CH623331A5 - Process for the preparation of 7beta-amino- and 7beta-acylamino-6alphaH-8-oxo-4-thia-1-azabicyclo[4.2.0]oct-2-ene-2-ca rboxylic acid derivatives - Google Patents

Description

The invention has for its object 7ß-acylamino-6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid derivatives of the general formula I

: ooh in which R is an acyl radical and E is a hydrogen atom, a methyl, bromomethyl or lower alkanoyloxy-methyl group, and the salts of these compounds with bases or acids.

The term acyl residue means one of the usual acyl residues in the cephalosporin and penicillin series. Preferred acyl radicals have the general formula

X-CHCO-, Y-CH2-CO- or Z-S (0) nCH2C0-

I.

A '

In particularly preferred acyl radicals, X denotes the thienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl or phenyl group, which may be replaced by one or two lower alkyl or alkoxy radicals, hydroxyl groups, hydroxymethyl groups, halogen atoms, nitro, amino, aminomethyl, Mercapto, lower alkylthio, trifluoromethyl, ureido, formamido or carboxymethylamino groups is substituted. A 'represents an amino, hydroxyl, formyloxy, carboxyl or sulfonic acid group. Y represents a cyano, azido or phenoxy group or a 5- or 6-membered heterocyclic radical which contains 1 to 4 nitrogen, oxygen and / or sulfur atoms as heteroatoms. Z represents a phenyl, pyridyl, lower alkyl, trifluoromethyl, trifluoro

ethyl or cyanomethyl group. n has the value 0.1 or 2. Specific examples of the 5- or 6-membered heterocyclic radicals are the thienyl, furyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl -, Syd-non, pyridyl and pyrimidyl group. The heterocyclic radical can be substituted by one or two lower alkyl radicals, halogen atoms, hydroxyl, nitro, amino or lower alkoxy groups, aryl radicals, such as the phenyl group, or lower aralkyl radicals.

The terms “lower alkyl, alkoxy, alkylthio and aralkyl residues” mean alkyl residues with 1 to 6 carbon atoms. Halogen atoms are preferably fluorine, chlorine and bromine atoms.

The term “removable carboxyl protecting group” means the usual residues as they are used to protect the carboxyl group in cephalosporin and penicillin chemistry. Numerous groups, in particular many ester groups, are known which are used to protect the carboxyl groups during subsequent chemical reactions and are split off again at a later reaction stage using customary methods. Specific examples of protective groups of the ester type are the 2,2,2-trichloroethyl group, C4-C6-tert-alkyl groups, such as the tert-butyl group, - C5-C7-tert.-alkenyl groups, Cs-C7-tert. -Alkynyl groups, Ci-Ce-alkanoyl-methyl groups, the N-phthalimidomethyl, benzoylmethyl, halobenzoylmethyl, methylbenzoylmethyl, methanesulfonylbenzoylmethyl, phenylbenzoylmethyl, benzyl, nitro-benzyl, methoxyl benzyl, benzity , Trimethylsilyl and triethylsilyl group. The type of ester group used depends, among other things, on what subsequent reaction conditions this group can withstand and under what conditions the protective group should be split off. Protecting groups which are split off by treatment with trifluoroacetic acid, hydrogenation or treatment with zinc dust and acetic acid are preferred if a β-lactam is condensed on a 6-membered ring. The choice of the protective group is not critical according to the invention, since the focus of the invention is on the synthesis of the new bicyclic ring system and not on the type of carboxyl protective groups.

The term "removable amino protecting group" or "protected amino group" is also a term known in peptide chemistry. It relates to amino groups which are protected or masked by another group and which can be split off again after the subsequent chemical reactions with the liberation of the amino group. Numerous groups are known in penicillin, cephalosporin and peptide chemistry for this purpose. Specific examples are the tert-butoxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, p-methoxybenzylcarbonyl, isoboronyloxycarbonyl and trityl groups, the methyl acetoacetate adduct and similar monovalent protective groups. Specific examples of divalent protective groups are the phthaloyl and 4,5-diphenyl-4-oxazolin-2-one groups. As is known, the phthalimido group is split off with hydrazine. The preparation and cleavage of the 4-oxazolin-2-one group is described in J. Org. Chem., Vol. 38, (1973), p. 3034. The type of protective group used depends on various factors, for example the subsequent chemical reactions and the conditions under which the protective group is to be split off. The type of amino protecting group is also not critical to the invention for the reasons given above.

The term “acyl residue” means the usual acyl residues of the semi-synthetic penicillins and cephalosporins. Specific examples of these acyl residues are the a-hydroxyphenyl-acetyl,

a-formyloxyphenylacetyl,

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a-aminophenylacetyl,

a-amino-4-hydroxyphenylacetyl-,

a-amino-4-hydroxy-3-fluorophenylacetyl,

a-amino-4-carboxymethylaminophenylacetyl-,

Trifluoromethylmercaptoacetyl,

Methylmercaptoacetyl,

Methylsulfonylacetyl,

2,2,2-trifluoroethylsulfinylacetyl,

Cyanoacetyl, cyanomethylmercaptoacetyl,

Cyanomethylsulfinylacetyl,

Cyanomethylsulfonylaceîyl-,

a-carboxy-2-thienylacetyl-,

a-carboxy-3-thienylacetyl-,

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a-carboxyphenylacetyl,

a-sulfophenylacetyl,

3-sydnone acetyl,

2-thienylacetyl,

3-thienylacetyl and 1-tetrazolylacetyl grappe.

The compounds of the general formula I contain a ring system which is related to the ring system of the naturally occurring cephalosporins, but cannot be prepared by fermentation. The starting compounds can therefore be prepared synthetically according to the following reaction schemes I, II and III, these schemes also showing precursors and intermediates. The methods according to the invention are defined in the claims.

Reaction scheme I

H

jCOOCHs N.

NC

II

N DMB

DMB = 2,4-dimethoxybenzyl

R'NH

BrCHCOCOOR

"? C00CH ',

R'NH

DMB

C00CH,

DMB

H H

H H

H H

SH

R'NH

L ^ -COOC ^

\

H

V

In Reaction Scheme I, R denotes any acyl radical or its derivative in which any chemically sensitive groups, such as carboxyl, hydroxyl or amino groups, are protected up to the last stage by a customary protective group. Numerous protecting groups are in the book by J.F.W. McOmie, Protective Groups in Organic Chemistry, Plenum Press, New York, 1973 and other reviews and books. R 'is an amino protecting group which is split off after formation of the 4-thio-l-azabicyclo [4.2.0] oct-2-ene structure. The 7-amino derivative obtained is then acylated by conventional cephalosporin chemistry methods with the corresponding acyl compound to give the compounds of the general formula I. R2 is a carboxyl protecting group which is split off at the end of the reaction sequence to form the end product or its salts.

