CH617703A5 - Process for the preparation of the syn-isomer or of a mixture of syn- and anti-isomers of novel antibiotically active 7 beta -acylamino-ceph-3-em-4-carboxylic acids - Google Patents

Description

The invention relates to a process for the preparation of the 65 syn isomer or a mixture of syn and anti isomer, the proportion of the syn isomer being at least 90% of new antibiotic 7ß-acylamido-ceph-3-em-4 carboxylic acids of formula I.

3rd

617703

r-c-co-nh men, such as Proteus and Pseudomonas strains, have a chemotherapeutic need.

It has now been found that this need is achieved with the aid of the compounds obtainable according to the invention which have an acylamido group of the formula 7-position

(I)

\

I.

0- (ch0) -c-2 m,

R

cooh

(ch0) -cooh 2 n where

B> S or> S- »0;

R thienyl or furyl;

Ra and Rb, which are the same or different, are hydrogen, Ci-C4-alkyl, C2-Gt-alkenyl, C3-C7-cycloalkyl, phenyl, naphthyl, thienyl, furyl, carboxy, C2-C5-alkoxycarbonyl or cyano; or Ra and Rb together with the carbon atom to which they are attached, C3-C7-cycloalkylidene or C3-C7-cycloalkenylidene;

m and n are each zero or 1, the sum of m and n being zero or 1; and

Z is a bridge connecting the nuclear sulfur atom and the carbon atom in the 4-position with 2 carbon atoms which can carry substituents and where there is a double bond between the C3 and Gt atoms of the bridge, or of their non-toxic derivatives.

Of these compounds, those in which B is> S are particularly preferred.

The present cephalosporin compounds are described with reference to "Cepham" [J. Amer. Chem. Soc. 84 (1962) 3400]; the term "cephem" refers to the basic structure of cepham with a double bond.

Cephalosporin antibiotics are widely used to treat diseases caused by pathogenic bacteria in humans and animals, for example in the treatment of diseases caused by bacteria resistant to other antibiotics such as penicillin compounds and in the treatment of patients sensitive to penicillin. In many applications it is desirable to use a cephalosporin antibiotic that has activity against both gram positive and gram negative microorganisms, and much research has been done to develop various types of broad spectrum cephalosporin antibiotics.

There is currently substantial interest in the development of broad-spectrum cephalosporin antibiotics that are highly active against gram-negative organisms. Existing commercially available β-lactam antibiotics tend to have relatively low activity against certain gram-negative organisms, such as Proteus organisms, which are increasingly causing human infection, and are also generally against Pseudomonas organisms in general inactive. Certain Pseudomonas organisms are resistant to the majority of existing commercially available antibiotic compounds, and the practical therapeutic use of aminoglycoside antibiotics, such as gentamicin, which have Pseudomonas activity, tends to be high due to the high toxicity of these compounds to be limited or complicated. It is known that the cephalosporin antibiotics are normally low in human toxicity, so the development of broad-spectrum cephalosporin antibiotics that have high activity against gram-negative organisms

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R-C-CO-NH-

II

N

10th

Ra

20th

25th

^ 0- (CH2) mC- (CH2) n-C00H Rb and are satisfied in the form of the syn isomer or as a mixture of syn and anti isomer, the proportion of the syn isomer being at least 90% can.

The designation syn and anti isomer takes place with regard to the configuration of the rest

Ra

I.

-0- (CH2) m-C- (CH2) n-C00H Rb with respect to the carboxamido group. The syn configuration is shown as follows.

30th

R-C-CO-NH-

N

Ra

35

0- (CH2) m-C- (CH2) n-COOH,

Rb, this configuration based on the work of Ahmad and Spenser [Can. J. Chem., 1961, 39 (1340)].

The compounds obtainable according to the invention have a broad-spectrum antibiotic activity which is distinguished in particular by a high activity against gram-negative microorganisms, including those which form β-lactamases, and furthermore have a high stability towards β-lactamases which are produced by some gram-negative organisms . A characteristic feature of the compounds is their high activity in vitro against gram-negative organisms such as Enterobacter clocae, Serratia marcescens and Klebsiella aerogenes. The compounds have a particularly high activity against strains of Escherichia coli, Haemophilus influenzae and Proteus organisms, e.g. B. strains of Proteus morganii and Proteus mirabilis.

Compounds in which at least one of Ra and Rb is not hydrogen also have an extraordinarily high activity against Pseudomonas organisms, e.g. B. Pseudomonas aeroginosa strains.

If Ra and / or Rb are Ci-Gt-alkyl, methyl, ethyl, n-propyl, isopropyl and butyl are suitable for this. Examples of C2-Gt alkenyl are vinyl and allyl; for C3-C7-cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl and cyclo-hexyl; and for C2-C5-alkoxycarbonyl to call ethoxycarbonyl. If Ra and Rb together with the carbon atom to which they are attached represent a C3-C7-cycloalkylidene or C3-C7-cycloalkenylidene group, cyclobutylidene, cyclopentylidene and cyclohexylidene are particularly suitable for this.

617703

4th

“Non-toxic” derivatives are those derivatives of the compounds of the formula I which are physiologically compatible in the dosage administered, in particular salts and esters.

Non-toxic salt derivatives that can be formed from the compounds of formula I include salts of inorganic bases, such as alkali metal salts (e.g. sodium and potassium salts) and alkaline earth metal salts (e.g. calcium salts), salts of organic bases (e.g. Procaine, phenylethylbenzylamine, dibenzylethylenediamine, ethanolamine, diethanolamine, triethanolamine and N-methylglucosamine salts) and optionally acid addition salts, e.g. B. with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, toluene-p-sulfonic acid and methanesulfonic acid. The salts can also be in the form of resinates, containing, for example, a polystyrene resin or cross-linked polystyrene-divinylbenzene copolymer resin containing amino or quaternary amino groups or optionally sulfonic acid groups, or optionally with a resin containing carboxyl groups, e.g. B. a polyacrylic acid resin are formed. The use of highly soluble salts of the compounds of the formula I with bases (for example alkali metal salts, such as the sodium salt) is generally advantageous in therapeutic use, since such salts are rapidly distributed in the body when administered. However, if insoluble salts of compounds of formula I are desired for special applications, e.g. B. for use in depot preparations, such salts in a conventional manner, for. B. with suitable organic amines.

Biologically compatible, metabolically labile ester derivatives that can be formed from the compounds of formula I include, for. B. acyloxymethyl ester, e.g. B. low alkanoyloxy methyl ester such as acetoxymethyl or pivaloyloxymethyl ester.

If the radical R in the formulas above is a furyl radical, this can be a fur-2-yl or fur-3-yl radical, and if R represents a thienyl radical this can be a thien-2-yl or thien-3-yl radical.

If Ra and Rb are different in the above formulas, the carbon atom to which they are attached may include an asymmetry center. Compounds of the formula I in which Ra and Rb are different can thus be present in the form of the diastereoisomers or else as mixtures thereof.

The compounds of the formula I obtainable according to the invention can be unsubstituted in the 3-position or can carry in this position any of the large number of substituents described in the literature which relate to cephalosporin compounds, the characteristic feature of those obtainable according to the invention Compounds which is 7-acylamido group.

The compounds obtainable according to the invention include, for example, those of the formula II

r-c-co-nh n

(II)

° - (Cli2) m-r (C1I2) n rb •

cooh • cooh wherein R, Ra, Rb, m and n have the above meanings and P is a hydrogen atom, a halogen atom, such as fluorine, chlorine or bromine, or an organic radical, e.g. B. represents a saturated or unsaturated, substituted or s unsubstituted organic radical having 1 to 20 carbon atoms, and their non-toxic derivatives.

If P is an unsaturated organic radical, it can have the formula

-CH = C

R2

15

correspond.

In this formula, R1 and R2, which are the same or different, mean hydrogen, carboxy, cyano, C2-C7-alkoxycarbonyl (e.g. methoxy or ethoxycarbonyl) or a 20 aliphatic, cycloaliphatic, aliphatic or aromatic radical.

As aliphatic radicals come in particular alkyl radicals, preferably Ci-Cö-alkyl, such as methyl, ethyl, isopropyl and n-propyl, as cycloaliphatic radicals those having 5 to 7 carbon atoms, z. B. C5-C7-cycloalkyl, such as cyclopentyl and cyclohexyl, and as aliphatic radicals those having 7 to 10 carbon atoms, for. B. phenylalkyl having 1 to 4 carbon atoms in the alkyl part such as benzyl and phenylethyl, into consideration.

Examples of aromatic residues are mono- and bicyclic 30 carbocyclic aryl residues with 6 to 12 carbon atoms, e.g. B. phenyl, nitrophenyl, tolyl and naphthyl. Typical substituted vinyl groups of the above formula include 2-carboxy vinyl, 2-methoxycarbonyl vinyl, 2-ethoxy carbonyl vinyl and 2-cyanovinyl.

35 P can also be a substituted methyl group of the formula

-CH2Y

where Y represents an atom or group, e.g. B. the residue of a nucleophile or a derivative of a residue of a nucleophile. Thus Y can e.g. B. can be derived from a variety of nucleophilic substances, which are characterized in that they contain a nucleophilic nitrogen, carbon, sulfur or oxygen atom and the execution-45 borrowed in the patents and the literature, which refer to the Cephalosporin chemistry relate are described. Examples of such nucleophiles include:

Nitrogen nucleophiles so Examples of nitrogen nucleophiles include tertiary aliphatic, aromatic, aliphatic and cyclic amines, e.g. B. tri- (Ci- to C6-alkyl) amines, such as triethylamine, and heterocyclic tertiary amines. The heterocyclic tertiary amines may optionally contain one or more further hetero-55 atoms in addition to the basic nitrogen atom, and they may be substituted or unsubstituted. The heterocyclic tertiary amines can thus z. B. be a pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, imidazole, triazole or thiazole; a condensed bi- or poly-cyclic Ana-60 logon of one of these heterocycles, e.g. B. purine or benzotriazole; and any of the above amines substituted with one or more aliphatic (e.g. lower alkyl such as methyl, ethyl, n-propyl or isopropyl), aryl (e.g. Ce to C12 mono- or bicyclic carbocyclic aryl, such as phenyl or naphthyl, araliphatic (e.g. phenyl-lower alkyl, such as benzyl or phenylethyl), low-alkoxymethyl (e.g. methoxymethyl, ethoxymethyl) , n-propoxymethyl or isopropoxymethyl), acyloxymethyl (e.g. low alkanoyl)

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oxymethyl- such as acetoxymethyl-, formyl-, acyloxy- (e.g. low alkanoyloxy- such as acetoxy-), carboxy-, esterified carboxy- (e.g. low alkoxycarbonyl- such as methoxycarbon-yl-) , Carboxy-lower alkyl (e.g., carboxymethyl), sulfo, lower alkoxy (e.g. methoxy, ethoxy, n-propoxy or isopropoxy), aryloxy (e.g. Phenoxy), aralkoxy (e.g. benzyloxy), alkylthio (e.g. methylthio or ethylthio), arylthio, arylthio, cyano, hydroxy, carbamoyl, N-mono-low alkylcarbamoyl- (e.g. N-methylcarbamoyl- or N-ethylcarbamoyl-), N, N-di-lower-alkylcarbamoyl- (e.g. N, N-dimethylcarbamoyl- or N, N-diethylcarbamoyl-), N- (Hydroxy-lower alkyl) -carbamoyl) - (e.g. N- (hydroxymethyl) -carbamoyl- or N- (hydroxyethyl) -carbamoyl-) or carbamoyl-lower-alkyl- (e.g. carbanoylmethyl- or carbamoylethyl) groups. Examples of radicals Y which can be obtained from nucleophilic heterocyclic tertiary amines of the above type include pyridinium, 3- and 4-carbamoylpyridinium, 3-carboxymethylpyridinium, 3-sulfopyridinium, thiazol-3-yl, pyrazole-l- yl, pyridazinium and benzotriazol-l-yl.

Another class of nitrogen nucleophiles includes azides, e.g. B. alkali metal azides such as sodium azide.

