phase is once more extracted with 200 ml. of methyl ethyl ketone. The organic layers are combined, dried with sodium sulfate and the solvent removed in vacuo until a volume of 10 ml. is reached. This solution is poured into 200 ml. of ether with stirring.The precipitated compound is filtered off, washed with ether and dried to yield 0.5 g. of [6R-[6α,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4 thiazolyl)[(phosphonomethoxy)imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo(4.2.0]oct-2-ene-2carboxylic acid, diphenylmethyl ester; m.p. 95-100 (dec.).

f) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]- amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trisodium salt 3.8 g. of diphenylmethyl ester product of part (e) are added to 19 ml. of anisole. The mixture is cooled to 0 and 38 ml. of trifluoroacetic acid are slowly added dropwise while the temperature is carefully maintained at 00. After the addition is completed, the mixture is stirred at 0 for an additional hour.The dark solution is then poured into 400 ml. of ether and the resulting precipitate is filtered off to yield 2.6 g. of [6F-[6a,7(Z)j]-3-[(aceWloxy)methyIj-7-[[(2-amino-4-thiazolyI) [(phosphonomethoxy)- imino]acetyl]amino]-8-oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trihydrate, m.p.

220225 .

This acid is converted to its trisodium salt by suspending in 40 ml. of methanol and adding 33 ml.

of a 1 N solution of sodium ethyl hexanoate in butanol. The mixture is stirred for one hour at 0 and diluted with 400 ml. of diethyl ether to precipitate 2.6 g. of [6R-[6a,7ss(Z)]]-3-[(acetyloxy)methyl]-7- [[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]-acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct2-ene-2-carboxylic acid, trisodium salt; m.p. 255-260 .

EXAMPLE2 [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]- acetyl]-aminol-8-oxo-5-thia-l -azabicyclo[4,2.0]oct-2-ene-2-carboxylic acid, sodium salt a) 2-Amino-α-[[diethoxyphosphinyl)methoxy]imino]-4-thiazoleacetic acid, m.p. 115-117 .

11.4 g. of 2-Amino-:r-oxo-4-thiazoleacetic acid are suspended in 50 ml. of water. The pH is adjusted to 6.5 by addition of solid potassium carbonate. When the pH of 6.5 is reached, a clear solution is obtained, and 10 g. ot [(aminooxy)methyl]phosphonic acid, diethyl ester from Example 1 (b) are added with stirring. The pH is maintained at 6.5 for 12 hours and then adjusted to 1.5 with concentrated HCI.

The solution is evaporated to dryness in vacuo, the residue is dissolved in methanol, and the insoluble material is filtered off. After evaporation of the methanol, about 1 50 ml. of diethyl ether are added and the mixture is stirred for 24 hours. The crystalline compound is filtered off to yield 1 5 g. of 2-amino-α- [[(diethoxyphosphinyl)methoxy]-imino]-4-thiazoleacetic b) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy]- imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester 2.5 g. of 2-amino-α-[[(diethoxyphosphinyl)-methoxy]imino]-4-thiazoleacetic acid from part (a), 3.66 g. of 7-aminocephalosporanic acid, diphenylmethyl ester, and 1.08 g. of N-hydroxybenzotriazole are dissolved with stirring in 1 50 ml. of 1: :1 dimethylformamide:acetonitrile mixture. After cooling to 0 2.16 g. of dicyclohexylcarbodiimide in 20 ml. of acetonitrile are added dropwise. The mixture is stirred at 0 for 12 hours. The insoluble urea is filtered off and the filtrate evaporated to dryness in vacuo. The oily residue is dissolved in ethyl acetate and subjected to column chromatography over silica gel using ethyl acetate as the eluant. 2 g. of pure [6R-[6cE,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4- thiazolyl)[[(diethoxyphosphinyl)methoxy]-imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2 ene-2-carboxylic acid, diphenylmethyl ester are obtained, m.p. 78-83 .

c) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4- thiazolyl)[[(diethoxyphosphinyl)methoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid, sodium salt 1 g. of the diphenylmethyl ester product from part (b) are suspended in 2 ml. of anisole. After cooling to 00, 4 ml. of trifluoroacetic acid are added dropwise with stirring. The temperature is maintained at 0 with stirring for an additional hour. The solution is then poured into 200 ml. of a mixture of ether/petroleum ether (2:1). The precipitated acid is filtered off to yield 0.7 g. of [6R [6,7ss(Z)]]-3-[(acetyloxy)methoxy]imino]acetyl]amino]-8-oXo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2 carboxylic acid, m.p. 97-102 .

This acid is dissolved in 5 ml. of acetone at 0 and 2.5 ml. of 1 N sodium ethyl hexanoate are added with stirring. After 1 5 minutes, 100 ml. of ether are added and the precipitated sodium salt is filtered off to yield 0.6 g. of [6R-[6a,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)- [[(diethoxyphosphinyl)methoxy]imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2 carboxylic acid, sodium salt, m.p. 102-107 .

EXAMPLE 3 [6R-[6ct,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl-1 H tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trisodium salt a) [6R-[6a, 7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[( 1-methyl 1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester Following the procedure of Example 1 (e) but substituting 7-amino-3-[[1-methyl-1azabicyclo[4.2.0]oct- H-tetrazol-5 yl)thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic, diphenylmethyl ester for the 7 ACA diphenylmethyl ester, one obtains [6R-[6a,7(Z)j]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)- imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl) 2-ene-2-carboxylic acid, diphenylmethyl ester, m.p. 160-165 .

b) [6R-[6α,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl- 1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trisodium salt The diphenylmethyl ester product from part (a) is treated with anisole and trifluoroacetic acid according to the procedure of Example 1 (f). The resulting acid product is converted to its trisodium salt by treatment with sodium ethyl hexanoate as set forth in Example 1 (f) to yield [6R-[6α,7ss(Z)]]-7-[[(2- amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trisodium salt, m.p. 175-180 .

EXAMPLE 4 [6R-[6,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[[(diethoxyphosphinyl)methoxy]imino]acetyl]amino]-3-[[(1 - methyl H-tetrazol-5-yl)thio] methyl-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt a) [6R-[6α,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1- methyl- 1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphen ylmethyl ester Following the procedure of Example 2 (b) but substituting 7-amino-3-[[(1 methyl-1 H-tetrazol-5 yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester for the 7-ACA diphenylmethyl ester, one obtains [6R-[6α;,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[[(diethoxy- phosphinyl)methoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio)methyl]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester.

b) [6R-[6α,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[[(diethoxyphinyl)methoxy]imino]acetyl]amino]-3-[[(1 methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt The diphenylmethyl ester product from part (a) is treated with anisole and trifluoroacetic acid according to the procedure of Example 2(c). The resulting acid product is converted to its sodium salt by treatment with sodium ethyl hexanoate as set forth in Example 2 (c) to yield [6R-[6α,7ss(Z)]]-7-[[(2- amino-4-thiazolyl)[[(diethoxyphosphinyl)-methoxy]imino]acetyl]amino]-3-[[( 1 -methyl-1 H-tetrazol-5 yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt.