The essential intermediate that gives the new scaffold the 6,7-cis configuration is the cis-l- (2,4-dimeth-oxybenzyl) -3-azido-4-oxazetidine-2-carboxylic acid methyl ester. This compound is obtained by cycloaddition of the imine obtained in the condensation of 2,4-dimethoxybenzylamine and glyoxylic acid methyl ester onto a mixed anhydride or

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Acid halide of azidoacetic acid obtained. The azido group of this intermediate is reduced to the 3-aminoazetidine derivative by catalytic or chemical hydrogenation, for example with zinc and acetic acid. The amino group can be protected by a removable amino protecting group, such as the tert-butoxycarbonyl group. A protected 3-aminoazidine derivative can also be prepared directly by substitution of a glycine derivative with a protected amino group. For example, 4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetic acid or N-phthalimidoacetic acid can be used in the cyclization reaction in the same way as azidoacetic acid to form the corresponding protected 3-aminoazetidine derivative.

Intermediate 3 or a protected 3-aminoazetidine described above can also be converted into the 2-methylsulfonate by a series of reaction steps, which is illustrated by compound 11 in Reaction Scheme II. Different reaction sequences can be used to prepare compounds similar to 11. Two alternative routes are specified in Reaction Scheme II, which lead from compound 3 to compound 11. It can be seen that the conversion of the azido group into the

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protected amino group is not limited to the two stages indicated in the reaction sequence, but can also take place at another stage. The reduction of the azido group is preferably carried out at the compound 3 stage in reaction scheme II or at the 3-azido-2-methyl-tosylate stage of the formula 12.

The methyl sulfonate of formula 11 is then gradually converted into the mercaptomethyl derivative 7, as indicated in Reaction Scheme III. The sulfonate is converted into the iodide, which in turn is replaced by a mercaptan such as p-meth

oxybenzyl mercaptan or triphenylmethyl mercaptan, is substituted. Cleavage of these derivatives by conventional methods gives the mercaptomethyl compound 7. The p-methoxybenzyl group is split off by treatment with a mercury (II) salt. The triphenylmethyl group is split off by treatment with a silver salt such as silver nitrate or silver tetrafluoroborate. It is therefore advantageous if other groups in the molecule are sensitive to mercury (II) ions.

10th

H H m i 'C00CH',

"3 '

Reaction scheme II .H

> CH20H

-N.

H

t-BOCNH

CH20Ts

H

I.

. I ^ CH? 0X

's "NH"

H -H

i _ CH20Ts

H

12th

H H

C00CH3 t-BOCNH-S —- 5— C00CH,

DMB iQ / r-

t-BOC = tert-butoxycarbonyl; Ts = tosyl

H

± CH20H

2 steps

DMB

Reaction scheme III

11

t-BOCNH *

r-CH2J

■>

0

/ 7 ~

\

H

H

R '"= p-methoxybenzyl or triphenylmethyl

The mercaptomethyl compound 7 is reacted with a β-bromo-a-ketocarboxylic acid ester. The bicyclic system as given in compound 8 is obtained. When a bromopyruvic acid ester is used, compound 8 is obtained in which E represents a hydrogen atom. When a 3-bromo-2-ketobutyric acid ester is used, compound 8 is obtained in which E represents a methyl group. These compounds are dehydrated to the corresponding 8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-enes of the formula 9. Conventional reagents such as thionyl chloride, trifluoroacetic anhydride or methanesulfonyl anhydride can be used for dehydration.

The compounds of the formula 9, in which E denotes a bromomethyl group, are brominated by radical chain bromination of the 3-methyl compounds according to the methods customary in cephalosporin chemistry 6o. The brominating agent used is, for example, N-bromosuccinimide in the presence of a free radical initiator, such as benzoyl peroxide or azo-bisisobutyronitrile.

The bromomethyl derivatives can be reacted with various salts of acetic acid to give the compounds of the formula 9 in which E denotes an acetoxymethyl group. Examples of these salts are sodium, potassium or silver acetate.

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The compounds of formula 10, i.e. The antibiotics of the invention are prepared from compounds of the formula 9 by cleaving off the amino protecting group and then acylating with the corresponding acyl compound. After the acylation, other protective groups which may be present can be split off. Sensitive groups, such as the amino or hydroxyl group, are protected during the acylation in the manner described above. Examples of acylation processes are the activation of the carboxyl group by using mixed anhydrides, activated esters or acid halides, or the use of coupling reagents such as dicyclohexylcarbodiimide.

When 2,4-dimethoxybenzylamine (Chem. Ber., Vol. 101 [1968], p. 3623) is reacted with methyl glycoxylate (Synthesis, [1972], p. 544), imine 1 is obtained. The reaction of this imine with the mixed anhydride of trifluoroacetic acid and azidoacetic acid (Tetrahedron Lett. [1973], p. 2319) gives the methyl cis-l- (2,4-dimethoxybenzyl) -3-azido-4-oxo-2-azetidinecarboxylic acid Formula 3. The implementation can be carried out in two stages. In the first stage, the mixed anhydride is produced, which is then added to a solution of the imine. In a one-step process, the azidoacetic acid is added to a solution of the imine and then trifluoroacetic anhydride is added. In the same way, other glyoxylic acid esters, such as the ethyl or propyl ester, can be used.

The 2,4-dimethoxybenzyl group is split off by oxidation. For example, in the treatment of N- (2,4-dimethoxybenzyl) β-lactam with potassium persulfate, the free β-lactam is obtained. This reaction is carried out in the presence of disodium hydrogen phosphate. For some derivatives, the pH is preferably adjusted to 5 to 6 to improve the yield. It was found that under these conditions the benzyl group is not split off like the dimethoxybenzyl group. However, those substituted benzyl residues which can be split off and which therefore have the same function as the dimethoxybenzyl group can be found by simple manual experiments.

Reduction of the 2-alkoxycarbonyl group with appropriate reducing agents, such as sodium borohydride, provides the 2-hydroxymethyl derivatives. The methoxycarbonyl group is particularly easily reduced to the corresponding alcohol with sodium borohydride.