If the Y radical is a derivative of a nitrogen nucleophile residue, it may e.g. B. be an amino radical or an acylamido radical. Compounds in which Y is amino can be derived from the corresponding compound in which Y is azido by reduction, e.g. B. by catalytic hydrogenation of the azide using a noble metal catalyst such as palladium or platinum. Compounds in which Y represents an acylamido group can be obtained by acylating a compound in which Y represents amino, e.g. B. by any method suitable for acylating an aminocephalosporin, e.g. B. Reaction of the amino compound with an acid chloride, acid anhydride or mixed anhydride of an acid corresponding to the desired acyl group and another acid.

Compounds in which Y is amino can also be reacted with a substituted isocyanate or isothiocyanate to obtain urea or thiourea derivatives.

Other compounds in which Y is a derivative of a residue of a nitrogen nucleophus can be obtained by reacting a compound in which Y is azido with a dipolarophile. Examples of suitable dipolarophiles include acetylenic, ethylenic and cyano-dipolarophiles.

Acetylenic dipolarophiles can be represented by the formula R'-feC'R4

are referred to, wherein R3 and R4, which may be the same or different, represent atoms or groups.

In general, it is preferred that R3 and preferably also R4 are electronegative NATO. Examples of such residues include cyano, CO2R5, COR5 (where R5 is e.g. hydrogen, lower alkyl, aryl or lower aralkyl) and trihalomethyl, e.g. B. trifluoromethyl.

However, R3 and preferably also R4 can be electropositive, e.g. B. alkoxy or alkylamino.

R3 and R4 together with the acetylenic group can form a ring system, such as. B. in an arine.

When R3 and R4 represent individual atoms or groups that are identical, the reaction with the azidoce-phalosporin creates a single compound. However, if they are different, a mixture of the positional isomers is generally obtained.

Ethylenic dipolarophiles can use the formula

R7 R9

in which R6, R7, R8 and R9, which may be the same or different, represent atoms or groups. Although R6, R7, R8 and R9 can all represent hydrogen, ethylene per se, like acetylene, reacts slowly or slowly with azido groups. R6 and R8 together can form a cyclic structure, e.g. B. form a carbocyclic structure with the äthenoi-den group such that the double bond is strained. Examples of ethylenic dipolarophiles that contain strained double bonds include norbornenes, trans-cycloalkenes and acenaphthylene.

Other ethylenic dipolarophiles that can be used include compounds of the formula R6 • R7C = CR8 • R9, wherein at least one of R6, R7, R8 and R9 is an electronegative group. R6 and R8 can thus be identical electronegative groups, R7 and R9 being different groups if desired. R7 and R9 can thus together form a ring system. Examples of such dipolarophiles include benzoquinone and nucleus-substituted benzoquinones and maleimide. Furthermore, R6, R7, R8 and R9 can all be identical electronegative groups. Electronegative groups that can be used include those listed in the section on acetylenic dipolarophiles, and examples of such compounds thus include dicyanoethylene and low mono- and dialkoxycarbonylethylene.

One or more of R6, R7, R8 and R9 can be electropositive if desired.

Cyano compounds, especially those activated by electronegative groups, can act as cyano-dipolarophiles. Examples of such dipolarophiles include low alkoxycarbonyl cyanides and dicyan.

Carbon nucleophiles

Examples of carbon nucleophiles include inorganic cyanides, pyrroles and substituted pyrroles, e.g. B. indoles, and compounds which provide stabilized carbanions, e.g. B. acetylenes and compounds with ß-diketone groups, for. B. acetoacetic and malonic acid esters and cyclohexane-l, 3-dione or enamines, inamines or enols.

The carbon nucleophiles can thus provide cephalosporin compounds which are distinguished by the fact that they have a substituent in the 3-position in which a carbonyl group is bonded to the cephalosporin nucleus via two carbon atoms. Such compounds can thus, as substituents in the 3-position, a radical of the formula

RIO

eCH2 ■ C • CO • R12 R11

in which R10 and R11, which may be the same or different, are selected from hydrogen; Cyano; low alkyl, e.g. B. methyl or ethyl; Phenyl; Phenyl, substituted e.g. B. by halogen, lower alkyl, lower alkoxy, nitro, amino or lower alkylamino; Carboxy; lower alkoxycarb-onyl; Mono- or diaryl-lower alkoxycarbonyl; lower alkylcarbonyl; Aryl-lower alkyl or C5 or C6 cycloalkyl and R12 is selected from hydrogen; low alkyl, e.g. B.

5

10th

IS

20th

25th

30th

35

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45

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617703

Methyl or ethyl; Phenyl; Phenyl substituted by e.g. B. halogen, lower alkyl, lower alkoxy, nitro, amino or lower alkylamino; Aryl-lower alkyl or Cs- or Ce-cycloalkyl.

Sulfur nucleophiles Examples of sulfur nucleophiles include thioureas including the aliphatic, aromatic, araliphatic, alicyclic and heterocyclic substituted thioureas, dithiocarbamates, aromatic, aliphatic and cyclic thioamides, e.g. B. thioacetamide and thiosemicarbazide, thiosulfates, thiols, thiophenols, thioacids, e.g. B. thiobenzoic acid or thiopi-colinic acid, and dithioic acids.

One class of sulfur nucleophiles includes those compounds of the formula R13 • S (0) nH, wherein R13 is an aliphatic radical, e.g. B. lower alkyl, such as methyl, ethyl or n-propyl radical; an alicyclic residue, e.g. B. low-cycloal-kyl, such as cyclohexyl or cyclopentyl radical; an aromatic residue, e.g. B. Cö- to Ci2-mono- or bicyclic carbocyclic aryl, such as phenyl or naphthyl radical; an aliphatic residue, e.g. B. Phenyl-lower (z. B. Ci to Gt -) - alkyl, such as the benzyl radical; or represents a heterocyclic radical and n denotes the numbers 0, 1 or 2. A preferred class of nucleophiles of the above formula are those of the general formula R14SH, wherein R14 is aliphatic, e.g. B. lower alkyl, such as methyl, ethyl or n-propyl, or lower alkanoyl, such as acetyl; araliphatic, e.g. B. phenyl-lower alkyl, such as benzyl or phenethyl or substituted phenyl-lower alkyl; alicyclic, e.g. B. cycloalkyl, such as cyclopentyl or cyclohexyl; aromatic, e.g. B. phenyl, substituted phenyl; or a heterocyclic radical which contains at least one 5- or 6-membered ring and has one or more heteroatoms selected from O, N and S. Such heterocyclic radicals R14 can be substituted, and examples of suitable heterocyclic groups include thia-diazolyl, e.g. B. 5-methyl-l, 3,4-thiadiazol-2-yl; Diazolyl; Tria-zolyl, e.g. B. triazol-4-yI; Tetrazolyl, e.g. B. l-methyltetrazol-5-yl, l-ethyltetrazol-5-yl or l-phenyltetrazol-5-yl; Thiazolyl; Thiatriazolyl; Oxazolyl; Oxadlazolyl, e.g. B. 2-phenyl-l, 3,4-oxadiazol-5-yl; Pyridyl, e.g. B. N-methylpyrid-2-yl; Pyrimidyl; condensed heterocyclic ring systems, such as benzimidazol-yl, benzoxazolyl, benzothiazolyl * such as benzothiazol-2-yl, triazolopyridyl or purinyl; and substituted derivatives of such condensed ring systems, e.g. B. nitrobenzothiazol-2-yl, such as 5- or 6-nitrobenzothiazol-2-yl.

Oxygen nucleophiles Examples of oxygen nucleophiles include water, alcohols, e.g. B. alkanols, such as methanol, ethanol, prapanol and butanol, and low alkane and alkene acids,

The expression “oxygen-nucfeophil” thus includes compounds of the general formula R15OH ,. wherein the residue may be Ris: lower alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl); low alkenyl (e.g.

Allyl); lower alkynyl (e.g. propynyl); lower cycloalkyl (e.g. cyclopropyl, cyclopentvl or cyclohexyl); lower-cycloalkyl-lower-alkyl (e.g. cyclopropylmethyl, cyclopentylmethyl or cyclohexylethyl); Aryl (e.g. phenyl or naphthyl); Aryl-lower alkyl (e.g. benzyl); a heterocyclic residue (e.g. a heterocyclic residue as defined for R14 such as N-methylpyrid-2-yl); a heterocyclic lower alkyl radical (e.g. furfuryl); or any of these residues, e.g. B. by one or more selected from lower alkoxy (e.g. methoxy or ethoxy), lower alkyl thio (e.g. methylthio or ethylthio), halogen (chlorine, bromine, iodine or fluorine), low alkyl (e.g. methyl or ethyl), nitro, hydroxy, acyloxy, carboxy, carbalkoxy, lower alkyl

carbonyl, lower alkylsulfonyl, lower alkoxysulfonyl,

Amino, lower alkylamino or acylamino.

When water is the nucleophile, the 3-hydroxymeth-yl-cephalosporin compounds are obtained. Such 3-hydroxy-methyl compounds and their non-toxic derivatives can have antibacterial activity and it should be noted that they can be metabolites of compounds of the general formula II, in which P represents acetoxymethyl. 3-hydroxymethyl-cephalosporins can be acylated to obtain derivatives which have the group 3-CH2 • O • -CO • R16 or 3-Œfc • O • CO • AR17, wherein A represents O, S or NH, R16 represents an organic radical and R17 represents hydrogen or an organic radical.

The radical R16CO- or R17A • CO- can be selected from the large class of those groups which are described in the literature and can have up to 20 carbon atoms. R16 and optionally R17 can thus each be a hydrocarbon radical or a radical which carries one or more atoms or groups as substituents,

and can therefore be selected from the following list, which is not to be considered complete:

i) CnH2n + 1, where n is an integer from 1 to 7,

e.g. B. 1 to 4. The rest can be straight or branched and optionally interrupted by an oxygen or sulfur atom or an imino group or by cyano, carboxy, lower alkoxycarbonyl, hydroxy, carboxycarbonyl (HOOC • CO •), halogen (z Chlorine, bromine or iodine) or amino. Examples of such groups include methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, sec-butyl and 2-chloroethyl.

ii) CnH2n-i, where n is an integer from 2 to 7. The rest can be straight or branched chain and, if desired, can be interrupted by an oxygen or sulfur atom or an imino group. Examples of such groups include vinyl and propenyl.

iii) R1S, wherein R18 is carbocyclic aryl (e.g. Ce to Cimano or bicyclic carbocyclic aryl), heterocyclic aryl (e.g. comprising a 5- or 6-membered ring which has at least one selected from O, Contains N and S), lower-cycloalkyl, substituted aryl and substituted cycloalkyl. Examples of this group include: phenyl; substituted phenyl, e.g. B. hydroxyphenyl, chlorophenyl, fluorophenyl, tolyl, nitrophenyl, aminophenyl, methoxyphenyl or methylthiophenyl; Thien-2- and -3-yl; Pyridyl; Cyclohexyl; Cyclopentyl; Cyclopropyl; Sydnon; Naphthyl; and substituted naphthyl e.g. B. 2-EthoxynaphthyI.

iv) RI8 (CH2) m, in which R18 has the meaning given above under iii) and m represents an integer from 1 to 4. Examples of this radical include methyl, ethyl or butyl substituted by the various typical R1S groups listed above under iii), e.g. B. low-cycloalkyl-Ci to Ct-alkyl and carbocyclic or heterocyclic aryl-Ci to Gi-alkyl, such as benzyl and the suitable substituted benzyl groups.

The 3-position substituents of the above type thus include low-alkanoyloxymethyl radicals, such as acetoxymethyl and isobutyryloxymethyl, low-alkenoyloxymeth-yl radicals, such as crotonyloxymethyl; Aroyloxymethyl radicals, such as benzoyloxymethyl; Carbamoyloxymethyl, N- (lower alkyl) carbamoyloxymethyl, such as N-methylcarbamoyloxymeth-yl and N- (haloalkyl) carbamoyloxymethyl, such as N- (2-chloroethyl) carbamoyloxymethyl.

Another important class of cephalosporin compounds are those with the group -CTfcHal in 3-position, in which shark means chlorine, bromine or iodine. Such compounds can primarily be used as intermediates

6

s

10th

15

20th

25th

30th

35

40

4S

50

55

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65

the production of active cephalosporin compounds may be valuable by the halogen atom through a nucleophile, e.g. B. a nitrogen, oxygen or sulfur containing nucleophile as described above is replaced.