EXAMPLE 5 [5S-[5cz,6,B,7(Z)]]-3-[(Acetyloxy) methyl]-7-[[(2-am ino-4-thiazolyl) [(phosphonomethoxy)imino]acetyl] amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt a) [5S-[5a, 6 7a]-3-[(Acetyloxy)methyl]- 7-amino-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., ss-sulfoxide) and[5R-[5α,6α;,7ss]]-3- [KAcetyloxy)methyll- 7-amino-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphen ylmethyl ester (i.e., a-suffoxide) A slurry of 50 g. of 7-aminocephalosporanic acid (7-ACA) in 1 liter of water is stirred magnetically while t-octylamine is added dropwise, thereby maintaining the pH between 7 and 8. After one hour, the undissolved solid is filtered (Celite) and the filtrate is treated with a solution prepared by adjusting a mixture of 10 ml. of t-octylamine and 20 ml. of water to pH 8.0 with 6N hydrochloric acid. The resulting solution is then treated with 10 ml. of salicyaldehyde. After 2 minutes a solid forms and after 5 minutes an additional 10 ml. of salicyladehyde is added.The slurry is stirred for an additional 10 minutes, cooled to 0 for 4.5 hours and filtered. The filter cake is slurried twice with 300 ml. of cold water and filtered.

The wet cake is dried at 600 in vacuo over large amounts of P205 to give 66 g. of tan solid 7salicylaldiminocephalosporanic acid, t-octylamine salt.

A slurry of 25.25 g. (0.05 mole) of the above t-octylamine salt (powdered with a mortar and pestle) in 250 ml. of dry acetonitrile is treated with 9.5 g. (0.05 mole) of p-toluenesulfonic acid monohydrate. After 10 minutes, a solution of 9.7 g. (0.05 mole) of diphenyldiazomethane in 50 ml. of acetonitrile is added over the course of 1 5 minutes. After one hour, the slurry is filtered, the solid is washed with acetonitrile, and the combined filtrate and washings are evaporated in vacuo. The resulting oil is chromatographed on a 300 g. silica gel column eluted with methylene chloride.Fractions (500 ml.) 2-3 contain 7.5 g. of the desired diphenylmethyl ester product plus some higher Rf impurity (monitored by silica gel TLC with 3:1 chloroform-ethyl acetate development): fractions 4-11 1 contain 12.3 g. of pure 7-salicylaldiminocephalosporanic acid, diphenylmethyl ester; NMR (CDCl3) a 1.97 (s, 3H, CH3CO); 3.23 and 3.60 (AB q, J = 19 Hz, 2H, C-2); 4.67 and 5.01 (AB q, J = 14Hz, 2H, C-3'); 4.99 (d, J = 5 Hz, 1 H, C-6); 5.20 (broadened d, J = 5 Hz, 1 H, C-7); 6.62 --- 7.60 (m, about 15H); 9.07 (broad s, 1H, -CH=N-).

A solution of 12.3 g. (0.023 mole) of the above diphenylmethyl ester product in 125 ml. of methylene chloride is cooled to 0 and a solution of 4.6 g. (0.023 mole) of 85% m-chloroperbenzoic acid in 70 ml. of methylene chloride is added over the course of 1 5 minutes. After one hour, the slurry is washed with a mixture of 100 ml. of 5% sodium bicarbonate and 50 ml. of 6% sodium sulfite solution.

The organic layer is dried and evaporated in vacuo. The resulting oil crystallizes from 70 ml. ef ethyl acetate giving 8.7 g. of a mixture of a- and ,B- sulfoxides. A second crop of 1.5 g. of a mixture of a- and ss- sulfoxides is also obtained. The major (a-) isomer has a lower field acetate methyl (2.02 ppm) and 0-2 quartet (3.57 and 4.10 ppm) when compared to those of the minor (,B) isomer (1.97, 3.26 and 3.94 ppm, respectively).

A slurry of 10 g. (0.018 mole) of the above 7-salicylaldiminocephalosporanic acid, diphenylmethyl ester, a- and ss-sulfoxide mixture in 100 ml. of ethyl acetate is treated with 3.42 g (0.018 mole) of ptoluenesulfonic acid monohydrate. After 5.5 hours, 300 ml. of ether is added and the gummy solid is triturated, filtered, and washed twice with ether. The moist solid is dissolved in 200 ml. of ethyl acetate and the solution is washed with 100 ml. of 5% sodium bicarbonate solution, dried, and evaporated to give 8.0 g. of residue.Chromatography on a 300 g. silica gel column eluted with 3:1 chloroform-ethyi acetate gives (500 ml. fractions): fraction 3, 1.0 g. of recovered 7-salicylaldiminocephalosporanic acid, diphenylmethyl ester; fractions 6-1 6, 4.5 g. of [5R=[5α,6α,7ss]]-3-[(acetyloxy)methyl]-7-amino-8-oxo- 5-thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenyl ester (i.e., a-sulfoxide isomer): NMR (CDCI3) ,,s 2.00 (CH3COO-); 3.43 and 4.06 ppm (AB q, C-2); fractions 22-30 (eluant is changed to ethyl acetate after fraction 16) 1.5 g. of [5S-[5α,6ss,7α]]-3-[(acetyloxy)methyl]-7-amino-8- oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., ss- sulfoxide isomer): NMR (CDCI3) # 2.10 (CH3COO-); 2.97 and 3.54 ppm (AB q, C--2).

b) [5S-[5α,6ss,7α[Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]- acetyi]amino]-8-oxo-5-thia- I -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester 1 g. of 2-amino-o-[(phosphonomethoxy)imino]-4-thiazoleacetic acid from Example 1(d), 1.82 g. of the ss-sulfoxide diphenylmethyi ester from part (a), and 0.52 g. of N-hydroxybenzotriazole are dissolved in 50 ml. of dimethyl sulfoxide. After the addition of 25 ml. of acetonitrile, the solution is cooled to 0 with stirring. 1.04 g. of dicyclohexylcarbodiimide are then added and stirring at 0 is continued for 1 5 hours. After this time, the insoluble urea is filtered off. The mother liquor is poured onto ice and the resulting precipitate is filtered off and washed with water. The crude product is suspended in 20 ml. of cold aqueous sodium bicarbonate solution and extracted three times with methyl ethyl ketone. The aqueous phase is filtered, acidified with phosphoric acid in the cold, and extracted three more times with methyl ethyl ketone. The organic layers are combined, dried, and the solvent is distilled off. The residue is dissolved in a few mls. of methanol and poured into diethyl ether to yield as a precipitate 1.5 g. of [5S-[5a,6,7a(Z)]]-3-[(aceWIoxy)methyI]-7-[[(2-amino-4-thiazolyI)[(phosphonomethoxy)- imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester, m.p. 165-170 .

c) [5S-[5α,6ss,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]- acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt The diphenylmethyl ester product from part (b) is suspended in 3 mi. of anisole at 0 and 6 ml. of trifluoroacetic acid are slowly added dropwise with stirring. After the addition is completed, the mixture is stirred for an additional hour at 00. The solution is then poured into 200 ml. of diethyl ether with stirring to yield as a precipitate 1 g. of [5S-[5α,6ss,7α]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4- thiazolyl)[(phosphonomethyl)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, m.p. 160-170 .