The alcohol can also be prepared by reducing the 2-carboxylic acid using customary methods. The carboxylic acid is obtained from the ester by hydrolysis with a base. For example, the methyl ester is saponified to give the carboxylic acid by treatment with sodium or potassium carbonate. The carboxylic acid can be converted into its acid chloride and reduced to the corresponding alcohol with sodium borohydride. The l- (2,4-dimethoxybenzyl) -2-carboxylic acid derivative can be reduced to the 2-hydroxymethyl derivative and converted into the corresponding tosylate. The dimethoxybenzyl group can be converted at this stage to the β-lactammethyltosylate intermediate, which is further reacted in the manner described.

The alcohol is reacted, for example, with p-toluenesulfonylchloride, benzenesulfonyl chloride, p-bromobenzenesulfonyl chloride or mesyl chloride to give compounds which contain a group which can be easily exchanged with iodide ions by nucleophilic substitution. The nucleophilic substitution of the sulfonate group by iodide ions and the subsequent nucleophilic substitution of the iodide with sulfur compounds provides the mercaptomethyl group or a group which can be converted into the corresponding mercaptomethyl compound. The triphenylmethylmercapto and p-methoxybenzylmercap to groups are typical groups which can be cleaved to free mercaptan in the manner described above.

The new ring structure is formed by a cyclization of the mercaptomethyl compound with a bromo-pyruvic acid derivative. The resulting product contains a hydroxyl group in the a position to the carboxyl group. Dehydration of this hydroxyl group introduces a double bond into the 2,3-position analogous to the cephalosporin series. The dehydration is preferably carried out with thionyl chloride and pyridine or trifluoroacetic anhydride.

The starting compounds for the process according to the invention are either commercial products or are prepared by known processes.

The salts of the compounds of general formula I and their esters can easily be hydrolyzed or saponified in vivo. The salts include the salts of the carboxyl group in the 2-position or in the side chain acid or the salts with acids, provided that a basic radical is present in the compounds of the general formula I. The salts with bases can be alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium salts, or ammonium or cyclohexylammonium salts. The salts with acids can be derived from inorganic or organic acids.

The compounds of the general formulas II and IV-b exist in the cis configuration in the 6- and 7-positions. The compounds can also exist as optical isomers. The invention encompasses both the optical isomers (epimers) separated from one another and their mixtures.

The compounds of general formula I are antibiotics with activity against gram-positive and gram-negative germs. For example, 7-phenoxyacetamido-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid has antibacterial activity against Staphylococcus aureus and Shigella para-dysenteriae. 7- (a-Aminophenylacetamido) -8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid additionally acts against Escherichia coli, Klebsiella pneumoniae, Serratia marcescens, Salmonella paratyphi, Shigella paradysenteriae and Enterobacter species. The compounds are therefore suitable for the treatment of bacterial infections and as a disinfectant.

The compounds of the general formula IV-b are valuable intermediates for the preparation of the compounds of the general formula I. The compounds of the general formula IV-b, in which R 'is hydrogen atoms, can be acylated with the customary acyl compounds of the cephalosporin or penicillin series . After the carboxyl protecting group has been split off, the corresponding compounds of the general formula I are obtained. The compounds of the general formula IV, in which R 'represents an amino protecting group, are valuable intermediates for the preparation of the compounds in which R' represents a hydrogen atom.

The examples illustrate the invention.

Regulation A

N- (2,4-Dimethoxybenyzl) -iminoacetic acid methyl ester

A mixture of 16.82 g (0.101 mol) of 2,4-dimethoxybenzylamine and anhydrous magnesium sulfate in 150 ml of methylene chloride is mixed at 25 ° C. with a solution of 10.05 g (0.114 mol) of methyl glyoxylate in 20 ml of methylene chloride. The mixture is stirred at room temperature for 15 hours, then filtered and the filtrate evaporated under reduced pressure. The imine remains as a dark orange colored goo.

Regulation B

4,5-diphenyl-2-oxo-4-oxazolin-3-ylacetyl chloride-

A mixture of 2.1 g (7.1 mmol) of 4,5-diphenyl-2-oxo-4-

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oxazolin-3-ylacetic acid (J. Org. Chem., Vol. 38 [1973], p. 3034), 5 ml of thionyl chloride and 20 ml of methylene chloride are heated under reflux for 2 hours. After cooling to room temperature, the solvent is distilled off under reduced pressure. The oily residue crystallizes on standing. The product is digested with a mixture of diethyl ether and hexane. Yield 2.0 g of the title compound of mp 104 to 112 ° C.

Instructions C Bromobyruvic acid ester A solution of 3.3 g (37.5 mmol) pyruvic acid and 7.9 g (37.5 mmol) chloroformic acid trichloroethyl ester in 20 ml anhydrous tetrahydrofuran is added dropwise at 0 ° C with 0.6 ml pyridine. After stirring at room temperature for 2 hours, the mixture is evaporated under reduced pressure, the residue is diluted with water and extracted with ethyl acetate. The ethyl acetate extract is washed with 5 percent hydrochloric acid, dried over magnesium sulfate, evaporated and distilled under reduced pressure. Yield 4.0 g (50% of theory) of trichloroethyl pyruvate of bp. 75 to 82 ° C / 17 torr.

3.7 g (17 mmol) of trichloroethyl pyruvate are heated to 65 ° C. and 1.1 ml (17 mmol) of bromine are added dropwise within 1 hour. During the bromine addition, carbon dioxide is passed through the reaction mixture to separate the hydrogen bromide formed. The reaction mixture is then cooled to room temperature, diluted with water and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate, evaporated and distilled under reduced pressure. Yield 1.8 g of Bromobyruvic acid trifloroethyl ester of bp 74 to 77 ° C / 0.01 Torr.

Bromopyruvic acid is reacted with diphenyldiazomethane. The bromobyruvic acid benzhydryl ester is obtained.

The tert-butyl ester is prepared by customary methods by reacting 0-tert-butyl-N, N'-diisopropylpseudourea (Ann. Chem., Vol. 597 [1955], p. 235) with pyruvic acid.