The term "low" as used here to designate aliphatic groups means, unless otherwise stated, that the remainder can contain up to 6 carbon atoms. The term "low" to designate cycloaliphatic radicals means that the radical can contain 3 to 7 (eg 5 to 7) carbon atoms.

A particularly interesting group among the compounds obtainable according to the invention are those of the formula III

cooh o-c-cooh

(iii)

where R is as defined above, Rc is methyl,

Represents ethyl, propyl, allyl or phenyl and Rd represents hydrogen, carboxy or preferably a radical as defined for Rc; or Rc and Rd together with the carbon atom to which they are attached form a cyclobutylidene, cyclopentylidene or cyclohexylidene radical, and W is selected from i) hydrogen,

ii) acetoxymethyl,

iii) benzoyloxymethyl,

iv) carbamoyloxymethyl,

v) N-methylcarbamoyloxymethyl,

vi) a residue of the formula

-CH = CHRZ,

where Rz is cyano, carboxy or a C2 to Cs alkoxycarbonyl radical, such as methoxycarbonyl or ethoxycarbonyl,

vii) the residue -CH2G, where G represents the residue of a nitrogen nucleophile, selected from compounds of the formula wherein Rf represents hydrogen, carbamoyl, carboxymethyl or sulfo, and pyridazine

viii) azidomethyl and ix) the radical CH2SRW, where Rw is selected from pyridyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiadiazolyl, oxadiazolyl and z. B. by lower alkyl or phenyl substituted variants of these radicals, such as N-methylpyrid-2-yl, 1-methyltetrazol-5-yl, l-phenyltetrazol-5-yl, 5-methyl-l, 3,4-thiadiazole 2-yl and 5-phenyl-l, 3,4-oxydiazol-2-yl,

as well as their non-toxic derivatives.

These compounds are characterized by a broad spectrum of activity of their antibiotic activity (including a very high activity against strains of Haemo-

617703

philus influenzae and Proteus organisms) and a high ß-lactamase stability and also show a particularly high activity in vitro against Pseudomonas organisms, such as strains of Pseudomonas aeruginosa.

Particularly preferred compounds of the above type due to their particularly high activity against Proteus and Pseudomonas organisms include the following:

(6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2-

(fur-2-yl) acetamido] -3-pyridiniummethylceph-

3-em-4-carboxylic acid (syn isomer)

(6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (for-

2-yl) acetamido] -3- (5-methyl-l, 3,4-thiadiazol-2-

ylthiomethyl) -ceph-3-em-4-carboxylic acid (syn isomer),

(6R, 7R) -3-carbamoyloxymethyl-7- [2- (2-carboxy-

prop-2-yloxyimino) -2- (fur-2-yl) acetamido] -

ceph-3-em-4-carboxylic acid (syn isomer),

(6R, 7R) -7- [2- (2-carboxypropo-2-yloxyimino) -2- (for-

2-yl) acetamido] -3- (trans-2-methoxycarbonyl-

vinyl) -ceph-3-em-4-carboxylic acid (syn isomer),

(6R, 7R) -7- [2- (2-carboxypro-2-yloxyimino) -2- (fur-

2-yl) -acetamido] -3-pyridaziniummethylceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) -7- [2- (2-carboxyprop-2-yloxyimino) -2- (for -2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) -3-acetoxymethyl-7- [2- (l-carboxycyclopent-

1-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-

3-em-4-carboxylic acid (syn isomer), (6R, 7R) -7- [2- (l-carboxycyclopent-l-yloxyimino) -

2- (fur-2-yl) acetamido] -3-pyridiniummethylceph-

3-em-4-carboxylic acid (syn isomer), (6R, 7R) -7- [2- (l-carboxycyclopent-l-yloxyimino) -2- (fur-2-yl) acetamido] -3- ( trans-2-carboxyvinyl) -ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) -7- [2- (l-carboxycyclopent-l-yloxyimino) -2- (fur-2- yl) -acetamido] -3- (l-methyltetrazol-5-ylthio-methyl) -ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-carbamoyloxymethyl-7- [2- (l-carboxy-cyclopent-l-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -7- [2 - (l-Carboxycyclopent-l-yloxy-imino) -2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) -3-acetoxymethyl -7- [2- (l-carboxybut-3-enyloxyimino) -2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) - 3-acetoxymethyl-7- [2- (l-carboxycyclobut-l-yloxyimino) -2-fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R ) -7- [2- (l-carboxycyclobut-l-yloxyimino) -2- (fur-2-yl) -acetamido] -3-pyridiniummethylceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -7- [2- (l-carboxycyclobut-l-yloxyimino) -2- (fur-2-yl) -a cetamido] -3- (l-methyltetrazol-5-ylthio-methyl) -ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) -3-carbamoyloxymethyl-7- [2- (l- carboxy-cyclobut-l-yloxyimino) -2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) -3-acetoxymethyl-7- [2 - (l-carboxypropoxy-imino) -2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) -3-acetoxymethyl-7- [ 2- (3-carboxypent-3-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-

4-carboxylic acid (syn isomer), (6R, 7R) -3-acetoxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2- (thien-2-yl) -acetamido] -ceph-3 -em-4-carboxylic acid (syn isomer)

7

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

617703

and their non-toxic derivatives, e.g. B. alkali metal salts such as the sodium and potassium salts.

Another interesting class among the cephalosporin antibiotics obtainable according to the invention comprises compounds of the formula IV s h

i.

r-c-co-nh-

n

0 '

o- (ch2) p-cooh

R-C-COOH

II

N Ra

\ i

N0- (CH2) m-C- (CH2) n-C00R20 Rb

(VI),

cooh

(iv),

wherein R and W are as defined above and p is 1 or 2, and their non-toxic derivatives.

These compounds have broad-spectrum antibiotic activity, coupled with high ß-lactamase stability. A characteristic feature of the compounds is their high activity against strains of Haemophilus influenzae, coupled with their particularly high activity against strains of Escherichia coli and Proteus organisms.

Particularly preferred compounds of the above type due to their particularly high activity against Escherichia coli and Proteus organisms include the following:

(6R, 7R) -3-acetoxymethyl-7- [2'-carboxymethoxy-imino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-azidomethyl-7- [2-carboxymethoxy-imino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) - 7- [2-Carboxymethoxyimino-2- (fur-2-yl) acetamido] -3- (l-methyltetrazol-5-ylthiomethyl) -ceph-3-em-4-carboxylic acid (syn-isomer), (6R, 7R) -3-carbamoyloxymethyl-7- [2-carboxy-methoxyimino-2- (fur-2-yl) acetamido] -ceph-3-em-4-carboxylic acid (syn isomer), (6R, 7R) - 7- [2-Carboxymethoxyimino-2- (fur-2-yl) -acet-amido] -ceph-3-em-4-carboxylic acid (syn isomer)

as well as their non-toxic derivatives, e.g. B. alkali metal salts such as the sodium or potassium salts.

The compounds of formula I are prepared according to the invention by using a compound of formula V

h ■

i h0n-

0 ^

B-

n.

(v),

COOK

1 <)

wherein

R19 is hydrogen or a carboxyl protecting group; and Z 'is a carbon bridge corresponding to Z, with the difference that the double bond can also be arranged in such a way that a ceph-2-em compound is present, or an acid addition salt or a silyl derivative of this compound with an acid of the formula VI

where R20 is a carboxyl protecting group, corresponds to the acylating agent in the form of the syn isomer or a mixture of syn or anti isomers condensed, cleaving off carboxyl protecting groups present and, if one started from a ceph-2-em compound, the resulting one Ceph-2-em compound isomerized to the corresponding Ceph-3 compound.

Compounds of the formula I obtained in which B> S- »0 can be reduced to the corresponding compounds in which B> S means, for example by reducing the corresponding acyloxysulfonium or alkyl-20 oxysulfonium salt, which by reaction with, for. B. acetyl chloride in the case of acetoxysulfonium salt was prepared in situ, the reduction z. B. with the aid of sodium dithio-nit or iodide ion, such as in a solution of potassium iodide in a water-miscible solvent, such as. B. 25 acetic acid, tetrahydrofuran, dioxane, dimethylformamide or dimethylacetamide. The reaction can be carried out at a temperature of from -20 to + 50 ° C.

Conversely, compounds of the formula I obtained, in which B> S, can be oxidized to the corresponding compounds, in which B> S- »0, for example by treatment with a peracid. The isomerization of the obtained ceph-2-em compounds to the corresponding ceph-3-em compounds can be carried out using a base.

35 If the process products are obtained as a mixture of the syn and anti isomers, the syn isomer can, for. B. can be obtained by conventional methods such as crystallization or chromatography. The syn and anti isomers can be prepared by suitable techniques, e.g. B. by their ultraviolet spectra, 40 by thin-layer or paper chromatography or by their NMR spectra. So shows z. B. the NMR spectrum of DMSO-d6 solutions of the syn compounds of formula I the doublet for the amide NH at a lower field than similar solutions of the 45 corresponding anti-isomers. These factors can be used to monitor or control reactions.

Non-toxic derivatives of Compounds I can be formed in any conventional manner, e.g. B. according to the known methods. So z. B. salts of bases can be prepared by reacting the cephalosporic acid with sodium 2-ethylhexanoate or potassium 2-ethylhexanoate. Biologically compatible ester derivatives can be obtained using conventional esterification agents. 1-Oxides can be treated by treating the corresponding cephalosporin sulfides with 55 a suitable oxidizing agent, e.g. B. with a peracid such as metaperiodic acid, peracetic acid, monoperphthalic acid or m-chloroperbenzoic acid, or with tert-butyl hypochlorite, which latter reagent is usually used in the presence of a weak base such as pyridine.

Suitable acylating agents are preferably acid halides of a corresponding acid of the formula VI, in particular the acid chlorides and acid bromides. Such acylating agents can be prepared by adding an appropriate acid or salt thereof with a halogenating agent, e.g. B. phosphorus pentachloride, thionyl chloride or oxalyl chloride. Treatment of the sodium, potassium or triethylammonium salt of the above

mentioned acid with oxalyl chloride is advantageous in that the isomerization is minimal under these conditions.

Acylations using acid halides can be carried out in aqueous or non-aqueous reaction media, advantageously at temperatures from - 50 to + 50 ° C, preferably from - 20 to + 30 ° C, optionally in the presence of an acid-binding agent. Suitable reaction media include aqueous ketones such as aqueous acetone, esters such as ethyl acetate, halogenated hydrocarbons such as methylene chloride, amides such as dimethylacetamide, nitriles such as acetonitrile, or mixtures of two or more such solvents. Suitable acid binding agents include tertiary amines (e.g. triethylamine or dimethylaniline), inorganic bases (e.g. calcium carbonate or sodium carbonate) and oxiranes such as low 1,2-alkylene oxides (e.g. ethylene oxide or propylene oxide) ) that bind the hydrogen halide that is released in the acylation reaction.

The acids of the formula VI can also be used in the form of the free acid as an acylating agent in the preparation of compounds of the formula I. Acylations using the free acids are advantageously carried out in the presence of a condensing agent, e.g. B. a carbodiimide, such as N, N'-diethyl, dipropyl or diisopropyl carbodiimide, N, N'-dicyclohexyl carbodiimide or N-ethyl-N'-y-dimethyl-aminopropyl carbodiimide; a carbonyl compound such as carbonyldiimidazole; or an isoxazolinium salt, such as N-ethyl-5-phenylisoxazolinium perchlorate. The acylation reactions of this type are advantageously carried out in an anhydrous reaction medium, e.g. B. methylene chloride, dimethylformamide or acetonitrile.

The acylation can also with other amide-forming derivatives of the acids of formula VI, such as. B. a symmetrical anhydride or a mixed anhydride (z. B. with piva-linic acid or formed from a halogen formate, such as a lower alkyl halide formate). The mixed or symmetrical anhydrides can be generated in situ. So z. For example, a mixed anhydride can be formed using N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline. Mixed anhydrides can also be formed with phosphorus-containing acids (e.g. phosphoric acid or phosphorous acid), sulfuric acid or aliphatic or aromatic sulfonic acids (e.g. p-toluenesulfonic acid).

To prepare the compounds of the formula I in which Ra or Rb are carboxy, it may be necessary in many cases to add the carboxy group, e.g. B. by substitution with a carboxyl blocking group, e.g. B. a group as defined above in relation to R19.