This acid is dissolved in 20 ml. of methanol and an equivalent amount of 1 N sodium ethyl hexanoate in butanol is added at 0 with stirring. After 30 minutes, 200 ml. of ether are added precipitating 0.9 g. of [5S-[51z,6X3,7(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphono- methoxy)imino]acetyl]amino]-8-oxo-5-thia -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt, m.p. > 1800.

EXAMPLE 6 [5R-[5α,6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]- amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide trisodium salt a) [5R-[5α,6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]- acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.O]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester 2-Amino-a-[(phosphonomethoxy)imino]-4-thiazole-acetic acid and the α-sulfoxide diphenylmethyl ester from Example 5(a) are reacted in the presence of N-hydroxybenzotriazole and dicyclohexylcarbodiimide according to the procedure of Example 5(b) to yield [5R-[5α,6α;,7ss(Z)]]-3- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-8-cXo-5-thia-1 azabicycio[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester.

b) [5R-[5α,6α,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]- acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt The diphenylmethyl ester from part (a) is treated with anisole and trifluoroacetic acid at 0 according to the procedure of Example 5 (c) to yield [5R-[5cz,6a,7/3(Z)]]-3-[(acetyloxy)methyl]-7-[[(2- amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid, 5-oxide.

This acid product is treated with sodium ethyl hexanoate to yield [5R-[5α,6α,7ss(Z)]]-3- [(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]acetyl]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt.

EXAMPLE 7 [5S-[5α,6ss-7α(Z)]]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl- 1 H-tetrazol-5-yl)thio[ethyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt a) [5S-[5α,6ss,7α(Z)]]-7-Amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., ss-sulfoxide) and [5R [5α,6α;,7ss]]-7-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct- 2-ene-2-carboxylic acid, 5-oxide, diphen ylmethyl ester (i.e., a-suffoxide) Following the procedure of Example 5 (a) but substituting 7-amino-3-[[(1 -methyl-1 H-tetrazol-5 yl)thiojmethyl]-8-oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid for the 7-ACA, one obtains a mixture of the desired sulfoxide products which are then separated chromatographically to yield the individual a- and ,B- sulfoxides.

b) [5S-[5α,6ss,7α(Z)]]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1- methyl- 1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4. 2. O]oct-2-ene-2 -carboxylic acid, 5oxide, diphenylmethyl ester 1 g. of 2-Amino-α-[(phosphonomethoxy)imino]-4-thiazolecacetic acid, from Example 1 (d), 1.82 g.

of [5S-[5α,6ss,7α]]-7-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester (i.e., ss-sulfoxide) from part (a), and 0.52 g. of N-hydroxybenzotriazole are dissolved in 100 ml. of dimethyl sulfoxide and 50 ml. of acetonitrile. The solution is cooled to 0 and 1.04 g. of dicyclohexylcarbodiimide in 20 ml. of acetonitrile are added dropwise with stirring. The temperature is maintained at 0 for 12 hours. After this time, the insoluble urea is filtered off.The mother liquor is poured into 500 ml. of ice water and the precipitated product is filtered off, washed with water and dried to yield 1.4 g. of [5S-[5α,6ss,7α(Z)]]-7- [[(2-amino-4-thiazolyl)-[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1 methyl 1 H-tetrazol-5 yl)thio] methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenyl methyl ester, m.p. 160-165 .

c) [5S-[5α,6ss,7α(Z)]]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1- methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thiaz-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5oxide, trisodium salt The diphenylmethyl ester product from part (b) is suspended at 0 in 3 ml. of anisole. Whiie stirring vigorously, 6 ml. of trifluoroacetic acid are added and the stirring is continued for an additional hour. The resulting solution is poured into 500 ml. of diethyl ether and the crystalline product is filtered off to yield 0.9 g. of [5S-[5α,6ss,7α(Z)]]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]- amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5-oxide, m.p. 166-160 .

This acid is converted to its trisodium salt by suspending the acid in 10 ml. of methanol and adding 6.3 ml. of a 1 N solution of sodium ethyl hexanoate in butanol. The mixture is stirred for 30 minutes and then diluted with 200 ml. of ether to crystallize out 0.7 g. of [55-[5a, 6,1, 7a(Z)j]-7-[[(2- amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt; m.p. > 2000.

EXAMPLE 8 [5R-[5α,6α,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl- 1 H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt a) [5R-[5α,6α;, 7/0rZ)]]-7-[[f2-Amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[{ 1methyl- 1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5oxide, diphenylmethyl ester Following the procedure of Example 7 (b) but substituting [5F-[5a,6a,7j-7-amino-3-[[(1 methyl H-tetrazol-5-yl)thio-methyl]-8-oxo-5-thia-1 -azabicyclo[4.2 .0]oct-2-ene-2-carboxylic acid, 5oxide, diphenylmethyl ester from Example 7 (a) for the p-suifoxide, one obtains [5R-[5α,6α;,7ss(Z)]]-7- [[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5 yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester b) [5R-[5α,6α,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1- methyl- 1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5oxide, trisodium salt The diphenylmethyl ester product from part (a) is treated with anisole and trifluoroacetic acid at 0 according to the procedure of Example 7 (c) to yield [5R-[5α,6α;,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)- [(phoxphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide.

This acid is converted to its trisodium salt by treatment with sodium ethyl hexanoate to yield [5R [5α7ss(Z)]]-7-[[(2-amino-5-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl-1H- tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0)oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt.