Instructions D 3-bromo-2-ketobutyric acid ester A solution of 1.30 g (7.35 mmol) of 3-bromo-2-ketobutyric acid in 15 ml of anhydrous benzene is mixed with a solution under argon as a protective gas and with vigorous stirring at room temperature of 1.85 g (9.6 mmol) of diphenyldiazomethane in 15 ml of anhydrous benzene. The addition of the diazo compound continues until a faint red color persists. This takes about 30 minutes. The solvent is then distilled off under reduced pressure and the yellow oily residue is dissolved in diethyl ether. The ether solution is filtered and evaporated. 3.12 g of crude benzhydryl ester are obtained. Chromatography on silica gel and elution with benzene give 2.43 g (95% of theory) of pure 3-bromo-2-ketobutyric acid benzoyl dry ester as the yellow oil after evaporation of the eluate.

A solution of 1.6 g (8.85 mmol) of 3-bromo-2-keto butyric acid and 7 g (4 equivalents) of O-tert-butyl-N ^ N'-diisopropyl-pseudourea in 14 ml of methylene chloride becomes 15 Stirred for hours at room temperature. The mixture is then filtered, the filtrate washed with aqueous sodium bicarbonate solution and brine, dried and evaporated. The oily residue is chromatographed on silica gel and with benzene as the eluent. The eluate is evaporated. Yield 1 g (45% of theory) of tert-butyl 3-bromo-2-ketobutyrate.

Example 1 Production of starting material 7β-phenoxyacetamido-6aH-2-hydroxy-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] octane-2-carbo, acidic acid benzhydrate ester A solution of 0.234 g (0.88 mmol) cis-3-Phenoxyacetyl-amino-4-oxo-2-mercaptomethylazetidine and 0.304 g (0.88 mmol) of 3-bromo-2-ketobutyric acid benzhydryl ester in 26 ml of anhydrous methylene chloride is treated with 122 [xliter (0 , 88 mmol) of triethylamine. The solution is stirred for 1 hour. The methylene chloride is then distilled off under reduced pressure and the residue is dissolved in ethyl acetate. The ethyl acetate solution is washed with 3N hydrochloric acid, 5 percent aqueous sodium bicarbonate solution and saturated saline. After drying, the ethyl acetate solution is evaporated under reduced pressure. 0.531 g of crude product remain. Chromatography of 0.466 g of the crude product on silica gel and with a mixture of ethyl acetate and hexane as the eluent gives 320 mg (78% of theory) of the title compound after evaporation of the eluate.

Example 2 Preparation of starting material 7β-phenoxyacetamido-6aH-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid benzhydryl ester A solution of 0.200 g (0.39 mmol) of 7ß-phenoxy-acetamido-6aH-2-hydroxy-3-methyl-8-oxo-4-thia-1-azabicyclo [4.2.0] octane-2-carboxylic acid benzhydryl ester and 282 (xliter of trifluoroacetic anhydride in 4 ml of anhydrous ethyl acetate 161 [xLiter (2.0 mmol) of pyridine are added dropwise with stirring at 0 ° and under argon as protective gas. After the addition has ended, the solution is allowed to warm to room temperature and stirred for 20 hours. The reaction mixture is then diluted with ethyl acetate, twice with 5 percent Washed sodium bicarbonate solution, 3N hydrochloric acid and brine. The ethyl acetate solution is dried over magnesium sulfate and evaporated under reduced pressure. Yield 300 mg of crude product. Chromatography on silica gel and with a mixture of ethyl acetate and benzene (1: 1) as eluent gives after evaporation of the Elu ats 21.8 mg (11% of theory Th.) Of the title compound in the form of white crystals and 42.1 mg (21% of theory) of the starting compound of mp 155 to 156 ° C.

Example 3 Preparation of starting material 7 β-phenoxyacetamido-6 <xH-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid A solution of 0.062 g (1.2 X10-4 mol) 7ß-phenoxyacet-amido-6aH-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid benzhydrate, 125 ml of anisole and 0.7 ml of trifluoroacetic acid in 2 ml of methylene chloride is stirred for 75 minutes under argon as a protective gas at 0 ° C. Thereafter, the trifluoroacetic acid and methylene chloride are distilled off under reduced pressure, and the residue is treated with ethyl acetate and dilute hydrochloric acid. The ethyl acetate extract is extracted with 5 percent aqueous sodium bicarbonate solution. The combined aqueous extracts are adjusted to a pH of 1.5 and extracted again with ethyl acetate. The combined organic extracts are dried over magnesium sulfate, filtered and evaporated. Finally, the residue is dried in a high vacuum. 25.2 mg of a yellow solid remain. Precipitation from a mixture of methylene chloride and hexane gives 18.7 mg (44% of theory) of the analytically pure title compound of mp 205 ° to 215 ° C. (dec.).

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Example 4 Preparation of starting material 7β-phenoxyacetamido-6aH-hydroxy-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] octane-2-carboxylic acid tert-butyl ester A solution of 0.083 g (0.31 mmol) of cis-3-phenoxyaceta-mido-4-oxo-2-mercaptomethylazetidine and 0.084 g (0.31 mmol) of tert-butyl 3-bromo-2-ketobutyrate in 10 ml of anhydrous methylene chloride is treated under argon as a protective gas at room temperature and 44 [xliter (0.31 mmol) of triethylamine were added with stirring. The solution is stirred for 75 minutes. Thereafter, the methylene chloride is distilled off under reduced pressure, the residue is dissolved in ethyl acetate, the ethyl acetate solution is washed with 3N hydrochloric acid, 5% aqueous sodium bicarbonate solution and brine, dried and evaporated under reduced pressure. 0.120 g of crude product remain. Chromatography on silica gel and with a mixture of ethyl acetate and hexane (1: 1) as the eluent yields 93.8 mg (70% of 1 h.) Of a colorless oil after evaporation of the eluate. After standing at room temperature, the oil solidifies. The crystalline title compound of mp 138 to 150 ° C. is obtained.

Example 5 Production of starting material 7 β-phenoxyacetamido-6 <xH-3-methyl-8-oxo-4-thia-1-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid tert-butyl ester A solution of 0.302 g (0.72 mmol) of the 2-hydroxy compound obtained in Example 4 and 200 μl (1.43 mmol) of trifluoroacetic anhydride in 6 ml of anhydrous ethyl acetate are added dropwise with 290 [iLiter (3.58 mmol) under argon as a protective gas at 0 ° C. Pyridine added. The solution is allowed to warm to room temperature and stirred for 20 hours. The reaction mixture is then diluted with ethyl acetate and washed with 5 percent aqueous sodium bicarbonate solution, 3N hydrochloric acid and brine. The ethyl acetate solution is then dried over magnesium sulfate and evaporated. The residue is chromatographed on silica gel and with a mixture of ethyl acetate and hexane as the eluent. The eluate is evaporated. Yield 49.5 mg (17% of theory) of the title compound as a yellow solid with a melting point of 147 ° to 149 ° C.