Any conversions of substituents in the 3-position which may be necessary in the preparation of special compounds of the formula I can, for. B. be carried out according to the methods described in the literature.

Starting compounds of the formula V, in which Z 'represents the group, can, for. B. by the method of BE-PS 774 480 and FR-PS 2 165 834. Starting materials of the formula V, wherein Z 'is a group of the formula

617703

represents, wherein shark is a halogen atom, such as fluorine, chlorine or bromine, z. B. as described in DT-OS 2 408 686.

The acids of formula VI can by reacting a glyoxylic acid of formula VIII

R — CO-COOH (VIII),

wherein R has the above meaning, or an ester thereof with a hydroxylamine derivative of the formula IX

Ra

H2N-0- (CH2) m-C- (CH2) n-C00R20 (IX),

I.

Rb wherein Ra, Rb, R20, m and n have the meanings given above. The acid or ester obtained can be in its or its syn and anti isomers, e.g. B.

separated by crystallization, chromatography or distillation, after which ester derivatives can be hydrolyzed to form the corresponding acid.

The acids mentioned can also by etherification of an acid of formula X

R-C-COOH

II

* (X),

OH

where R is as defined above, e.g. B. by reaction with a compound of formula XI

Ra

I.

T— (CH2) m- C - (CH2) n-COOR20 (XI),

Rb wherein Ra, Rb, R20, m and n have the above meanings and T represents halogen, such as chlorine, bromine or iodine, sulfate or sulfonate, such as tosylate. The isomers can be separated before or after etherification. The etherification reaction is suitably carried out in the presence of a base, e.g. As potassium tert-butoxide or sodium hydride, and is preferably carried out in an organic solvent, such as. B. dimethyl sulfoxide, a cyclic ether, such as tetra-hydrofuran or dioxane, or an N, N-disubstituted amide, such as dimethylformamide. Under these conditions, the configuration of the oximino group is retained essentially unchanged by the etherification reaction.

Carboxyl blocking groups R20 and optionally R19, which are used in the preparation of the compounds of the formula I or in the preparation of necessary starting materials, are desirably those groups which can be easily cleaved off in a suitable stage of the reaction sequence, advantageously as the last stage. However, in some cases it may be advantageous to use biologically acceptable, metabolically labile carboxyl blocking groups, such as acyloxymethyl groups (e.g. pivaloyloxymethyl), and to retain them in the final product in order to obtain a biologically acceptable ester derivative of a compound of formula I.

Suitable carboxyl-blocking groups are known to the person skilled in the art, a list of representative blocked carboxyl groups in BE-PS 783 449 ent9

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

617703

10th

hold is. Preferred blocked or protected carboxyl groups include aryl-lower alkoxycarbonyl groups, such as p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl and diphenylmethoxycarbonyl; and lower haloalkoxy carbonyl groups such as 2,2,2-trichloroethoxycarbonyl. The carboxyl blocking or protective group can then be removed by any suitable method described in the literature, such as. B. by acid or base catalyzed hydrolysis or by enzymatically catalyzed hydrolysis.

If the carboxyl protective group R20 is a t-butyl or a diphenylmethyl group, the intermediates of the formula XII

R-C-CO-NH-

Hi

H

1/

0 ^

N.

R

a

(xii)

cooh

° - (CH2) m "Ì * (CH2) n'C00R

20th

b r

themselves have antibiotic properties. However, these are generally relatively low in comparison with those of the compounds of the formula I. The compounds of formula XII are also new.

The antibiotic compounds obtainable according to the invention can be formulated for injection and can be prepared in unit dose form in ampoules or in multidose containers with an added preservative. The compositions may be in forms such as suspensions, solutions or emulsions in oily or aqueous vehicles and may contain formulating agents such as suspending agents, stabilizing agents and / or dispersing agents. Alternatively, the active ingredient may be in the form of a powder for remanufacturing with a suitable vehicle, e.g. B. sterile pyrogen-free water, before use.

The antibiotic compounds can also be in a suitable form for absorption by the gastrointestinal tract. Tablets and capsules for oral administration can be in unit dosage form and common excipients such as binders, e.g. Syrup, gum arabic, gelatin, sorbitol, tragacanth or polyvinylpyrrolidone; Fillers such as lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; Lubricants such as magnesium stearate, talc, polyethylene glycol or silicon dioxide; Disintegrants such as potato starch; or acceptable wetting agents such as sodium lauryl sulfate. The tablets can be coated according to the known methods. Oral liquid preparations can be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs or as a dry product for remanufacturing with water or another suitable vehicle before use. Such liquid preparations can contain conventional additives, such as. B. suspending agents, e.g. B. sorbitol syrup, methyl cellulose, glucose / sugar syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; Emulsifiers, e.g. B. lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles, which may include edible oils, e.g. B. almond oil, fractionated coconut oil, oily esters, propylene glycol of ethyl alcohol, and preservatives, such as. B. methyl or propyl p-hydroxybenzoate or sorbic acid. The antibiotic compounds can also be formulated as a suppository, e.g. B. conventional suppository bases, such as cocoa butter or other glycerides.

In veterinary medicine, the compositions may e.g. B. formulated as intramammary preparations either in long-acting or quick-release bases. In general, the compositions can range from 0.1% 10 upwards, e.g. B. 0.1 to 99%, preferably from 10 to 60%, of the active material, depending on the method of administration. If the compositions comprise dosage units, each unit preferably contains 50 to 1500 mg of the active ingredient. The dosage used to treat the adult male is preferably in the range of 500 to 5000 mg per day, depending on the route and frequency of administration, although higher daily doses may be necessary in the treatment of pseu domonas infection .

The antibiotic compounds obtainable according to the invention can be used in combination with other therapeutic agents such as antibiotics, e.g. B. penicillins, tetracyclines or other cephalosporins.

The following examples illustrate the invention. 25 All temperatures are given in ° C. The structure of the compounds was confirmed by NMR spectroscopy (preparations and examples) and IR spectroscopy (examples only).

so manufacture 1

2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn isomer)

The pH of a mixture of 4.2 g of fur-2-ylglyoxylic acid, 4.5 g of tert-butoxycarbonylmethoxyamine and 50 ml of water was adjusted to 5.0 with a 2N sodium hydroxide solution. The solution obtained was stirred for 16 hours. The pH of the solution was raised to 7.0 and the solution was washed twice with ether. The aqueous solution was acidified to pH 1.8 under ether and further extracted with ether. The combined ether extracts were washed (water, saturated saline), dried and concentrated to give 7.62 g of a solid which was crystallized from CCI4 to give 3.67 g (46%) of the title compound of F = 105.1 to 106.2 ° C were obtained; 45 Xmax. (PH 6 phosphate buffer) 277.5 nm (s = 16 300).

Preparation 2 2-tert-butoxycarbonylmethoxyimino-2- (thien-3-yl) -acetic acid (syn isomer) thien-3-ylglyoxylic acid and tert-butoxycarbonylmethoxy-amine were reacted as described in Preparation 1, the title compound of F = 102.6 to 104.4 ° C (from CCI4); > .max. (pH 6 phosphate buffer) 258 nm (s = 13 700).

50

Preparation 3 2-RS-a-tert-butoxycarbonylbenzyloxyimino-2- (fur-2-yl) acetic acid (syn isomer)

a) i) A mixture of 24.5 g of N-hydroxyphthalimide, 60 16.5 g of anhydrous potassium carbonate, 41 g of tert-butyl-a-bromophenylacetate and 225 ml of dimethyl sulfoxide was stirred for 18 hours and then in 1.21 water poured. The precipitated solid was filtered off, washed well with water, dried and crystallized from denatured alcohol (methylated spirits), 41 g (78%) of N- [a- (tert-butoxycarbonyl) benzoyloxy] phthalimide from F = 120.6 to 121.5 ° C were obtained.

ii) 11.4 ml of 100% strength were added to a solution of 40 g of the above oxyphthalimide in 500 ml of dichloromethane

11

617 703

Hydrazine hydrate added. Precipitation was immediately bubbled. The mixture was stirred for 1.5 hours after which sufficient 5N ammonium hydroxide solution was added to dissolve the precipitate. The two layers were separated and the aqueous layer was extracted once with methylene chloride. The combined organic extracts were washed (water, saturated saline), dried and concentrated, giving 25 g (98%) of tert-butyl-a- (aminooxy) phenyl acetate as colorless crystals of F = 48.2 to 49.6 ° C were obtained.

b) Fur-2-ylglyoxylic acid and tert-butyl-a- (aminooxy) phenylacetate were reacted as described in Preparation 1, the title compound being obtained in 42% yield from F = 97.9 to 98.9 ° C ( from CCk); Xmax. (PH 6 phosphate buffer) 278 nm (e = 18,400).

Preparation of 4 2-tert-butoxycarbonylmethoxyimino-2- (thien-2-yl) acetic acid (syn isomer)

To a stirred suspension of 0.96 g of sodium hydride (60% dispersion in oil) in 40 ml of tetrahydrofuran was added 1.71 g of 2-hydroxyimino-2- (thien-2-yl) acetic acid (syn isomer). The mixture was stirred for 30 minutes, after which 25 ml of dimethyl sulfoxide was added and stirring was continued for another hour. To the mixture was added 1.78 g of tert-butyl chloroacetate, which was stirred for 16 hours and then poured into 300 ml of water. After washing twice with ether, the aqueous phase was acidified to a pH of 1.7. Extraction with ether and concentration of the washed (water, saturated saline) and dried extracts gave 2.71 g of a solid which was crystallized from CCk, with 0.952 g (33%) of the title compound of F = 88.3 to 91, Was 3 ° C; A. max. (pH 6 phosphate buffer) 270.5 and 288.5 nm (e = 9200 and 10 800).

Preparation 5 2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) acetic acid (syn isomer)

A solution of 14.1 g of 2- (fur-2-yl) -2-hydroxyiminoacetic acid (syn isomer) in 100 ml of dimethyl sulfoxide was suddenly added to a solution of 22.4 g of potassium tert, which was stirred with a magnetic stirrer. -butoxide in 400 ml of dimethyl sulfoxide, the reaction mixture being kept under an atmosphere of dry nitrogen. A gel was formed, which became a finely divided yellow solid when stirred. Stirring was continued for 1 hour, and then a solution of 24.0 g of tert-butyl-2-bromo-2-methylpropionate in 50 ml of dimethyl sulfoxide was added to the reaction mixture over 1 hour at room temperature. After the addition had ended, the resulting solution was stirred for a further hour. The reaction was poured into 1.51 ice water and acidified to pH 1.8 with concentrated hydrochloric acid under 500 ml ether. The two layers were separated and the aqueous layer extracted with further ether. The combined 15 ether extracts were washed once with water and then extracted with an aqueous sodium bicarbonate solution. The combined alkaline extracts were acidified under ether to pH 1.8 with concentrated hydrochloric acid, and the acidic solution was further extracted with 20 ether. The combined ether extracts were washed (water, saturated saline), dried and concentrated to a yellow oil which crystallized under high vacuum (22.41 g, 83%), Xmax. (EtOH) 272.5 nm (s = 15,400).

25 The above solid (22.4 g) was recrystallized from 25 ml CCk to give 16.42 g (61%) of the title compound; F = 72.5 to 74.2 ° C (73.0 ° C).

Preparations 6 to 20 30 Method A

The dipotassium salt of 2- (fur-2-yI) -2-hydroxyiminoacetic acid (syn-isomer) was generated under an atmosphere of dry nitrogen and alkyed with the appropriate halogen-tert.-butyl ester as described in Preparation 5 -35 liert. The products were isolated in a conventional manner by pouring them into water, acidifying and extracting them.

Method B

As method A, but using a halogen 40-diphenyl methyl ester.

The half esters obtained by these processes are listed in Table I.

O

Table 1

, o2h n

N> Rq-C02R2 °

Manufacturing

R1

RM

method

F

Xmax, nm e

t values in d6-DMSO

No.