EXAMPLE 9 [5S-[5α,6ss,7α(Z)]]-7-[[(2-Amino-4-thiazolyl)[[diethoxyphosphinyl)methoxy]imino]-3- [[(1-methyl-1H-tetrazolyl-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt a) [5S-[5α,6ss,7α(Z)]]-7-[[(2-Amino-4-thiazolyl)[[(diethoxyphosphinyl)methoxy]imino]-3- [[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester 0.5 g. of 2-Amino-α-[[(diethoxyphosphinyl)methoxy]imino]-4-thiazoleacetic acid from Example 2(a), 0.75 g. of [5S-[5α,6ss,α ;]]-7-amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1- azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, diphenylmethyl ester from Example 7 (a), and 0.2 g. of N-hydroxybenzotriazole are dissolved in 1 50 ml. of dry dimethylformamide. The solution is cooled to 0 and 0.43 g. of dicyclohexylcarbodiimide are added with stirring. After 24 hours at 00, the insoluble urea is filtered off and the mother liquor is evaporated to dryness.The residue is dissolved in 10 ml. of acetone and column chromatographed over silica gel using acetone as the eluent to yield 0.8 g. of [55-[5a,6/3,6a(Z)]]-7-[[(2-amino-4-thiazolyl)[[(diethoxyphosphinyl)methoxyjiminojacetyl]- amino]-3-[[(1-methyl-1H-tetrazol-6-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene2-carboxylic acid, 5-oxide, diphenylmethyl ester; m.p. 112-115 .

b) [5S-[5α,6ss,7α(Z)]]-7-[[(2-Amino-4-thiazolyl)[[(diethoxyphosphinyl)methoxy]imino]acetyl]amino]-3- [[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt 1.43 g. of the diphenylmethyl ester product from part (a) are added to 3 ml. of anisole and cooled with stirring to 0 . At this temperature, 6 mI.oftrifluoroacetic acid are added dropwise. Stirring is continued for one hour at 00.The solution is then poured into 400 ml. of ether and the crystalline product is filtered off to yield 0.78 g. of [5S-[5,6,B,7cg(Z)]]-7-[[(2-amino-4-thiazolyl)[[(diethoxy- phoxphinyl)methoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide; m.p. 117-122 .

This acid is dissolved in 5 ml. of methanol and 0.43 g. of sodium ethyl hexanoate in 3 ml. of butanol are added at 00. After stirring for five minutes, 200 ml. of ether are added and the precipitating product is filtered off to yield 0.61 g. of [5S-[5α,6ss,7α(Z)]]-7-[[(2-Amino-4-thiazolyl)[[(diethoxy- phosphinyl)methoxy]imino]acetyl]amino]-3-[[( 1-methyl-1 H-tetrazolyl-5-yl)thio]methyl]-8-oxo-5-thia-i azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, sodium salt; m.p. 155-160 .

EXAMPLE 10 [6R-[6α7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]- amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, trisodium salt a) [6R-(6a, 7ss]]-3-[(Acetyloxy)methyl]-7-amino-8-oxo-5-thia- 1 -azabicyclo[4. 2. O]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester [5 R-[5α,6α,7ss]]-3-[(Acetyloxy) methyl]-7-a mino-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5-oxide, diphenylmethyl ester from Example 5(a) is added to methylene chloride and cooled to 00. An equimolar amount of p-toluenesulfonic acid followed by an equimolar amount of mchloroperbenzoic acid in methylene chloride is added.After the reaction is completed, the slurry is treated with 5% sodium bicarbonate and 5% sodium sulfite. The organic layer is dried and evaporated in vacuo. Preparative thin layer chromatography of the residue yields [6F-[6a,7]-3-[(acewloxy)methyl]- 7-amino-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenyl ester.

b) [6R-[6α,7ss(Z)]]-3-[(Acetyloxy)methyl-7-[[(2-amino-thiazolyl)[(phosphonomethoxy)imino]acetyl]- amino]-8-oxo-5-thia- I -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester.

2-Amino-a-[(phosphonomethoxy)imino]-4-thiazoleacetic acid from Example 1 (d) and the [6R [6α7ss]]-3-[(acetyloxy)methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester from part (a) are reacted in the presence of N-hydroxybentotriazole and dicyclohexylcarbodiimide according to the procedure of Example 5 (b) to yield [6R-[6α,7ss(Z)]]-3- [(acetyloxy)methyl-7-[[(2-amino-4-thiazolyl)-[(phosphonomethoxy)imino]acetyl]amino]-8-oxo-5-thia1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, diphenylmethyl ester.

c) [6R,-[6alpha;,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethxoy)imino]acetyl]amino]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, trisodium salt.

The diphenylmethyl ester product from part (b) is treated with anisole and trifluoroacetic acid at 0 according to the procedure of Example 5(c) to yield [6R-[6a,7p(Z)]]-3-[(acetyloxy)methyl]-7-[[(2- amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2ene-2-carboxylic acid, 5,5-dioxide.

This acid is converted to its trisodium salt by treatment with sodium ethyl hexanoate to yield [6R,[6alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(-phosphonomethxoy)imino]acetyl]amino]8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid, 5,5-dioxide, trisodium salt.

EXAMPLE 11 [6R,[6alpha;,7ss(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(-phosphonomethxoxy] imino]acetyl]amino]-8-oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid a) [[[[(2-Chlorophenyl)methylene]amino]oxy]methyl]-phosphonic acid A mixture of 1.27 g. of 2-chlorobenzaldehyde, 1.54 g. of [(aminooxy)methyljphosphonic acid, and 39. of 4A molecular sieves is refluxed for 40 minutes in 30 ml. of ethanol. After filtration, the solvent is evaporated in vacuo and the yellow residue is treated with ether/petroleum ether until crystallization takes place. Recrystallization from dioxane yields light yellow crystalline [[[[(2-chlorphenyl)methylene]amino]oxy]methyl] phosphonic acid, m.p. 132-134 .

b) [[[[(2 -Chlorophen yl)methylene]amino]oxy]methyli phosphonic acid, monoethyl ester 12.5 g. of [[[[(2-Chlorophenyl)methylene]amino]oxy]methyl]phosphonic acid and 2.3 g. of ethanol are stirred in 100 ml. of tetrahydrofuran at 00. A solution of 10.3 g. of dicyclohexylcarbodiimide in 100 ml. of tetrahydrofuran is added dropwise. After four hours the reaction is completed and the solution is filtered and evaporated in vacuo to yield an oily residue of [[[[(2-chlorophenyl)methylene]amino]oxyj- methyl]phosphonic acid, monoethyl ester which contains about 1 5% of the diethyl ester.

c) 2-Amino-α[[(ethoxyhydroxyphosphinyl)methoxy]imino]-4-thiazoleacetic acid The [[[[(2-chlorophenyl)methylene]amino]oxy]methyl]phosphonic acid, monoethyl ester is reacted with 2-amino-a-oxo-4-thiazoleacetic acid, hydrochloride salt in water at a pH of about 2.5 to yield 2 amino-α-[[(ethoxyhydroxyphosphinyl)methoxy]imino]-4-thiazoleacetic acid.

d) [6R,[6alpha;,7ss(Z)]]-3][(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[[(ethoxyhydroxyphosphinyl) methoxy]imino]acetyl]amino]-8-oxo-5-thia 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

The 2-amino-α-[[(ethoxyhydroxyphosphinyl)methoxy]imino]-4-thiazoleacetic acid form part (c) is reacted with 7-aminocephalosporanic acid, diphenylmethyl ester in the presence of dicyclohexylcarbo- diimide according to the procedure of Example 1 (e) to yield [6R,[6a,7,B(Z)]]-3-[(acetyloxy)methyl]-7- [[(2-amino-4-thiazolyl)[[(ethoxyhydroxyphosphinyl)methoxy]imino]acetyl]amino]-8-oxo-8-thia azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester.