Example 6

7β-phenoxyacetamido-6 aH-3-bromomethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid tert-butyl ester A suspension of 30.0 mg ( 0.075 mmol) cis-7β-phen-oxyacetamido-6aH-3 ~ methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid tert-butyl ester and 28 mg (0.15 mmol) of N-bromosuccinimide in 5 ml of carbon tetrachloride are degassed, a small amount of azobisbutyronitrile is added and the mixture is heated under reflux for 2 hours. After cooling, the mixture is filtered, the filtrate evaporated to dryness, the residue dissolved in ethyl acetate, the ethyl acetate solution washed with 5% aqueous sodium bisulfite solution, dried over magnesium sulfate and evaporated to dryness. The residue is chromatographed on silica gel with a solution of 5% ethyl acetate in chloroform. The eluate is evaporated and the residue is digested with a mixture of methylene chloride and hexane. 10.8 mg of the title compound are obtained as a light yellow amorphous solid.

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Example 7

7β-phenoxyacetamido-6aH-3-acetoxymethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid A mixture of 48 mg (0.1 mmol) of the bromomethyl derivative of Example 6 and 200 mg of silver acetate in 10 ml of acetone are stirred at room temperature for 24 hours. The mixture is then filtered, the filtrate is evaporated to dryness and the residue is chromatographed on silica gel with a solution of 5% ethyl acetate in chloroform. The eluate is evaporated. The tert-butyl ester of the title compound remains.

The tert-butyl ester is dissolved in ice-cold trifluoroacetic acid, which contains 10% anisole. The solution is stirred at 0 ° C for 30 minutes. The solvent is then distilled off under reduced pressure, the residue is taken up in ethyl acetate and extracted with 5 percent aqueous sodium bicarbonate solution. The aqueous extract is carefully acidified and extracted with ethyl acetate. The ethyl acetate extract is dried over magnesium sulfate and evaporated to dryness. After digesting with hexane, the title compound is obtained.

Example 8

In the reaction of the 7ß-tert-butoxycarbonylamino-6aH-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid tert-butyl ester with N-Bromosuccinimide according to Example 6 is the 7β-tert-butoxycarbonylamino-6aH-3-bromomethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid tert .-Butyl ester obtained.

The reaction of the bromomethyl derivative with sodium acetate or silver acetate according to Example 7 gives the 7β-tert-butoxycarbonylamino-6aH-3-acetoxymethyl-8-oxo-4-thia-l-aza-bicyclo [4.2.0] oct-2- en-2-carboxylic acid tert-butyl ester.

In the reaction of the tert-butyl ester with trifluoroacetic acid according to Example 7, the 7β-amino-6aH-3-acetoxy-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2 -Carbon acid obtained.

Example 9 Preparation of starting material 7 β-phenoxyacetamido-6 aH-2-hydroxy-8-oxo-4-thia-l-azabicyclo [4.2.0] octane-2-carboxylic acid trichloroethyl ester A solution of 273 mg (1.02 mmol) cis-3 Phenoxyaceta-mido-4-oxo-2-mercaptomethylazetidine and 305 mg (1.02 mmol) of trichloroethyl ethyl bromide in 30 ml of methylene chloride are slowly mixed with 0.110 ml of triethylamine at 0 ° C. After stirring for 2 hours at room temperature, the mixture is evaporated to dryness, the residue is dissolved in ethyl acetate, the ethyl acetate solution is washed with 5 percent hydrochloric acid, 5 percent aqueous sodium bicarbonate solution and saturated sodium chloride solution, evaporated to dryness and on silica gel with a mixture of ethyl acetate and hexane (1: 1) chromatographed. The eluate is evaporated. Yield 256 mg (52% of theory) of the title compound.

Example 10 Production of Starting Material 7β-Phenoxyacetamido-6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-4-carboxylic acid A solution of 0.477 g (1 mmol) of 7ß- cooled to 0 ° C. Phenoxyacetamido-6aH-2-hydroxy-8-oxo-4-thia-l-azabi-cyclo [4.2.0] octane-2-carboxylic acid trichloroethyl ester in 10 ml of ethyl acetate is mixed with 65 ml of trifluoroacetic anhydride and then with 362 ml of pyridine. The reaction mixture is then stirred at room temperature for 15 hours

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and then diluted with ethyl acetate. The ethyl acetate solution is washed with aqueous sodium bicarbonate solution, 3N hydrochloric acid and saturated sodium chloride solution, then dried and evaporated. The ester of the title compound remains, which is recrystallized from benzene. Yield 157 mg (34% of theory).

70 mg of the ester obtained are dissolved in 24 ml of a mixture of dimethylformamide and glacial acetic acid (1: 1). The solution is mixed with 500 mg of zinc dust within 90 minutes, which was previously treated with 5 percent hydrochloric acid for 3 minutes, washed with water, ethanol and ether and then dried. The reaction mixture is stirred for 3 hours at room temperature, diluted with water, acidified with 3N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with a large amount of 5 percent aqueous sodium bicarbonate solution. The aqueous solution is adjusted to a pH of 2 with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is dried and evaporated under reduced pressure and finally in a high vacuum. The residue is digested with a mixture of diethyl ether and hexane, then dissolved in methylene chloride and precipitated with hexane. The title compound of F. 194 to 195 ° C (dec.) Is obtained.

Example 11 Preparation of starting material 7β- (a-aminophenylacetamido) -6aH-8-oxo-4-thia-l-azabicycIo [4.2.0] oct-2-en-2-carboxylic acid 500 mg of benzombromate pyruvate are dissolved in 8 ml of benzene and 1 ml of tetrahydrofuran dissolved, cooled to 10 ° C and treated with a solution of 286 mg diphenyldiazomethane in 10 ml benzene. The solution is stirred until decolorized and then evaporated to dryness. The residue is dissolved in 5 ml of methylene chloride, cooled to 0 ° C., and 465 mg of cis-3- (a-tert-butoxycarbonylaminophe-nylacetamido) -4-oxo-2-mercaptomethylazetidine are added. The reaction mixture is stirred for 1 hour and then evaporated to dryness. The residue is dissolved in a mixture of ethyl acetate and water. The ethyl acetate extract is washed with 1 percent hydrochloric acid, aqueous sodium bicarbonate solution and brine, dried and evaporated. The benzhydryl ester of 7- (a-tert-butoxycarbonylaminophenylacetamido) -2-hydroxy-8-oxo-4-thia-l-azabicyclo [4.2.0] octane-2-carboxylic acid remains.