° C

(Solvent)

RI

r20

6

^> CHCH3 *

-C (CH3) 3

A

69.8-73.4 °

277 (pH6 buffer)

15,500

5.31; 8.56

8.58

7

-CH2-

-C (CH3) 3

A

107 °

271 (EtOH)

13,700

5.32

8.56

8th

> c

-C (CH3) 3

A

106.8-107.3 °

277.5 (pH6 buffer)

15,100

8.03; 8.30

8.63

9

^ XH (CH2) 3CH3 *

-CHPh2

B

102-104 °

275 (EtOH)

12,700

5.1; 8.16;

3.07 (CH)

8.7; 9.18

617703

12

Table I (continued)

Manufacturing RI No.

r20

Method F

Xmax, nm (solvent)

x values in d6-DMSO

RI

R20

10th

11

^ CHCH2CH3 * \ JZ2H5

X

C2H5

-CHPI12 B

-CHPh2 B

271.5 (EtOH)

14,100

5.13; 8.11 9.07

269 (EtOH) 13,200 8.08; 9.22

3.09 (CH)

3.10 (CH)

12

13

14

16

17th

^; CH (CH2) 2CH3 * -CHPh2 B * -CHPh2 B ^ CH-CH (CH3) 2 * -CHPh2 B

15 ^ CH-CH2CH = CH2 * -C (CH3) 3A

XH3

SC02C (CH3) 3

-C (CH3) 3 A

-C (CH3) 3 A

116-117 ° 270 (EtOH) 14,750

270 (EtOH) 13,400

270.5 266.5 (EtOH)

77.0-80.3 ° 276.5 (pH6 buffer)

91.5 °

276.5 (pH6 buffer)

13,700 13,250

17,500

16,700

5.10; 7.9-8.9; 3.08 (CH) 9.1 (de-DMSO)

5.32; 7.8-9.2 3.07 (CH) (de-DMSO)

5.14; 7.68; 8.95 3.05 (CH) 9.15 (CDCb)

4.26; 4.86; 4.91 8.60 5.38; 7.44 (de-DMSO)

8.12; 8.50 8.57 (de-DMSO)

91.5-93.8 ° 276 (pH6 15,800 8.39; 8.56 8.56

Buffer) (de-DMSO)

18th

19th

20th

, CHs *

-C (CH3) 3 A 113-114 ° 278 (pH6

Buffer)

17,200

7.4-8.3

8.59

-C (CH3) 3 A +

\ xhc2H5

-CH2

-CHPh2 B

* Indicates (RS) isomers + N-benzyl-2-phenylethylammonium salt, F = 129 °

Preparation 21 2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2- (thien-2-yl) acetic acid (syn isomer) The title compound was obtained from 2-hydroxyimino-2- (thien-2-yl) -acetic acid (syn-isomer) and tert-butyl-2-bromo-2-methylpropionate in a similar manner as described in Preparation 5 in 78% yield as a colorless oil and was characterized as the N-benzyl-2-phenylethylammonium salt , F = 201.3 to 201.9 ° C (from ethanol).

Preparation 22 2- (2-tert-butoxycarbonylethoxyimino) -2- (fur-2-yl) acetic acid (syn isomer)

To a mixture of 8.9 g of methyl acetohydroximate [CH3 • C (: NOH) ■ OCH3] and 12.8 g of tert-butyl acrylate, a solution of 0.1 g of potassium tert-butojcydate in 1 ml of tert. -Butanol added. The mixture was kept at 0 ° C. for 65 hours, then washed with water, dried and distilled, 2.37 g (11%) of 2-tert-butoxycarbonylethylmethyl

5.76; 8.74; 8.33 8.54 (CH3)

5.49; 8.6-8.9 3.15 (CH)

Acetohydroximate of F = 85 to 87 ° C / 1.2 mm Hg was obtained.

To a solution of 1.26 g of fur-2-ylglyoxylic acid in 50 ml of water was added 2.15 g of 2-tert-butoxycarbonylethylmethyl-tohydroximate and enough methanol to obtain a homogeneous mixture which was maintained at pH-55 for 30 minutes Value of 1.5 was stirred. The pH was adjusted to 4.5 with 2N sodium hydroxide solution and the mixture was stirred for a further 16 hours after which the reaction was almost complete. Methanol was removed under reduced pressure, the pH of the residue was raised to 7.0 60 and the aqueous mixture was washed twice with ether. The aqueous phase was acidified to pH 1.7 in the presence of dichloromethane and the phases were separated. The aqueous phase was extracted twice more with dichloromethane. The combined 65 dichloromethane extracts were washed with water, dried and concentrated to give 1.53 g of a fawn solid (mixture of syn and anti isomers, 85:15) which were recrystallized from CCk, where

13

617703

0.975 g (34%) of the title compound were obtained, F = 74.7 to 77.2 ° C; Xmax. (pH 6 buffer) 277 nm (e = 16,500).

Preparation 23 tert-butyl-l-bromocyclopentane carboxylate To a mixture of 36.99 g of 1-bromocyclopentane carboxylic acid and 35 ml of anhydrous ether in a 500 ml pressure bottle containing a magnetic stir bar, 3.5 ml of concentrated sulfuric acid and then 150 ml of precondensed isobutane added. The bottle was sealed and stirred at room temperature for 20 hours. The bottle was then opened, excess butene was evaporated and the residue in ether was washed with an aqueous sodium bicarbonate solution and water, dried and concentrated. The residue was distilled under reduced pressure, 33.6 g (70%) of the title ester (bp. = 66 to 74 ° C / 0.5 to 2.0 mm Hg); Vmax. (CHBra) 1702 cm-1; x (CDCb) 7,78,8,20 (cyclopentane protons) and 8,54 [C (CH) 3].

Preparation 24 diphenylmethyl a-bromohexanoate 1.95 g of a-bromohexanoic acid in 25 ml of petroleum ether (bp. 40 to 60 ° C) were mixed with a diphenyldiazomethane stock solution in petroleum ether (bp. 40 to 60 ° C) (approx. 3.8 mmol / 10 ml) with dropwise addition and stirring until a light violet color persists. The mixture became 2nd

Stirred for hours at room temperature after which the solvent was removed in vacuo. The obtained oil in ethyl acetate was washed with a saturated aqueous sodium bicarbonate solution and then with water and dried. Removal of the solvent gave 3.0 g (90%) of the title ester, Xmax. (EtOH) 252, 258,263.5, 267.5 and 276 nm (e 1650,1600,1350,1150 and 850).

io Preparations 25 to 34

a-Halogen-substituted carboxylic acid esters Method A

The appropriate a-halocarboxylic acid was treated with isobutene and concentrated sulfuric acid in a pressure bottle at room temperature for 10 to 40 hours according to the method described in the preparation 23, whereby the tert-butyl esters listed in Table II were obtained.

Method B

20 The appropriate a-halocarboxylic acid in a solvent such as. B. ether, petroleum ether, ethyl acetate, was treated with a diphenyldiazomethane solution until a weak persistent color was observed. The ester was seen with alkali as described in Preparation 24 to give the diphenylmethyl esters listed in Table II.

Table II X-RI-CO2R20

Manufacturing X No.

RI

r20

Ester vmaxcm-1 (CHBr3) method

t values (solvent)

RI

r20

25 Cl -CH2-

26 Br "> C (CH3) 2

-C (CH3) 3 -C (CH3) S

A A

1735 1716

4.06 (CDCb) 8.53

5.74; 8.22 (CDCb) 8.51

27th

28

Br

Br

PCHCH2CH3 *

V "

^ \ c2H5

-CHPh2

-CHPhû

B

B

1737

1729

5.29; 7.97; 9.07 (dô-DMSO)

3.10 (CH)

7.81; 9.10 (dfi-DMSO) 3.06 (CH)

29

30th

31

32

33

Br

Br

Br

Br

Br

^> CH (CH2) 2CH3 *

> -0

CHCH (CH3) 2 *

> 0

-CHPh2

-CHPha

-CHPh2

-C (CH3) 3

-C (CH3>

B

B

B

1730

1725.1245 1738 1710 1714

5.24; 7.7-8.9; 9.12 (d <s-DMSO)

5.45.7.8-9.3 (de-DMSO)

5.40; 7.79; 9.0; 9.08 (dfr-DMSO)

7.9; 8.0-8.9

6.9-7.6; 7.7-8.3

3.09 (CH) 3.04 (CH)

3.10 (CH)

8.51

8.52

34

Br -CH2

-CHPh2

B

6.29; 8.2-9.1

3.08 (CH)

* Indicates (RS) isomers

617703

14

Preparation 35 di-tert-butyl-2-bromo-2-methylmalonate To a stirred suspension of 1.7 g of sodium hydride (80% dispersion in oil) in 60 ml of tetrahydrofuran under a nitrogen atmosphere were 11.52 g of di-tert. -butylme-thylmalonate added. The mixture was stirred at 60 to 70 ° C for 1.5 hours to give a clear solution. This solution was cooled to -25 ° C and a solution of 2.6 ml of bromine in 30 ml of methylene chloride was quickly added. The solution was allowed to warm to room temperature and then concentrated. The residue in ether was washed with water, dried and fractionally distilled under reduced pressure to give 7.56 g (49%) of the title compound, bp 78-86 ° C / 1.0 mm Hg; vmax. (CHBrs) 1730 cm-1 (COaBu1); the (CDCb) values include 8.05 [s, C (CH3) 3] and 8.53 [2s, CHs and C (CH3) 3],

Preparation 36 tert-butylethyl-2-bromo-2-methylmalonate The title compound was prepared in a similar manner as in preparation 35 in 83% yield, bp. 64 to 68 ° C / 0.03 mm Hg.

Preparation 37 1-bromomethylcyclopropane-1-carboxylic acid The bromination of the cyclobutane carboxylic acid led to the corresponding bromic acid and to the title compound (yield approx. 15%), F = 83 to 84 ° C (petroleum ether, bp. 60 to 80 ° C); t (dö-DMSO) values 6.25, 8.65 and 8.90.

Preparation 38 t-butyl-2-bromo-3-formyloxypropionate A solution of 12.8 g of t-butyl acrylate in 50 ml of chloroform and 11.3 ml of formic acid was stirred in an ice bath while a solution of 15.75 was added dropwise in two hours g of N, N-dibromobenzenesulfonamide in a mixture of 50 ml of chloroform and 5.7 ml of formic acid was added. The mixture was stirred at room temperature for a further 16 hours and then filtered. The filtrate was washed successively with water, three times with pH 8 buffer and concentrated saline. The solution was dried, evaporated to an oil and distilled. This gave 20.47 g of the title compound, boiling point 69 to 71 ° C / 1.0 mm Hg; x (CDCb; 60 MHz), 1.93 (s, formyl) and 8.48 (t-butyl protons).

Preparation 39 N- (lt-butyloxycarbonyl-2-formyloxyethoxy) phthalimide 50.6 g of t-butyl-2-bromo-formyloxypropionate were added to a solution of 32.6 g of N-hydroxyphthalimide and 60 ml of triethylamine in 120 ml of dry dimethylformamide added and the mixture stirred for 18 hours at room temperature. The mixture was poured into 1 liter of ice water and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were washed with sodium bicarbonate solution until the wash was colorless and then with water and concentrated saline. The ethyl acetate solution was dried and evaporated under reduced pressure to 53.2 g of an oily solid which, after crystallization from ethanol, gave 20.85 g of the title compound, melting point 64.5 to 67.5 ° C .; t (DMSÖ-d6: 60 MHz) 1.67 (s, formyl), 2.11 (s, phthalimide protons), 4.99 (t, J 4 Hz: 0-CH CC> 2tBu), 5.46 (d , J 4 Hz: -CH2) and 8.54 (s, t-butyl).

Preparation of 40 N- (l-t-butyloxycarbonyl-2-hydroxyethoxy) phthalimide A solution of 2.46 ml of phosphorus oxychloride in 35 ml of chloroform was added to a stirred ice-cold solution of

10.3 g of N- (l-t-butyloxycarbonyl-2-formyloxyethoxy) phthalimide were added in a mixture of 185 ml of chloroform and 235 ml of methanol. The mixture was stirred for a further half an hour at room temperature and then treated with about 10 g of solid sodium bicarbonate before being evaporated to dryness. The residue was partitioned between ether and water and the aqueous phase extracted with further ether. The combined extracts were washed successively twice with sodium bicarbonate solution and then with water and concentrated saline. After evaporating the dry ether extracts, 7.01 g of a yellow resin-like solid was obtained, which was crystallized from ether. 2.81 g of the title compound were obtained, melting point 86.8 ° C .; t (CDCb: 60 MHz), 2.14 (s, broad, phthalimide protons), 5.42 (m, 0-CH-), 6.01 (M, CH2) and 8.44 (t-butylproons) .