Treatment of this ester procduct with trifluoroacetic acid and anisole according to the procedure of Example 1 (f) yields [6R,[6alpha;,7ss(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(ethoxyhydroxy phosphonomethxoy)imino]acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

EXAMPLE 12 [6R,[6alpha;,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(ethoxyhydroxyphosphinyl)methoxy]imino]acetyl]amino]-3 [[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

a) [[[[(2-Chlorophenyl)methylene]amino]oxy]methyl]-phosphonic acid, mixed anhydride with 1 H- imidazole- 1 -carboxyllc acid, lH-imidazole salt.

A solution of 12.5 g. of [[[[(2-chlorophenyl)methylene]amino]oxy]methyl]phosphonic acid in 10 ml. of dioxane/tetrahydrofuran (abs.) is treated with a solution of 0.81 g. of carbonylbisimidazole to yield as a white solid [[[[(2-chlorophenyl]methylene)amino]oxy]methyl]phosphonic acid, mixed anhydride with 1H-imidazole-1-carboxylic acid, 1H-imidazole salt, m.p. 109-11 (dec.).

b) [[[[(2-Chlorophenyl)methylene]amino]oxy]methyl]phosphonic acid, monoethyl ester.

The product from part (a) is refluxed for 30 minutes in 10 ml. of ethanol. The solvent is evaporated and the residual oil is dissolved in 20 ml. of methylene chloride and extracted with 50 ml. of 0.1 N hydrochloric acid and 50 ml. of water. The organic layer is dried and evaporated to yield [[[[(2 chlorophenyl)methylene]amino]oxy]methyl]phosphonic acid, monoethyl ester as a light yellow oil.

c) 2-Amino-α-[[(ethoxyhydroxyphosphinyl)methoxy]imino]-4-thiazoleacetic acid.

The [[[[92-chlorophenyl)methylene]amino]oxy]methyl]phosphonic acid, monoethyl ester is reacted with 2-amino-a-oxo-d-thiazoleacetic acid, hydrochloride salt in water at a pH of about 2.5 to yield 2 amino-α-[[(ethoxyhydroxyphosphinyl)methoxy]imino]-4-thiazoleacetic acid.

d) [6R,[6alpha;,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(ethoxyhydroxyphosphinyl)methoxy]imino]acetyl]amino] 3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid.

The 2-amin[α-[[(ethoxyhydroxyphosphinyl)methoxy]imino]-4-thiazoleacetic acid from part (c) is reacted with 7-amino-3-[[(1 1-methyl-1 H-tetrazol-5-yl)thio] methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0] oct-2-ene-2-carboxylic acid, diphenylmethyl ester in the presence of dicyclohexylcarbodiimide according to the procedure of Example 1 (e) to yield [6R,[6a,7,B(Z)]]-7-[[(2-amino-4-thiazolyi)[[(ethoxy- hydroxyphosphinyl)methoxy]imino]acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5 thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, diphenylmethyl ester.

Treatment of this ester product with trifluoroacetic acid and anisole according to the procedure of Example 1(f) yields [6F-[6a,7(Z)j]-7-[[(2-amino-4-thiazolyl) [[(ethoxyhydroxyphosphinyl)methoxy] imino]acetyl]amino-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct 2-ene-2-carboxylic acid.

EXAMPLES 13-43 Following the procedure of Examples 1 to 12 but employing the 7-aminocephalosporanic acid ester shown in Col. I and the phosphonic acid shown in Col. II one obtains the ester shown in Col. III.

Removal of the ester protecting group yields the acid product shown in Col. IV.

Example X R9 R1 R2 R3 R4 AND R4' n 13 -O-#-CH3 # -H -H -H -C2H5 one 14 -O-#-CH3 -C(CH3)3 -H -H -H -CH3 zero 15 -O-#-CH3 # -H -CH3 -CH3 -H zero 16 -O-#-CH3 # -OCH3 -H -H -H zero 17 -O-#-CH3 # -H -H -H -C2H5 two 18 -O-#-CH3 # -H -C2H5 -C2H5 -H zero 19 -O-#-C2H5 # -H -H -H -n-C3H7 zero 20 H # -H -H -H -H zero 21 H # -H -CH3 -H -C2H5 zero

Example X R9 R1 R2 R3 R4 AND R4' n 22 -O-#-NH2 # -H -H -H -H zero 23 -O-#-NH2 # -H -H -H -C2H5 zero 24 -O-#-NH2 # -H -H -H -H one 25 -O-#-NH2 # -H -H -H -H two 26 -O-#-NH2 # -H -CH3 -CH3 -H zero 27 # # -OCH3 -H -H -CH3 zero 28 # # -H -CH3 -H -H zero 29 # # -H -H -H -H zero

Example X R9 R1 R2 R3 R4 AND R4' n 30 # # -H -H -H -H one 31 # # -H -H -H -n-C4H9 zero 32 # # -OCH3 -H -H -H zero 33 # # -H -CH3 -C2H5 -H zero 34 # # -H -CH3 -CH3 -C2H5 zero 35 # # -H -H -H -CH3 zero

Example X R9 R1 R2 R3 R4 AND R4' n 36 # # -H -H -H -H zero 37 # # -H -H -H -C2H5 one 38 # # -H -H -H -H zero

Example X R9 R1 R2 R3 R4 R4' n 39 # # -H -H -H -H -CH3 one 40 -O-#-CH3 # -H -H -H -H -C2H5 two 41 # # -OCH3 -H -H -H -C2H5 zero 42 -O-#-CH3 # -H -CH3 -CH3 -H -C2H5 zero 43 # # -H -H -H -H -t-C4H9 zero

The acid products of Examples 13 to 43 can be converted to the sodium or potassium, or when R, and R4 are hydrogen to the trisodium or tripotassium salt, according to known procedures. Of course, in Examples 35 and 36 the tetrasodium or tetrapotassium salt would be obtained.

The products of Examples 13 and 43 are obtained as the syn or anti isomer depending upon the configuration of the phosphonic acid shown in Col. II. Also when R2 and R3 are not the same, the products are obtained in the D-, L- or D,L-form depending upon the optical activity of the phosphonic acid shown in Col. II.

EXAMPLE 44 [6R-[6α,7ss(Z)]]-3-[[(4-(Aminocarbonyl)pyridino]methyl]-7-[[2-amino-4-thiazolyl)[(phosphono- methoxy]imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodi u m salt A mixture of 0.005 mole of the trisodium salt product of Example 1, 0.0075 mole of 4 pyridinecarboximide, 1 2 g. of potassium thiocyanate, and 7.5 ml. of water are heated at soc for 24 hours. The resulting solution is passed through a chromatography column filled with Amberlite XAD-2.