200 mg of the carboxylic acid in 4 ml of ethyl acetate are mixed with 150 [x liter of pyridine. The solution is cooled to -10 ° C. and stirred for 1 hour with 50 [xliter of thionyl chloride, then diluted with water, acidified and extracted with ethyl acetate. The ethyl acetate extract is washed with 5 percent aqueous sodium bicarbonate solution and brine, dried and evaporated. The residue is chromatographed on silica gel with a mixture of benzene and ethyl acetate (5: 1) as the eluent. The eluate is evaporated. The protected derivative of the title compound remains. Yield 50 mg.

The protective groups are removed by stirring a solution of 118 mg of the product in 10 ml of methylene chloride, 0.2 ml of anisole and 2.0 ml of trifluoroacetic acid for 45 minutes at 0 ° C. under argon as the protective gas. The reaction mixture is allowed to warm to room temperature and then evaporated to dryness in a high vacuum. The salt of the trifluoroacetic acid of the title compound remains, which is digested with diethyl ether and reprecipitated from a mixture of methanol and diethyl ether.

Example 12 Preparation of Starting Material 7ß- (a-Amino-p-hydroxyphenylacetamido) -6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

A solution of 265 mg (1 mmol) of N-tert-butoxycarbonyl-p-hydroxyphenylglycine in 10 ml of anhydrous tetrahydrofuran is mixed with 0.14 ml of triethylamine. After cooling to -10 ° C., a solution of 1 mmol of isobutyl chloroformate in 2 ml of tetrahydrofuran is added dropwise, and the reaction mixture is stirred for 20 minutes. A mixture of 270 mg (1 mmol) of cis-3-amino-4-oxo-2-azetidine methyl tosylate and 0.14 ml of triethylamine in 5 ml of 50% aqueous tetrahydrofuran is then added, cooled to 0 ° C. The resulting solution is stirred at low temperature for 1 hour and then allowed to warm to room temperature. The solvents are then distilled off and the aqueous residue is diluted with water and extracted with ethyl acetate. The aqueous solution is covered with a layer of ethyl acetate, cooled and acidified. The phases are separated and the aqueous solution is extracted with ethyl acetate. The organic solutions are dried and evaporated. The cis-3- (a-tert-butoxycarbonylamino-p-hydroxyphenylacetamido) -4-oxo-2-azetidinylmethyl tosylate is obtained.

The tosylate is reacted with sodium iodide and then with p-methoxybenzyl mercaptan. The p-methoxy-benzylthio derivative is obtained, which is cleaved according to Example 24. The cis-3- (a-tert-butoxycarbonylamino-p-hydroxyphenylacetamido) -4-oxo-2-mercaptomethylazetidine is obtained.

This compound is reacted with benzoyl bromopyruvate in accordance with Example 11 and the subsequent reaction sequence up to the title compound.

Example 13

7ß- (2-Thienylacetamido) -6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid An anhydrous solution of 7ß-amino-6aH-8-oxo-4 -thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid trichloroethyl ester in ethyl acetate, which has been obtained from 0.012 g of the tert-butoxycarbonyl derivative, is mixed with 0.2 ml of 2-thienylacetylchloride and 0.2 ml triethylamine treated. The reaction mixture is stirred at room temperature for 2 hours and then diluted with aqueous sodium bicarbonate solution. The organic phase is separated off, washed with 3N hydrochloric acid, dried and evaporated. The 7-thienylacetamido derivative remains.

The ester is reacted with zinc dust and acetic acid according to Example 10 to give the title compound.

Example 14

7β-phenoxyacetamido-6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid

An anhydrous solution of 7ß-amino-6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid trichloroethyl ester in ethyl acetate is cooled to 0 ° C. and with one equivalent each of phenoxyacetyl chloride and Triethylamine added. After stirring for 1 hour, the reaction mixture is washed with dilute hydrochloric acid and brine. The organic phase is dried and evaporated. The trichloroethyl ester of the title compound is obtained.

The trichloroethyl ester is reacted with zinc dust and acetic acid according to Example 10 to give the title compound.

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Example 15

7ß-methylsulfonylacetamido-6aH-8-oxo-4-thia-1-azabicyclo- [4.2.0] oct-2-en-2-carboxylic acid A solution of 200 mg (1 mmol) of 7 ß-amino-6aH-8- oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid trichloroethyl ester and 0.14 ml triethylamine in 10 ml dimethylformamide is combined with 236 mg (1 mmol) of the N-hydroxysuccinimide ester of methylsulfonyl acetic acid Stirred for 2 hours at room temperature. The reaction mixture is then poured into ice water and the solution extracted with ethyl acetate. The aqueous phase is adjusted to a pH of 2 and extracted with ethyl acetate. The combined ethyl acetate extracts are evaporated and the ester is cleaved according to Example 10 to give the title compound.

Example 16

The 7β-6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid trichloroethyl ester is acylated with one of the 20 carboxylic acids mentioned below:

a-formyloxyphenylacetic acid,

Trifluoromethylmercaptoacetic acid, 25

Methyl mercaptoacetic acid, I 2,2,2-trifluoroethylsulfinyl acetic acid,

Cyanoacetic acid,

Cyanomethylmercaptoacetic acid,

Cyanomethylsulfinyl acetic acid, 30

Cyanomethylsulfonylacetic acid,

a-carboxy-2-thienylacetic acid,

a-carboxy-3-thienylacetic acid,

a-sulfophenylacetic acid,

3-thienylacetic acid or 3s

1-tetrazolylacetic acid.

The acid or its activated derivative is used. Sensitive or disruptive groups are protected. The acylation is carried out according to Examples 11 to 17 or 15. Then all protective groups are split off. The corresponding 7β-acylamino-6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is obtained.

Example 17

When using the a- (N-tert-butoxycarbonylamino) -4-hydroxy-3-fluorophenylacetic acid or a- (N-tert-butoxycarbonyl-bonylamino) -4- (tert-butoxycarbonylmethylamino) -phenyl- so acetic acid in the process According to Example 12, the following compounds are obtained: 7β- (a-amino-4-hydroxy-3-fluorophenylacetamido) -6 <xH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2- en-2-carboxylic acid and 7ß- (a-amino-4-carboxymethylaminophenylacetamido) -6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-ss 2-carboxylic acid.