Preparation 41 N- (lt-butyloxycarbonyl-2-mesyloxyethoxy) phthalimide 1.35 ml of methanesulfonyl chloride was added to a solution of 2.65 g of N- (lt-butyloxycarbonyl-2-hydroxyethoxy) phthalimide in 25 ml of pyridine and the mixture was added for 18 hours stirred at room temperature. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate and washed successively with water, dilute hydrochloric acid, sodium bicarbonate solution and water. After evaporation of the dried ethyl acetate solution, a residue which, after crystallization from ethanol, gave 0.47 g of the title compound, melting point 108.0 to 109.2 ° C .; x (DMSO-d6: 60 MHz) 2.08 (s, phthalimide protons), 4.88 (m, O-CH CÖ2tBu), 5.34 (m, -CH2-), 6.70 (S, CH3) and 8.51 (s, t-butyl).

Preparation 42 N- (lt-butyloxycarbonylvinyloxy) phthalimide A mixture of 1.44 g of N- (lt-butyloxycarbonyl-2-mesyl-oxyethoxy) phthalimide and 0.60 ml of triethylamine dissolved in 20 ml of ethyl acetate was stirred at room temperature for 24 hours . The mixture was washed successively with water, dilute hydrochloric acid and water. Evaporation of the dried ethyl acetate solution gave 0.967 g of a solid which, after crystallization from ethanol, gave 0.491 g of the title compound, melting point 115.4 to 116.2 ° C .; t (DMSO-d6: 60 MHz), 2.09 (s, phthalimide protons), 454 (q, J 4 Hz: = CH2) and 8.46 (s, t-butyl).

Preparation 43 t-butyl-3-phthalimido-oxy-A1-pyrazoline-3-carboxylate A stirred solution of 8.0 g of N- (lt-butyloxycarbonylvynyloxy) phthalimide in 400 ml of ether was made protonally at 0 ° C. with ethereal diazomethane , from 12.0 g of N-methyl-N-nitro urea, treated until there was a permanent yellow color. The mixture was stirred at room temperature overnight, then treated with additional ethereal diazomethane and stirred for a further two days. During this time, some solvent was lost by evaporation and a white solid settled, which was collected and washed with ether. 5.677 g of pyrazoline were obtained, melting point 123.1 ° C., Xmax. (Ethanol) 236.5, inflexion (s = 10 900) and 294 nm (s = 1900).

Preparation 44 t-butyl-1-phthalimidooxycyclopropane carboxylate A solution of 17.0 g of t-butyl-3-phthalimido-oxy-A1-pyrazoline-3-carboxylate in 510 ml of toluene was heated under reflux for 5 hours, after which the solvent was removed under reduced pressure was evaporated. The residue was taken up in ethyl acetate and successively with 2N-hydrochloric acid,

s

10th

15

20th

25th

30th

35

40

45

50

55

60

65

saturated aqueous sodium bicaibonate and water, dried and evaporated. 16.02 g of the remaining yellow solid were chromatographed on 400 g of Merck silica gel, eluted with ether and gave a resinous substance which, after crystallization from ether / petroleum ether, gave 8.73 g of the title compound, melting point 78.6 ° C.

Xmax. (ethanol) 236.5, inflexion (s = 10 600) and 293 nm (e = 1900).

Preparation 45 t-butyl-1-aminooxyclopropane carboxylate 3.4 g of t-butyl 1-phthalimidooxycyclopropane carboxylate in 55 ml of dry dichloromethane was stirred for 1 hour with 1.17 ml of hydrazine hydrate at room temperature. The precipitate was filtered off and washed with dichloromethane. The filtrate was washed successively with 5N ammonium hydroxide, water, concentrated brine, dried and evaporated. The oxyamine was obtained as a yellow oil (1.832 g), t (CDCb), 4.2 (2H, s, broad (NH2)), 8.50 (9H, s, -C (CH3>), 8.75 (4H, m, -CH2CH2-).

Preparation 46 (1-t-Butyloxycarbonylcyclopropyl) oxyiminofur-2-ylacetic acid 1.83 g of t-butyl-1-aminooxycyclopropanecarboxylate in ethanol was added to a solution of 1.33 g of Fur-2-ylglyoxylic acid in 27.5 ml of water. The pH was adjusted to 4.5 by adding 2N sodium hydroxide. Enough ethanol was added to obtain a homogeneous solution (total volume of ethanol about 30 ml). The mixture was stirred at room temperature for 5 hours and as much 2N sodium hydroxide was added as was necessary to maintain the pH of 4.5. The ethanol was removed under reduced pressure, the residue was diluted with water and adjusted to a pH of 9 by adding 2N sodium hydroxide. The solution was washed with ether, acidified to pH 1.5 with concentrated hydrochloric acid and extracted with ether. The extract was washed with water, dried and evaporated to a yellow-green resinous substance (1.957 g). Crystallization from nitromethane gave 426 mg of the title compound, melting point 118 to 119.5 ° C; Vmax. (CHBn) 3500-2400 (CO2H), 1756 (CO2R) and 1690 cm-1 (CO2H).

example 1

a) (6R, 7R) -3 ~ acetoxymethyl-7- [2-tert-butoxy-carbonylmethoxyimino-2- (fur-2-yl) -acetamido] -ceph-3 -em-4-carboxylic acid (syn-isomer ) 0.45 ml of oxalyl chloride at 5 ° C to a stirred solution of 1.35 g of 2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn isomer) in 50 ml of dry methylene chloride, the Contained 0.7 ml of triethylamine and 1 drop of dimethylformamide. The solution was stirred at 5 ° C for 1 hour and then evaporated to dryness at 5 ° C. The residue was suspended in 50 ml acetone and within 30 minutes to a stirred ice-cooled solution of 1.36 g (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid in 100 ml water and 50 ml Acetone containing 1.0 g sodium bicarbonate was added. The reaction mixture was stirred for 1 hour after which the acetone was removed under reduced pressure. The residue was acidified to pH 1.8 and this mixture was extracted with ether. The combined extracts were washed (water, saturated saline), dried and evaporated to give 2.52 g (96%) of the title compound as a pale yellow foam, [oc] d + 28.5 ° (c 0.96, DMSO) ; Xmax. (pH 6 phosphate buffer) 276.5 nm (s = 17 900).

15 617703

b) (6R, 7R) -3-acetoxymethyl-7- [2-carboxymethoxy-imino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid, disodium salt (syn-isomer)

A solution of 1.422 g (6R, 7R) -3-acetoxymethyl-7- [2-s tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn -Isomeres) and 0.25 ml anisole in 5 ml trifluoroacetic acid was kept at room temperature for 5 minutes. The mixture was concentrated under reduced pressure, 10 ml of ethyl acetate was added, and the mixture was evaporated again. The residue was partitioned between ether and a sodium bicarbonate solution. The ether layer was further extracted with sodium bicarbonate solution and the combined alkaline extracts were acidified to a pH of 1.8 under ether. The acidic mixture was extracted with ether and the combined extracts were washed (water, saturated saline), dried and evaporated to give the dicarboxylic acid corresponding to the title compound (942 mg, 74%); diex (dó-DMSO) values include 0.24 (d, J 8 Hz, NH), 4.13 20 (dd, 7-H) and 5.31 (s, CH2CO2H).

900 mg of this diacid in 9 ml of acetone were neutralized with a solution of 700 mg of sodium 2-ethylhexanoate in 5 ml of acetone. The mixture was stirred for 10 minutes, then the precipitated solid was filtered off, washed with a little acetone and dried to give 807 mg (60%) of the title compound, [ci] d + 15 ° (c 1.08, DMSO); vmax. (Nujol) 1766 cm-1 (β-lactam).

30th

Examples 2 to 26 General Procedure for the Preparation of (6R, 7R) -7- (2-Aryl-2-carboxy-Ri-oxyiminoacet-amido) -3- (Substituted) -ceph-3-em-4-carbon- 35 acids (syn isomers) and their salts

Method A

Following the procedure of Example 1, a solution of 1 equivalent of the appropriate 2-aryl-2-tert-butoxycarbonyl-ri-oxyiminoacetic acid (syn isomer) in 1 equivalent of methylene chloride was added, which may contain some tropics of N, N-dimethyl -formamide and 1 equivalent of triethylamine contained, treated for 1 hour at 0 to 5 ° C with 1 equivalent of oxalyl chloride. The mixture was then evaporated to dryness. The residue was suspended or dissolved in acetone and to 45 a stirred ice-cooled solution of 1 to 1.2 equivalents of (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid in water or a mixture added from acetone and water containing 2 to 2.5 equivalents of sodium hydrogen carbonate. The reaction mixture was stirred for 0.5 to 2.5 hours, allowing the temperature to rise to room temperature. The pH was adjusted to 1.5 to 2.0 and the product extracted with ethyl acetate, alternatively ether or methylene chloride can be used. The organic layer was washed with water and / or saturated brine, dried and evaporated, the corresponding (6R, 7R) -3-acetoxymethyl-7- (2-aryl-2-tert-butoxycarbonyl-Rti-oxyiminoacetamido) - ceph-3-em-4-carboxylic acid (syn isomer) was obtained, which was characterized by the optical rotation and / or spectroscopy, so the tert-butyl esters were treated by treatment with trifluoroacetic acid containing aisole for at least 5 Minutes at room temperature. The reaction mixture was evaporated in vacuo and the product was isolated by trituration or by partitioning between ethyl acetate (or ether) 65 and an aqueous sodium hydrogen carbonate solution, separating the aqueous extracts, acidifying these extracts with ethyl acetate and isolating the title dicarboxylic acid in a conventional manner. The products are listed in Table III.

Method B

It corresponds to method A, but using the suitable 2-aryl-2-diphenylmethoxycarbonyl-Ri-oxyiminoacetic acid (syn isomer) instead of the tert-butyl ester. The products are listed in Table III.

Method C

It corresponds to method A or B, but the dicarboxylic acid was converted into its ditrium salt by treating a solution of the acid in acetone with a solution of Na-2-ethylhexanoate in acetone. The precipitated disodium salt was washed and dried. The products are listed in Table III.

Method D

It corresponds to method A, but using a (6R, 7R) -3- (substituted methyl) -7-amino-ceph-3-em-4-carboxylic acid or a salt thereof instead of the (6R, 7R) -3-acetoxymethyl ) -7-aminoceph-3-em-4-carboxylic acid was used. The products are listed in Table IV.

rp

Table III

(y)

(x) h h cònh. = 2 s

N

0-R3 CCLH

—Ch2o.co.ch3

Example RP no.

RI

Salt method [a] D Ämax, nm e

(DMSO) (pH 6 buffer)

ß-lactam vmax, cm-1 (Nujol)

x values * in d6-DMSO at 100 MHz

Rq

2 // from

-CH2-

Disodium A, C

+ 26.5 °

263 292

14,900 10,200

1762

0.15

4.10

5.32

3 Q

-CH2-

+ 35 °

262

19,700

1798

0.26

4.05

5.27

// V

^> CHPh **

+ 48 °

277.5

18,700

1778

0.13; 0.20 4.08; 4.16

4.28; 4.32 (CH) 2.3-2.6 (Ph)

// v

X

CHCHs **

Disodium A, C + 63 ° 275

16,800 1764

0.29

4.10

5.27 (CH) 8.54 (CH3)

Table III (continued)

Example RP no.