The column is washed with water and the titied compound is eluted with a mixture of water:methanol (8:2). The methanol is evaporated from the eluate and the aqueous solution is lyophilized. The amorphous residue is triturated with ether and filtered under suction to yield [6R-[6a,7,B(Z)]]-3-[[4- (aminocarbonyl)pyridino] methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-8- oxo-5-thia-l -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, disodium salt.

EXAMPLES 45-53 Following the procedure of Example 44 but employing the cephalosporanic acid sodium salt shown in Col. I and the pyridine compound shown in Col. II, one obtains the product shown in Col. III.

Example R1 R2 R3 R4 R4' n Z 45 -H -H -H -X -X one -#NH2 (4) 46 -H -H -H -Na -Na two -#NH2 (3) 47 -OCH3 -H -H -Na -Na zero -H 48 -H -H -H -C2H5 -C2H5 zero -H 49 -H -H -H -CH3 -CH3 one -#NH2 (4) 50 -H -CH3 -CH3 -Na -Na zero -#NH2 (2) 51 -H -C2H5 -H -Na -Na zero -H 52 -H -H -H -C2H5 -H zero -#NH2 (4) 53 -H -H -H -C2H5 -H zero -H

The products of Examples 45 to 53 are obtained in the syn or anti configuration depending upon the configuration of the 3-acetoxymethyl starting material shown in Col. I. Similarly, when n is one the compounds are obtained as the a- or /3-sulfoxide depending upon the orientation of the 3-acetoxymethyl sulfoxide starting material. Also, when R2 and R3 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col.

I.

EXAMPLE 54 [6R-[6(g,7p(Z)]]-7-[2-Amino-4-thiazolyl)[(phosphonomethoxy]imino]acetyl]amino]-3-]](5-methyl-1,2,4- thiadiazolyl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trisodium salt 0.002 mole of the trisodium salt product of Example 1 is brought into solution in 100 ml. of a phosphate buffer at a pH of 6.4. Then 0.0024 mole of 5-methyl-1,3,4-thiadiazolyl-2-thiol is added. The solution is heated at 600 for six hours. After cooling, the pH is adjusted to 7.0 and the solution is chromatographed on Amberlite XAD-2. The fraction containing the desired product is freeze dried to yield [6R-[6α,7ss(Z)]]-7-[[(2-amino-4-thiazolyl)[(phosphonomethyoxy)imino]acetyl]amino]-3-[[(5-methyl- I ,3,4-thiadiazolyl)-thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trisodium salt EXAMPLES 55-60 Following the procedure of Example 54 but employing the cephalosporanic acid sodium salt shown in Col. I and the thiol shown in Coi. II, one obtains the product shown in Col. III

Col.II H S-h etero

Example R1 R2 R3 R4 R4' n hetero 55 -H -H -H -C2H5 -C2H5 zero # 56 -H -CH3 -CH3 -Na -Na two # 57 -OCH3 -CH3 -H -CH3 -CH3 one # 58 -H -H -H -Na -Na zero # 59 -H -H -H -Na -Na one # 60 -H -H -H -C2H5 -H two # The products of Examples 55 to 60 are obtained in the syn or anti configuration depending upon the configuration of the -acetoxymethyl starting material shown in Col. I.Similarly, when n is one the compounds are obtained as the a- or jB-sulfoxide depending upon the orientation of the 3-acetoxymethyl sulfoxide starting material. Also, when R2 and R3 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col.

I.

EXAMPLE 61 [5S-[5α,6ss,7α(Z)]]-3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)acetyl]- amino]-8-oxo-5-thia- 1 -azabicyclo(4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodi u m salt.

The product of Example 5 can also be prepared by the following procedure.

1 9. of [6R,[6a,7(Z)]] -3-[(Acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)- iminojacetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid from Example 1 is dissolved in 10 ml. of trifluoroacetic acid at 00,0.39 g. of m-chloroperbenzoic acid are added, and the solution is stirred at 0 for 1.5 hours. Then 500 ml. of diethyl ether are added and the precipitated product is filtered off to 0.85 g. of [5S-[5a!,6p7(Z)]]-3-[(acetyloxy)methyl]-7-[[(2-amino-4-thiazolyl) [(phosphonomethoxy)i mino] acctyl]amino]-8-oxo-SJthia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid; m.p. 160--1700.

This acid can be converted to its trisodium salt by treatment with sodium ethyl hexanoate as set forth in Example 5.

EXAMPLES 62-70 Following the procedure of Example 61 the sulfides shown in Col. I can be oxidized to the p- sulfoxide shown in Col. II.

Example R1 R2 R3 R4 x 0 II 62 -H -H -H 2 5 -H -O-C-CH 63 -H -H -H -H -H N - N -S II CH3 64 -H -H -H -C2H5 2 5 4 N ,N cH3 0 65 -OCH3 CH3 CH3 -H -H -O-C-CH 0 66 -H -H -H -CH3 -CH3 w -CH 67 -H -C H -H -H -H -N Ii -s CH3 0 II 68 -H -H -H -H -H -O-C-NH 0 69 -H -H -H -C 5 2 5 -0-NHZ 0 70 -H -CH3 -CH3 -C 2H5 2 2H5 -O-l-CH

The products of Examples 62 to 70 are obtained in the syn or anti configuration depending upon the configuration of the sulfide starting material shown in Col. I. Also, when R2 and R3 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. l.

EXAMPLE 71 [6R-[6α,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[(1-methyl-1H- tetrazol-5-yl)thio] methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5,5-dioxide, trisodium salt [5R-[5α,6α;,7ss(Z)]]-7-[[(2-Amino-4-thiazolyl)[phosphonomethoxy)imino]acethyl]amino]-3-[[(1- methyl H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid from Example 8 is dissolved in trifluoroacetic acid and reacted with m-chloroperbenzoic acid according to the procedure of Example 53 to yield [6R-[6a,7,B(Z)]]-7-[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]- acetyl]amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene2-carboxylic acid, 5,5-dioxide.

This acid can be converted to its trisodium salt by treatment with sodium ethyl hexanoate as set forth in the previous Examples.

EXAMPLES 72-78 Following the procedure of Example 71 the a-sulfoxides shown in Col. I can be oxidized to the sulfones shown in Col. II.

Example a1 R2 R3 R4 a' x Example R1 R2 R3 Fi4 R4 X4 4 0 72 -H -H -H -H -H -O-C-CH3 0 73 -H -H -H 2 S -H O C CH 74 -H -CH3 -CH3 -H -H N- N --II*N -S 4N II "N CH3 75 -OCH3 -H -H -i-C3H7 -i-C3H7 N - N -s i cH 3 0 76 -H -C H -H -H -H -O^l-NH

Example R1 R2 a3 R4 R4, x o It 77 -H -n-C3H7 -H -H -H -0-C-CH3 78 -H -H -H -CH3 -CH3 N N 63 The products of Examples 72 to 78 are obtained in the syn or anti configuration depending upon the configuration of the a-sulfoxide starting material shown in Col. I. Also when R2 and R3 are not the same, the products are obtained in the D-, L- or D,L-isomeric form depending upon the optical activity of the starting material shown in Col. I.