623331

Example 18 Preparation of starting material 7ß- (a-carboxyphenylacetamido) -6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid

Equimolar amounts of the N-hydroxysuccinimidyl ester of a-tert-butoxycarbonylphenylacetic acid, cis-3-amino-4-oxo-2-azetidine methyl tosylate and triethylamine are stirred in dimethylformamide for 2 hours at room temperature. The reaction mixture is then poured into ice water and the aqueous solution is washed with ethyl acetate, acidified to a pH of 2 and extracted with ethyl acetate. The ethyl acetate extracts are evaporated. The cis-3- (a-tert-butoxycarbonylphenylacetamido) -4 ~ oxo-2-azetidinylmethyl tosylate remains.

When this tosylate is reacted according to Example 12, the title compound is obtained.

Example 19

In the acylation of 7β-amino-6aH-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid with 2-thienylacetic acid, phenoxyacetic acid, methylsulfonylacetic acid, a- Formyloxyphenylacetic acid, trifluoromethylmercaptoacetic acid, 2,2,2-trifluoroethylsulfinylacetic acid, cyanoacetic acid, cyanomethylmercaptoacetic acid, cyanomethylsulfinylacetic acid, cyanomethylsulfonyl acetic acid, a-carboxy-2-thienyles-sacetic acid 3-acetic acid, coxyacyl acid, 1-tetrazolylacetic acid, a-amino-phenylacetic acid, a-amino-p-hydroxyphenylacetic acid, a-amino-4-hydroxy-3-fluorophenylacetic acid, a-amino-p-carb-oxymethylaminophenylacetic acid or a-carboxyphenylacetic acid using the free acid or an activated derivative, with sensitive or interfering groups being protected, according to Examples 11 to 13 or 15 and subsequent elimination of all protective groups, the corresponding 7β-acylamino-6aH-3-methyl-8-oxo-4-thia-l-azabicyclo [ 4.2.0] oct Get -2-en-2-carboxylic acids.

Example 20

In the acylation of 7β-amino-6aH-3-acetoxymethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid with 2-thienylacetic acid, phenoxyacetic acid, methylsulfonylacetic acid, a- Formyloxyphenylacetic acid, trifluoromethylmercaptoacetic acid, 2,2,2-trifluoroethylsulfinylacetic acid, cyanoacetic acid, cyanomethylmercaptoacetic acid, cyanomethylsulfinylacetic acid, cyanomethylsulfonyl acetic acid, a-carboxy-2-thienylacetic acid, a-sulfoxyacetic acid, a-sulfoxyacetic acid, Tetrazolylacetic acid, a-aminophenylacetic acid, a-amino-p-hydroxyphenylacetic acid, a-amino-4-hydroxy-3-fluorophenylacetic acid, a-amino-p-carboxymethylaminophenylacetic acid or a-carboxyphenyl acetic acid using the free acid or its activated derivative, wherein sensitive or disruptive groups are protected, according to Examples 11 to 13 or 15 and subsequent removal of the protective groups, the corresponding 7β-acylamino-6aH-3-acetoxymethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] Obtain oct-2-en-2-carboxylic acids.

B

Claims (4)