RI

salt

Method [a] D

(DMSO)

/.max, nm

(pH 6 buffer)

ß-lactam vmax, cm-1 (Nujol)

x-values® in d6-DMSO at 100 MHz

RI

n

10th

r ~ n

■ ^ C (CH3) 2

Disodium A, C + 95 ° 274 16,800 1768 0.32 4.05 8.47

Disodium A, C + 62 ° 276 16,800 1756 0.38

^ CHCH2CH = CH2 ** disodium A, C + 40 ° 276 15.400 1760

> 0

X

, C02H

CH3

A

+ 43 ° 274.5 10.100 1760

0.29

Disodium A, C + 76.5 ° 275 15,500 1756 0.38

0.37

4.10, 7.90 and 8.28

-4.15 4.1-4.8; 5.34;

7.38

4.13 4.16

8.20; 8.50

8.36

11

O- X>

from + 28 ° 274 14,600 1780 0.31 4.09 7.56; 8.08

12 // V

13

CC> 2Et /

r <**

CH3

; CH (CH2) 3CH3 **

B

+ 21 ° 275.5 17.200 1790

0.33 4.16 5.80; 8.33; 8.80

+ 45 ° 274 19,150 1771 0.31 4.11

5.40; 8.2; 8.6; 9.1

Example RP no.

R1

salt

method

15

17th

18th

19th

20th

14 N. ^ TCHCIftCEb ** - B

^ ^ ~ ^: C (C2H5) 2 - B

16 (["^: CH (CH2) 2CH3 ** - B

çy> h-o

-CH2CH2-

0 '

B

^ CHCH (CH3) 2 ** - B

y \\> C (CH3) 2 - A

21 ij ^

** Indicates (RS) isomers * Values for free acids

Table III (continued)

[<*] D Xmax, nm e ß-lactam T values * in d6-DMSO at 100 MHz

(DMSO) (pH 6 vmax, cm "

Buffer) (Nujol) x y Rq

+ 57 ° 274 18,000 1776 0.35 4.10 5.45; 5.50

4.13 8.12; 9.01

+ 44 ° 272.5 17,000 1773 0.41 4.16 8.1; 9.2

4-13 ° 273 16 900 1780 0.37 4.10 5.40.5.43

'4.12 8.2; 8.5; 9.1

+ 41 ° 273 18,250 1782 0.4 4.18 5.65; 8.0-9.2

+ 69 ° 273 18,100 1781 0.38 4.14 5.61; 5.69

7.85; 9.0

+ 62.5 ° 262 13,900 1784 0.37 4.10 8.51

+ 31 ° 276.5 15,800 1784 0.28 4.19 5.68; 7.34

+ 43 ° 276 17,250 1788 0.33 4.17 5.68; 8.7-9.0

rp - conh

Table IV

(y)

(x) H H

V 0-

0-Rq.C0oH

? ^ P

-n

CH2Y

co2h

Example RP RI

No.

Salt method [a] D Xmax, nm e

(Solution (pH6 buffer)

medium)

ß-Lactam t »values in d6-DMSO at 100 MHz vmax, cm-1:

(Nujol) x y

RI

22

-CH2- —N3

D + 35 ° 275

(Dioxane)

15,200 1770 0.14 4.10 5.31

23

U V

-OCONHCH3

D + 41.2 ° 277 17,850 1780 0.48 4.18 7.95; 8.3

(DMSO)

24th

25th

CX> 0

—OCONH2 disodium D

-OCONH2

D

+ 47.5 ° 264 13,900 1770 0.25 4.13 5.33

(DMSO)

+ 26 ° (DMSO)

277.5 15,100 1788 0.34 4.12 7.56; 8.10

26

M ^ ^ C (CH3) 2 -OCONH2 disodium D + 44 ° 274.5 14.950 1773 0.44 4.15 8.52

(H2O)

617703

Example 27

(6R, 7R) -7- [2-carboxymethoxyimino-2- (fur-2-yl) acetamido] -3- (l-methyltetrazol-5-ylthiomethyl) -ceph-3-em-4-carboxylic acid (syn- Isomeres)

A solution of 0.97 g of 2-tert-butoxycarbonylmethoxy-imino-2- (fur-2-yl) acetic acid (syn isomer) in 20 ml of methylene chloride was added dropwise to a stirred solution at room temperature within 15 minutes 1.484 g diphenyl-methyl- (6R, 7R) -7-amino-3- (l-methyltetrazoI-5-ylthiometh-yl) -ceph-3-em-4-carboxylate and 0.743 g dicyclohexylcarbo-. diimide added in 45 ml of methylene chloride. After stirring for a further 2 hours, the solvent was removed by evaporation and the residue was stirred for 5 minutes with 50 ml of ethyl acetate and filtered. The filtrate was washed with saturated sodium bicarbonate solution, diluted with an equal volume of water and then with brine (25 ml each), dried and evaporated to 2.5 g of a foam which was dissolved in benzene and purified by chromatography on 70 g of silica gel. Elution with benzene: ethyl acetate (10: 1), combining the appropriate fractions and evaporation to dryness gave 2.05 g of a foam which was dissolved in ethyl acetate and poured into low boiling petroleum ether, 2.02 g (90%) Diphenylmethyl- (6R, 7R) -7- [2-tert.butoxycarbonylmethoxyimino-2- (fur-2-yl) acetamido] -3 - (l-methyltetrazol-5-ylthiomethyl) -ceph-3-em-4- carboxylate (syn isomer) were obtained as a white amorphous solid. [a] g-102 ° (c 0.99, CHCb); W. (EtOH) 278 nm (s = 19,800).

A solution of 1.93 g of this diester in a mixture of 7.7 ml of trifluoroacetic acid and 1.9 ml of anisole was kept at 0 ° C. for 10 minutes and then added to 850 ml of a mixture of saturated sodium bicarbonate and water (1: 3) . After stirring for 10 minutes, the mixture was washed with ethyl acetate, covered with more ethyl acetate (200 ml) and acidified to pH 2 with concentrated hydrochloric acid. The organic phase was separated, washed with water and brine, dried and evaporated to 1.54 g of a foam. Thin layer chromatography indicated that the deprotection was incomplete and the product was again treated with 4.3 ml of trifluoroacetic acid and 1.1 ml of anisole for 15 minutes at 20 ° C, after which the product was described as a foam (1.3 g) was isolated. This foam in ethyl acetate was introduced into low boiling petroleum ether to give 0.8 g (59%) of the title dicarboxylic acid as an amorphous white solid. [cc] d3-99 ° (c 1.05, acetone); Xmax. (0.1m pH 6 phosphate buffer) 277nm (e = 21,900); Vmax. (Nujol) 1780 cm "1; the t (dô-DMSO) values include 0.19 (d, NH), 4.14 (dd, 7-H), 5.30 (s, CH2CO2H).

Example 28

(6R, 7R) -3- (carbamoyloxymethyl-7- [2-carboxy-methoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn isomer) 2.08 Diphenylmethyl- (6R, 7R) -7-amino-3-carbamoyloxy-methyl-ceph-3-em-4-carboxylate-toluene-p-sulfonic acid salt was dissolved in a mixture of 60 ml of ethyl acetate and 60 ml of a saturated aqueous sodium bicarbonate solution The ethyl acetate layer was separated, washed with water, dried and evaporated to a foam.

1.0 g of 2-tert-butoxycarbonylmethoxyimino-2- (fur-2-yl) acetic acid (syn isomer) and 0.76 g of dicyclohexylcarbodiimide, dissolved in a small volume of anhydrous methylene chloride, were added to a solution of the above amine, dissolved in 20 ml of anhydrous methylene chloride, added. The reaction mixture was stirred at 3 ° C for 35 minutes, during which N, N'-dicy-

20th

clohexylurea crystallized. This was filtered off and the filtrate evaporated to an oil which solidified when triturated with diisopropyl ether. The solid product was dissolved in ethanol and decolorized with activated carbon. Evaporation of the solution gave 2.08 g (86%) of diphenylmeth-yl- (6R, 7R) -3-carbamoyloxymethyl-7- [2-tert.-butoxycarbon-ylmethoxyimino-2- (fur-2- yl) -acetamido] -ceph-3-em-4-carb-oxylate (syn isomer); F = 97 to 98 ° C; [ct] D + 5.5 ° (c 1.00, DMSO); Xmax. (EtOH) 276.5 nm (s = 17,250). 10 6 ml of trifluoroacetic acid was added to a slurry of 2.08 g of the above diester in 6 ml of anisole, and the reaction mixture was stirred at 20 ° C for 25 minutes. The solution was poured into a mixture of ethyl acetate and an aqueous sodium bicarbonate solution, the aqueous layer was separated and washed with ethyl acetate. 100 ml of ethyl acetate and 2N hydrochloric acid were added to reduce the pH to 2. The organic layer was then separated, washed with water, dried and evaporated to a yellow oil. 20 NMR spectroscopy showed that the product

(6R, 7R) -3-carbamoyloxymethyl-7- [2-tert-butoxycarbonyl-methoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer ).

This acid was treated with 4 ml of anisole and 4 ml of trifluoroacetic acid-25 acid for 30 minutes at 20 ° C, and the reaction mixture was partitioned between ethyl acetate and an aqueous sodium bicarbonate solution. The aqueous layer was washed with ethyl acetate and acidified to pH 2 with 2N hydrochloric acid under ethyl acetate. Evaporation of the ethyl acetate layer 3 »gave a solid which was purified by precipitation from ethyl acetate with isopropyl ether and filtering off, giving 620 mg (44%) of the title dicarboxylic acid from F = 159 to 161 ° C .; [a1 + 35 ° (c 1.0, DMSO); Xmax. (pH 6 phosphate buffer) 275 nm 35 (e = 15,400); vmax. (Nujol) 1778 cm-1, the x (d6-DMSO) values include 0.20 (d, NH) 4.15 (dd, 7-H) 5.32 [s, C (CH3) 2],

Examples 29 to 42 General Procedure for the Preparation of (6R, 7R) -7- [2-Carboxy-Ri-oxyimino-2- (fur-2-

yl) -acetamido] -3- (substituted) -ceph-3-em-4-carboxylic acids (syn isomers) using dicyclohexylcarbodiimide i) to a solution of diphenylmethyl- (6R, 7R) -7-amino-3- (Substituted) -ceph-3-em-4-carboxylate (1 equivalent) and dicyclohexylcarbodiimide (1 to 1.3 equivalents) in dry methylene chloride, a solution of the suitable 50-nets 2-tert-butoxycarbonyl at 0 to 25 ° C. -Ri-oxyimino-2- (fur-2-yl) -acetic acid (syn-isomer) (1 to 1.15 equivalents) added in dry methylene chloride. After stirring for 0.5 to 5.0 hours, the dicyclohexylurea was removed by filtration and the filtrate evaporated. The residue in ethyl 55 acetate or methylene chloride was washed successively with aqueous sodium bicarbonate, water and brine, dried and evaporated. The diester was purified by chromatography on silica or, after decolorization with activated carbon, by trituration or recrystallization. The 60 product was characterized by its NMR spectrum and thin layer chromatography.

When the 7-amino starting material was available as an acid addition salt, the free base was released by shaking with a mixture of ethyl acetate (or methylene chloride) and an excess of an aqueous sodium bicarbonate solution. After washing with water and brine, the organic layer was evaporated to dryness and the free amine used as described above.

40

45

21st

617703

ii) Method A

The protecting group of the diester intermediates thus derived was removed by dissolving in a mixture of trifluoroacetic acid (3 to 10 ml / g diester) and anisole (0.8 to 12 ml / g diester) and standing for 5 minutes to 2.5 hours removed between 0 ° C and room temperature. The mixture was concentrated under reduced pressure and added to a mixture of ethyl acetate or ether and excess aqueous sodium bicarbonate, and the aqueous layer was washed with ethyl acetate. The aqueous phase was covered with ethyl acetate and acidified to pH 1 to 2 with hydrochloric acid. The organic layer was washed, dried and evaporated to give the desired dicarboxylic acid.

ü) Method B

In some cases where treatment with trifluoroacetic acid was insufficient to achieve complete deprotection, the monoester intermediate (generally the tert-butoxycarbonyl group is slower than the diphenylmethoxycarbonyl group is split off) again with trifluoroacetic acid and anisole, and the acid was isolated as described above.

iii) Method C.

The 3-carboxyvinyl derivative described in Example 36 was prepared from a 7-amino derivative in which both carboxyl groups were protected as diphenylmethyl esters. The protective groups were removed from the triester obtained by method B, the desired tricarboxylic acid being obtained.

The properties of the reaction products are listed in Table V.

(x) conh -

Table V

(y)

H

OJ

k0-Rq-C02H

& ■

co h 2

At- RI

game

No.