The acid products of Examples 1 to 78 can also be converted to various ester forms

according to known procedures.

Claims

1. A compound of the general formula

wherein: the

group is in the syn or anti configuration: R represents hydrogen, sodium, potassium, benzyl, p-methoxybenzyl, diphenylmethyl, t-buWl,.

-CH2-0- lower alkyl,

R1 is in the cr-configuration and represents hydrogen or methoxy; R2 represents hydrogen, methyl, ethyl, i-propyl or n-propyI; R3 represents hydrogen, methyl, ethyl, i-propyl or n-propyl; R4 and R4 are the same and represent hydrogen, sodium, potassium, or lower alkyl, or one is hydrogen and the other is lower alkyl; R5 represents hydrogen or lower alkyl; n is 0, 1 or 2; X represents hydrogen,

R6 represents hydrogen or lower alkyl; R7 represents hydrogen, lower alkyl, -(CH2)rn-n-(Iower alkyl)2, -(CH2)m-C00R8 or -(CH2)rn-503F8; R8 represents hydrogen, sodium, or potassium; m is 1,2,3 or 4.

2. A compound as claimed in claim 1, in the imino form.

3. A compound as claimed in claim 1 or 2, wherein the oximino substituent

is in the syn configuration.

4. A compound as claimed in claim 1, wherein R is hydrogen, sodium or potassium; R, is hydrogen; R2 and R3 are both hydrogen; R4 and R4 are the same and are hydrogen, sodium, potassium, methyl or ethyl; n is O or 1, and when n is one the sulfoxide is in the p-configuration; X is hydrogen,

R7 is hydrogen, methyl, -(CH2)2N(CH3)2, -CH2-COOR8; R8 i is hydrogen, sodium or potassium; and wherein the

group is in the syn configuration.

5. A compound as claimed in claim 4, wherein X is hydrogen.

6. A compound as claimed in claim 4, of the general formula XXI,

wherein Z is hydrogen or

7. A compound as claimed in claim 4, wherein x is

8. A compound as claimed in claim 4, wherein x is

R7 is hydrogen, methyl, -CH2-COOR8'-CH2-SO3R8' or -(CH2)2N(CH3)2; and R8 is hydrogen, sodium or potassium.

9. The compound of claim 8 wherein X is

10. A compound as claimed in claim 9 wherein R4 and R4 are the same and are hydrogen, sodium or potassium.

11. A compound as claimed in claim 10, wherein n is zero.

12. [6F-[6a,7(Z)]]4-[[(2-amino-4-thiazolyI) [[phosphonomethoxy)imino]acetyl]amino]-3-[[( 1 - methyl H-tetrazol-5-yl)thio]-methyl]-8-oxo-5-thia- 1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trisodium salt.

13. A compound as claimed in claim 10, wherein n is one.

14. [55-[5a,6,1,7a(Z)]]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]acetyl]amino]-3-[[( 1 - methyl H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5oxide, trisodium salt.

15. A compound as claimed in claim 7, wherein R4 and F41 are both ethyl.

16. [5S-[5α,6ss,7α(Z)]]-7-[[(2-amino-4-thiazolyl)[[(diethyoxyphosphinyl)methoxy]imino]acetyl]- amino]-3-[[(1-methyl-1H-tetrazol-5-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2carboxylic acid, 5-oxide, sodium salt.

17. A compound as claimed in claim 2, wherein X is

18. A compound as claimed in claim 17, wherein R4 and R4 are the same and are hydrogen, sodium or potassium.

19. A compound as claimed in claim 18, wherein n is zero.

20. [6R-[6α,7ss(Z)]]-3-[(acetyloxy)methyl-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)imino]- acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, trisodium salt.

21. A compound as claimed in claim 18, wherein n is one.

22. [55-[5a,6,1,7a(Z)]]-3-[(acetyloxy) methyl]-7-[[(2-amino-4-thiazolyl)[(phosphonomethoxy)- imino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, 5-oxide, trisodium salt.

23. A compound as claimed in claim 17, wherein R4 and R4 are both ethyl.

24. [6R-[6α,7ss(Z)]]-3-[(acetyloxy) methyl]-7-[[(2-amino-4-thiazolyl) [[(diethoxyphosphinyl)methoxy]imino]acetyl]amino]-8-oxo-5-thia-1 -azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid, sodium salt.

25. A separate optical isomer of a compound as claimed in claim 1, wherein R2 is different from R3.

26. A separate configurational isomer of a compound as claimed in claim 1.

27. A compound as claimed in claim 1, and named in any one of the foregoing individual examples.

28. A compound as claimed in any preceding claim, for use in the method of treatment of a bacterial infection.

29. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound as claimed in claim 1, or a physiologically acceptable salt thereof.

30. A composition as claimed in claim 29 wherein R is hydrogen, sodium or potassium; R1 is hydrogen; R2 and R3 are both hydrogen; R4 and R4 are the same and are hydrogen, sodium, potassium, methyl or ethyl; n is zero or one, and when n is one the sulfoxide is in the p-configuration; Z is hydrogen,

R7 is hydrogen, methyl, -CH2COOR8'-CH2SO3R8' or -(CH2)2N(CH3)2; and R8 is hydrogen, sodium or potassium.

31. A method of preparing a compound of the general formula I,

wherein R, Ra, R2, R3, R4, R4, F4,, and n are are defined in claim 1, and Xis hydrogen,

wherein R7 is as defined in claim 1, which method comprises acylating a 7-aminocephalosporanic acid ester of the general formula III,

wherein R, and X are as defined herein, and Rg is an ester protecting group, with an activated derivative of the acid of the general formula IV,

wherein R2 and R3 are as defined herein and R4 and R4 are both hydrogen or lower alkyl, or one is hydrogen and the other is lower alkyl, in the presence of a coupling agent, to yield an ester of the general formula V,

wherein R1, R2, R3 are as defined herein R4 and R4 are both hydrogen or lower alkyl or one is hydrogen and the other is lower alkyl, and if required replacing the ester protecting group.

32. A method as claimed in claim 31, wherein the coupling agent is dicyclohexylcarbodiimide.

33. A method as claimed in claim 31 or 32, wherein the ester protecting group F9 is benzyl, diphenylmethyl, p-methoxy-benzyl or t-butyl.

34. A method as claimed in any one of claims 31 to 33, wherein the ester protecting group F9 is removed by treatment with trifluoroacetic acid and amisole to yield the corresponding trifluoroacetic acid salt and converting the salt to the acid product, R is hydrogen.