623331 (1) a compound of the general formula II NH, COOK' in which E has the above meaning and R2 represents a hydrogen atom or a removable carboxyl protecting group, with an acylating agent RX ', where R has the above meaning and any sensitive substituents of the radical R which are present are protected by removable protective groups and X' is a hydroxyl group, a halogen atom or an activating ester residue or a mixed anhydride residue, reacted and 1. Process for the preparation of 7β-acylamino-6aH-8- Oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid - Derivatives of the general formula I CO OH in which R is an acyl radical and E is a hydrogen atom, a methyl, bromomethyl or lower alkanoyloxymethyl group, and their salts with bases or acids, characterized in that * 2 55 Connections to this ring system are the subject of intensive research and numerous scientific publications and patents. About eight cephalosporins are currently being introduced into antibiotic therapy. Analog ring systems in which the ring sulfur atom has been moved to a different position of the six-membered ring cannot be obtained by the same methods as are known for the cephalosporins. Only chemical processes are suitable for producing this ring system. A ring system, the production of which has been tried with varying degrees of success, is 8-oxo-4-thia-l-azabicyclo [4.2.0] octane, which has been given the trivial name isocephalosporin and has the following formula: 623331 2nd 5 10th 15 20th 25th 30th 35 40 45 50 55 «0 65 2. The method according to claim 1, characterized in that E represents a hydrogen atom, a methyl or acetoxy methyl group. (2) when R 2 is a carboxyl protecting group or there are protecting groups within the radical R, the protecting groups are split off and, if appropriate, the compound obtained is converted into its salt by reaction with a base or an acid. 3rd 623 331 14. The method according to claim 13, characterized in that Y is a cyano, azido, phenoxy, thienyl, tetrazolyl or sydnone group. 15. The method according to claim 14, for the preparation of 7ß- (2-thienylacetamido) -6c (H-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, thereby characterized in that 7ß-amino-6ccH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-car-bonic acid or its derivative protected on the carboxyl group with the reactive derivative of the 2nd -Thienylacetic acid acylated and then cleaves off any protective group. 16. The method according to claim 14, for the preparation of 7ß- (2-thienylacetamido) -6aH-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2- carboxylic acid, characterized in that 7ß-amino-6aH-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] -oct-2-en-2-carboxylic acid or its on the carboxyl group protected derivative is acylated with the reactive derivative of 2-thienylacetic acid and then the protective group is removed. 17. The method according to claim 14, for the preparation of 7β- (2-thienylacetamido) -6aH-3-acetoxymethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, characterized in that 7ß-amino-6aH-3-acetoxymethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid or its derivative protected on the carboxyl group with the reactive Acylated derivative of 2-thienylacetic acid and then cleaves off any protective group. 18. The method according to claim 3, characterized in that R is the group Z-S (0) nCH2C0. 19. The method according to claim 18, characterized in that Z is a phenyl group. 20. The method according to claim 18, characterized in that Z is a pyridyl group and n has the value 0. 21. The method according to claim 18, characterized in that Z is a methyl group. 22. The method according to claim 18, characterized in that Z is a trifluoromethyl group. 23. The method according to claim 18, characterized in that Z is a trifluoroethyl group. 24. The method according to claim 18, characterized in that Z is a cyanomethyl group. 25. Application of the method according to claim 1 to starting compounds of the formula II, in which E is a bromomethyl group and R2 is a removable carboxyl protecting group, as obtained from compounds of the formula IV-b 15 28. Use according to claim 27, characterized in that the group (R ') 2N is the tert-butoxycarbonylamino group and R2' is the tert-butyl group. 29. Application of the method according to claim 1 to starting compounds of the formula II in which E is a lower alkanoyloxymethyl group and R2 is a removable carboxyl protecting group, as they come from compounds of the 10th 20th CH2Br COOR (VI Ii) wherein R2 'is a removable carboxyl protecting group and (R') 2N-25 is a protected amino group can be obtained by reacting this compound VIII with the salt of a lower alkane carboxylic acid and splitting off the amino protecting group. 30. Use according to claim 29, characterized in that 3 E is the acetoxymethyl group. 31. Use according to claim 30, characterized in that the salt of the lower alkane carboxylic acid is sodium, potassium or silver acetate. 32. Use according to claim 31, characterized in that the group (R ') 2N is the tert-butoxycarbonylamino group and R2 'is the tert-butyl or benzhydryl group. 40 The cephalosporins obtainable by fermentation or by ring expansion of penicillins all have the 8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene structure: 45 (r ') 2N—: dv-t>: wherein R2 'is a removable carboxyl group and (R') 2N- is a protected amino group can be obtained by brominating this compound IV-b with a bromo radical-donating compound in the presence of a free radical initiator and cleaving the amino-protecting group. 26. Use according to claim 25, characterized in that the bromine radical-providing compound is N-bromosuccinimide. 65 27. Use according to claim 26, characterized in that the free radical initiator is azobisisobutyronitrile or benzoyl peroxide. 3. The method according to claim 2, characterized in that R is the group XCHCO, Y-CH2CO or Zr-S (0) nCH2C0 I. A ' X denotes the thienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl or phenyl group or one by one or two lower alkyl or lower alkoxy radicals, hydroxyl or hydroxymethyl groups, halogen atoms, nitro, amino, aminomethyl, mercapto , lower alkylthio, trifluoromethyl, ureido, formamido or carboxymethylamino groups is substituted phenyl group, A 'is an amino, hydroxyl, formyloxy, carboxyl or sulfo group, Y is a cyano, azido or phenoxy group or a 5- or O-membered heterocyclic radical having 1 to 4 nitrogen, oxygen and / or sulfur atoms as heteroatoms, the heterocyclic radical optionally being substituted by one or two lower alkyl or lower alkoxy radicals, halogen atoms, nitro, Hydroxyl, amino or phenyl groups is substituted, Z is a phenyl, pyridyl, lower alkyl, trifluoromethyl, trifluoroethyl or cyanomethyl group and n is 0, 1 or 2. 4. The method according to claim 3, characterized in that R is the group XCHCO is. I. A ' 5. The method according to claim 4, characterized in that X is a thienyl, phenyl, 4-hydroxyphenyl, 4-hydroxy-3-fluorophenyl or 4-carboxymethylaminophenyl group. 6. The method according to claim 5, characterized in that A 'is an amino or hydroxyl group. 7. The method according to claim 5, for the preparation of 7ß- (a-aminophenylacetamido) -6aH-8-oxo-4-thia-l-aza-bicyclo [4.2.0] oct-2-ene-2-carboxylic acid, thereby characterized in that 7ß-amino-6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid or its derivative protected on the carboxyl group with the reactive derivative the a-aminophenylacetic acid protected on the amino group is acylated and the protective groups are subsequently split off. 8. The method according to claim 5 for the preparation of 7β-Mandelamido-6 aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, characterized in that 7ß- Amino-6 <xH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid or its derivative protected on the carboxyl group is acylated with the reactive derivative of the mandelic acid protected on the hydroxyl group and then the protective groups split off. 9. The method according to claim 5 for the preparation of 7ß- (a-aminophenylacetamido) -6aH-3-methyl-8-oxo-4-thia-l-azabi-cyclo [4.2.0] oct-2-en-2-carboxylic acid , characterized in that 7ß-amino-6a-H-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid or its derivative protected on the carboxyl group acylated with the reactive derivative of a-aminophenyl acetic acid protected on the amino group, and the protective groups are subsequently split off. 10. The method according to claim 5 for the preparation of 7β-Mandelamidoj6aH-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] -oct-2-ene-2-carboxylic acid, characterized in that that 7ß-amino-6aH-3-methyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid or its derivative protected on the carboxyl group with that on the Hydroxyl group protected reactive derivative of mandelic acid and then cleaves off the protective groups. 11. The method according to claim 5, for the preparation of 7β- (a-aminophenylacetamido) -6aH-3-acetoxymethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, characterized in that 7ß-amino-6aH-3-acetoxymethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-en-2-carboxylic acid or its derivative protected on the carboxyl group with the other the amino group protected reactive derivative of a-aminophenylacetic acid is acylated and then the protective groups are split off. 12. The method according to claim 5, for the preparation of 7ß-Mandelamido-6aH-3-acetoxymethyl-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, thereby featured, that 7ß-amino-6aH-3-acetoxymethyl-8-oxo-4-thia-l-azabicyclo- [4.2.0] oct-2-en-2-carboxylic acid or its derivative protected on the carboxyl group with that on the hydroxyl group protected reactive derivative of mandelic acid and then cleaves off the protective groups. 13. The method according to claim 3, characterized in that that R is the group Y-CH2CO. 4th The preparation of 7β-phenylacetamido-7a-methyl-6aH-8-oxo-4-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid and the corresponding 2,3-dihydro compound are described in J. Chem. Soc. 1973, p. 1321. These compounds do not have the 2,3-double bond, which is presumably necessary for the biological activity of these compounds, and / or they have a 7 a-methyl group, which is missing in natural cephalosporins. These two compounds were reported to show no antibiotic activity when tested at high concentration against three strains of bacteria. The aforementioned publication also describes a derivative with a trans configuration, namely 7a-phenylacetamido-6aH-8-oxo-4-thia-l-aza [4.2.0] octan-2-carbonic acid. This compound also showed no antibiotic effect. Attempts to produce the ring system without the methyl group and with the 2,3-double bond were apparently unsuccessful. Further unsuccessful attempts to prepare such compounds are described in J. Chem. Soc. Perkin 1,1974, p. 2092.