35. A method as claimed in any one of claims 31 to 34, wherein the activated derivative of the acid of the general formula IV is the n-hydroxybenzotriazole ester.

36. A method as claimed in claim 35, wherein the n-hydroxybenzotriazole ester is prepared by treating the acid of the general formula IV with n-hydroxybenzotriazole and dicyclohexylcarbodamide.

37. A method as claimed in any one of claims 31 to 34; wherein F1 is methoxy, and the activated derivative of the acid of general formula IV is the acid chloride.

38. A method as claimed any one of claims 31 to 37 wherein n is one, and the a- and/or P- sulfoxide of formula III are/is prepared by converting the 7-amino cephalosporanic acid to the Schiff base ester of the general formula VI,

wherein F1, X and F9 are as defined in claim 31, oxidising with a percarboxylic acid to a mixture of - and p-sulfoxide Schiff base cephalosporin esters, and cleaving the Schiff base sidechain by treatment with toluenesulfonic acid, and separating the a- and psulfoxide 7-amino cephalosporanic acid esters if required.

39. A method as claimed in claim 38, wherein the percarboxylic acid is m-chloroperbenzoic acid.

40. A method as claimed in any one of claims 31 to 37, wherein n is 2 and the sulfone of formula III is prepared by oxidising the corresponding a-sulfoxide (n is 1).

41. A method as claimed in any one of claims 31 to 40, when, in the compound of the general formula IV, R4 and R4 are both lower alkyl, wherein the compound of the general formula IV is obtained by reacting an aminoalkoxyphosphoric acid diester of the general formula VII,

wherein R2 and R3 are as defined in claim 31, with the glyoxylic acid of the formula VIII,

at a pH of from 6 to 6.5.

42. A method as claimed in any one of claims 31 to 40, when in the compound of formula IV R4 and R4 are both hydrogen, wherein the compound of the formula IV is prepared by treating the diester of formula VII,

wherein R2 and R3 are as defined in claim 31, and R4 and R4 are lower alkyl with acid or trimethylchlorosilane and sodium iodide to yield an acid of the general formula IX,

which is then reacted with the glyoxylic acid of the formula VIII,

43.A method as claimed in claim 41 or 42 wherein the diester of the general formula VII, is prepared by reacting the phthalimide phosphonic acid diester of the general formula X,

wherein R4 and R4 are lower alkyl with hydrazine.

44. A method as claimed in claim 43, wherein the compound of the general formula X is prepared by reacting a phosphonic acid diester of the general formula XI,

wherein R2 and R3 are as defined in claim 31 and R4 and R4 are lower alkyl, with N-hydroxyphthalimide in the presence of diethylazodicarboxylic acid and triphenylphosphine.

45. A method as claimed in claim 43, wherein the compound of the general formula Xis prepared by reacting a compound of the general formula XII,

wherein F10 is methyl or tolyl and R2 and R3 are as defined in claim 31 and R4 and R4 ere lower alkyl, with a compound of the general formula XIII,

wherein R" is an alkali metal ion.

46. A method as claimed in claim 45, wherein the compound of the general formula XII, is prepared by reacting a phosphonic acid ester of the formula XI,

wherein R2 and R3 are as defined in claim 31 and R4 and R4' are lower alkyl, with a sulfonic acid chloride of the general formula R10-SO2-Cl, wherein R10 is methyl of tolyl.

47. A method as claimed in any one one of claims 31 to 40, when in the compound of the general formula IV, one of R4 and R4 is hydrogen and the other is lower alkyl, wherein the compound of the formula IV is prepared by reacting the phosphonic acid monoester of the general formula XIV,

wherein R2 and R3 are as defined in claim 31, and R4 and R4 are as hereindefined, with the gloxylic acid of formula Vlil art a pH of about 2.5.

48. A method as claimed in claim 47, wherein the monoester of formula XIV is prepared by reacting a phosphoric acid of formula X,

wherein R2 and R3 are as defined in claim 31, with o-chlorobenzaldehyde to yield a compound of the general formula XV,

and reacting the compound of the general formula XV with a lower-alkyl alcohol to yield the monoester of formula XIV and also the corresponding diester.

49. A method as claimed in claim 47, wherein the monoester of general formula is prepared by treating the phosphonic acid of the general formula XVI,

wherein R2 and R3 are as defined in claim 31, with carbonylbisimidazole and then lower-alkyl alcohol.

50. A method of preparing a compound of the general formula II,

wherein R, R1, R,, R3, R4, R4 X and n are as defined in claim 1, which comprises reacting the corresponding compound of the general formula I, as defined in claim 1 and wherein R is hydrogen and X is

with pyridine or a polar solvent and in carbomoyl substituted pyridine in a polar solvent and in the presence of a catalyst.

51. A method as claimed in claim 50, wherein the polar solvent is water.

52. A method as claimed in claim 50 or 51, wherein the catalyst is an alkali metal thiocyanate.

53. A method of preparing a compound of the general formula I, as defined in claim 1, wherein X is

which comprises reacting the corresponding compound of the general formula I in which R is hydrogen and Xis

with a mercaptan of the formula XVII, hetero-S-H (XVI I) or an alkali metal mercaptan salt of the formula XVII I, hetero-S-alkali metal (XVI II).

54. A method of preparing a compound of the general formula I, as defined in claim 1, wherein n is 1 and the sulfoxide is in the P position, which comprises directly oxidising the corresponding sulfide compound of the formula I.

55. A method of preparing a compound of the formula I as defined in claim 1, wherein n is 2, which comprises directly oxidising the corresponding a-sulfoxide.

56. A method as claimed in claim 54 or 55, wherein the oxidation is carried out by treatment with a percarboxylic acid.

57. A method as claimed in claim 56, wherein the percarboxylic acid is m chloroperbenzoic acid or peracetic acid.

58. A method as claimed in any one of claims 54 to 57, wherein the reaction is carried out at from 00 to 250C.

59. A method of preparing a compound of the general formula I, as defined in claim 1, wherein R, R4, R4, and R8 are sodium or potassium, which comprises treating the corresponding compound of the general formula 1, wherein R, R4 and R8 are hydrogen with the salt forming ion sodium or potassium.

60. A method of preparing a compound of the general formula I, as defined in claim 1, wherein R is

which comprises reacting corresponding acid of the formula I with a compound of the formula XIX,

wherein halo is chlorine or bromine, in an inert solvent at or below ambient temperature.

61. A method of preparing a compound of the general formula I, as defined in claim 1, wherein R is

which comprises treating the corresponding acid of formula I, with a compound of the formula XX,

wherein L is hydroxy or bromine.

62. A method of preparing a compound of the general formula I as defined in claim 1, substantially as hereinbefore described with reference to any one of the foregoing individual examples.

63. The features hereinbefore disclosed or their equivalents in any novel combination.