Me- [<x] D Xmax, nm method (solvent) (solvent)

β-lactam x values in d6-DMSO at 100 MHz vmax, cm "1

(Nujol) x y R3

29 ^ X (CH3) 2

N N

-CH2S-

N

B -12 ° (HaO) 278 20,050 1781 0.33 4.1 8.51

(pH 6 buffer)

30 yC (CH3) 2

31 -CHi-

CHs

-CH2OCONH2

B

-CH = CHC02CH3 B (trans)

+ 62 ° (EtOH) 275 14,850 1775 0.24 4.14 8.52 (pH 6 buffer)

—108 ° (aq. 295 26,200 1775 0.20 4.08 5.32 NaHCOs) (pH 6 buffer)

32 ^ C (CH3) 2

N N

-CH2S-

SX CHs

-48 ° (DMSO) 278 21,800 1780 0.38 4.1 8.49; 8.57

(pH 6 buffer)

33 C (CH3) 2

Cl

B

+ 92.5 ° (CHCb)

272.5 (EtOH)

16,600 1780 0.34 4.11 8.51

34

CH2S-.

p, j A -89 ° 221 23,900 1,772 0.42 4.10 7.9; 8.3

W J (DMSO) 283 21,550

S '(pH 6 buffer)

35

-CH = CHC02C2Hs B -8 ° (aq. 295 26,200 1780 0.38 4.09 7.9; 8.3

(trans) NaHCÓ3) (pH 6 buffer)

617703

22

Table V (continued)

Example - R'i game

No.

Me- [a] d) .max, nm E

thode (solvent) (solvent)

β-lactam x values in d6-DMSO at 100 MHz vmax, cm-1 -. -

(Nujol) x y RI

36

-CH = CHC02H (trans)

-15 ° (aq. 294.5 31,200 1779

NaHCOs) (pH 6 buffer)

0.38 4.07 7.9; 8.3

37

N-N

-CTfeS-A N

. V

A -71 ° 279

(CHCb) (pH 6 buffer) 22,000 1780 0.42 4.15 7.9; 8.28

38

CH3

-CH2OCONH2 A + 52 °

(EtOH)

274.5 15,700 1778 0.45 4.14 7.9; 8.25

(pH 6 buffer)

39

-CH = CHC02CH3 B -85 ° 295 26,800 1780 0.33 4.05 7.90; 8.25

(trans) (5% NaHCOs) (pH 6 buffer)

40 ^ C (CH3) 2 -CH = CHC02CH3 B -104.4 295 27,200 1779 0.34 4.09 8.52; 8.60

(trans) (5% NaHCOs) (pH 6 buffer)

41 -CH2-

42

> 0

H

H

B + 84 ° 281.5 15,100 1774

(5% NaHCOs) (pH 6 buffer)

B + 162 ° 283 13.800 1775

(5% NaHCOs) (pH 6 buffer)

0.19 4.08 5.31

0.37 4.05 7.9; 8.25

Example 43

(6R, 7R) -7- [2- (1-carboxycyclopent-1-yloxy-imino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid (syn-isomer)

a) A stirred solution of 5.50 g diphenylmethyl (6R, 7R) -7-aminoceph-3-em-4-carboxylate and 5.23 g propylene oxide in 100 ml dry methylene chloride was added dropwise at -5 ° C within Treated for 20 minutes with a solution of 2- (l-tert-butoxycarbonylcyclopent-l-yloxyimino) -2- (fur-2-yl) aceto-tyl chloride (syn isomer) in methylene chloride (see below). The resulting solution was stirred at 0 ° C for 40 minutes and allowed to warm to 22 ° C with stirring for an additional hour. 15 ml of methanol was added and stirring was continued for 15 minutes. The solution was washed with a 2N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated saline solution. After drying and clarifying with activated carbon, a foam was obtained by evaporation, which was dissolved in ether and added dropwise to petroleum ether, 8.3 g (83%) of diphenylmethyl- (6R, 7R) -7- [2- (l -tert.-butoxycarbonylcyclopent-l-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylate (syn isomer) were obtained as a colorless powder. [<x] d = 43 ° (c 0.1, CHCb); Xmax. (EtOH) 277 nm (e = 17,300).

b) 6 g of the diester prepared under a) above in 30 ml of anisole at 0 ° C. were treated with 24 ml of trifluoroacetic acid and the solution was stirred for 30 minutes. The reaction mixture was allowed to warm to 22 ° C with stirring for a further 2 45 hours and was then concentrated in vacuo to about 20 ml. The residual oil was partitioned between ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was extracted with a bicarbonate solution and the combined 50 alkaline layers were washed with ethyl acetate and ether. The aqueous layer was covered with ethyl acetate and adjusted to pH 1.5 with concentrated hydrochloric acid. The resulting organic layer was washed with saturated saline, dried 55 and evaporated to a foam containing the title acid.

The foam was dissolved in a buffer containing 0.1 mol of sodium acetate, 0.1 mol of acetic acid and 0.2 mol of sodium chloride (75 ml) with the aid of sodium bicarbonate. The solution was treated with Amberlite XAD-8 (50 ml) and the pH was adjusted to 4.8 with 2N hydrochloric acid. The resulting stirred suspension was treated with neutral aluminum oxide (Woelm) (20 g) while the pH was kept at 4.8. The suspension was stirred for 20 minutes and placed on a column with 25 g of neutral 65 aluminum oxide (Woelm). The title acid was eluted with 3000 ml of the above buffer and with 500 ml of a 2% aqueous sodium acetate solution. The eluates were freeze-dried and in minimal water

23

617703

quantity dissolved again. After adjusting the pH to 1.5 with concentrated hydrochloric acid, the acidic liquids were extracted with ethyl acetate, and the combined extracts were dried and evaporated to form a foam. Trituration with ethyl acetate, petroleum and ether gave the title acid as a colorless solid (3.5 g, 88%); [oi] d + 162 ° (c 0.01.5% aqueous NaHCÛ3); Xmax. (pH 6 phosphate buffer) 282 nm (e = 14,000); vmax. (Nujol) 1775 (β-lactam), 1710 (CO2H) and 1680 and 1528 cm-1 (CONH); the x (DMSO-d6) values include 0.37 (d, J 8 Hz, CONH), 2,10,3,24 and 3,31 (m, furyl protons), 4.05 (dd, J 5 and 8 Hz, 7-H), 4.80 (d, J 5 Hz, 6-H) and 7.90 and 8.25 (2 X broad m, cyclopentyl protons). The NMR spectrum also showed the presence of V2 mol of ethyl acetate and water.

The acylating agent used in step a) above was obtained as follows:

A stirred suspension of 3.75 g of phosphorus pentachloride in 120 ml of dry methylene chloride and 6.53 g of dimethyl acetamide was at -10 ° C. with 2- (l-tert-butoxycarbonylcy-clopent-l-yloxyimino) -2- (f ur-2-yl) acetic acid (syn-isomer) (5.82 g) treated in small proportions to keep the temperature below -5 ° C. After stirring for 15 minutes, the solution was treated with 40 g of ice and stirred for 20 minutes to obtain the corresponding acid chloride in the organic layer.

Examples 44 to 48 General procedure for the preparation of (6R, 7R) -3- (optionally substituted) -7- [2-carboxy-R <! - oxyimino) -2-fur-2-yl) -acetamido] - ceph-3-em-4-carboxylic acids (syn isomers) s by treating an ester of a (6R, 7R) -3- (optionally substituted) -7-aminoceph-3-em-4-carboxylic acid with an acid chloride ( syn-isomer)

A 2- (tert-butoxycarbonyl-ri-oxyimino) -2- (fur-2-yl) acetic acid (syn isomer) was converted into its acid chloride as described in Examples 2 to 24 10. A solution of 1 to 1.3 equivalents of the acid chloride in methylene chloride was added dropwise at -5 to + 5 ° C over a period of 10 to 30 minutes to a solution of 1 equivalent of diphenylmethyl- (6R, 7R) -3- (optionally substituted ) -7-aminoceph-3-em-4-carboxylate in dry methylene chloride, which contained 5 to 20 equivalents of propylene oxide. The reaction mixture was stirred for about 1 to 3 hours at 0 ° C. to room temperature and then washed successively with 2N-hydrochloric acid, aqueous sodium bicarbonate solution, water and / or brine. The dried organic layer was evaporated and the residue was purified by trituration, precipitation, chromatography or crystallization.

The diphenylmethyl- (6R, 7R) -3- (optionally substituted) -7- [2- (tert-butoxycarbonyl-Rti-oxyimino) -2- (fur-2-yl) -acetamido] -ceph-3- obtained em-4-carboxylate (syn isomer) was subjected to deprotection as described in Examples 29-42, Methods A and B, for the diesters. The products are listed in Table VI.

xs

20th

Table VI

\ y) M?

conh -

n-v o-rq-c02h

At- RI

game

No.

Me- [a] D

thode (solvent)

Amax, nm (solvent)

β-lactam x values in d6-DMSO at 100 MHz vmax, cm-1

(Nujol) x y RI

44 -CH2-

-CH = CHC02Et b (trans)

294.5

26,300 1780 0.12 4.04 5.30

45 -CH2-

-CH = CHCN

B

291.5

21,800 1785 0.08 4.01 5.29

46 -CH2-

CH2S.

-N

N / A

T

-38 ° (DMSO)

277.5 23,600 1775 0.21 4.19 5.30

47 ^ C (CH3) 2 -H

B + 113 °. 279.5 13.400 1777 0.41 4.09 8.5

(aq. NaHCOs)

N-

-N

48

x>

I.

CH3

-97.3 ° (CHCb)

279

21,900 1782 0.32 4.11 7.6; 8.1

617703

24th

Example 49

a) (6R, 7R) -benzoyloxymethyl-7- [2- (2-tert-butoxy-

carbonyl-prop-2-yloxyimino) -2- (fur-2-yl) -acet-amido3-ceph-3-em-4-carboxylic acid (syn-isomer)

A suspension of 313 mg of phosphorus pentachloride in 4 ml of dry methylene chloride was treated at −10 ° C. with 0.7 ml of N, N-dimethylacetamide, followed by portions with 446 mg of 2- (2-tert-butoxycarbonylprop-2-yloxyimino) - 2- (fur-2-yl) acetic acid (syn isomer) was treated. The resulting solution was stirred at -10 ° C for 30 minutes, treated with about 1 g of ice and stirred at below 0 ° C for 15 minutes. The organic phase was added dropwise to a solution of 502 mg (6R, 7R) -7-amino-3-benzoyloxymethylceph-3-em-4-carboxylic acid in 2 ml of N, N-dimethylacetamide and 2 ml of acetonitrile containing 1.09 ml Triethylamine, at below is 0 ° C. The solution was stirred at 0 to 5 ° C for 2 hours, 0.3 ml of methanol was added, and stirring was continued for 15 minutes. The solution was diluted with 20 ml of methylene chloride and washed successively with 2N hydrochloric acid, water and brine, dried and evaporated to give 1.02 g of a gum. A solution of this gum in 6 ml of ethyl acetate was added dropwise to 200 ml of stirred petroleum ether, bp. 40 to 60 ° C., the title acid being obtained as an off-white powder in a yield of 83% (769 mg); [oi] d + 260 (c 1.05, acetone); Xmax. (pH 6 phosphate buffer) 233.5 nm (g = 19,200) and 274 nm (e = 18,600);

Vmax. (Nujol) 1790 cm "1 (β-lactam); the x (d6-DMSO) values include 0.29 (d, J 8 Hz, NH), 4.03 (dd, J 8 and J 5 Hz, 7 -H), 8.50 [s, C (CH3) 2] and 8.58 [s, C (CH3) s].

30th

b) (6R, 7R) -3-benzoyloxymethyl-7- [2- (2-carboxy-prop-2-yloxyimino) -2- (fur-2-yl) acetamido] -ceph-3-em-4- carboxylic acid (syn isomer)

A solution of 620 mg (6R, 7R) -3-benzoyloxymethyl-7- [2- (2-tert-butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) -3s acetamido] -ceph-3 -em-4-carboxylic acid (syn isomer) in 0.6 ml anisole and 3 ml trifluoroacetic acid was stirred at 20 ° C for 25 minutes. The solution was partitioned between ethyl acetate and an aqueous sodium bicarbonate solution, and the pH was adjusted to 8 by adding solid sodium carbonate. The aqueous phase was separated, washed with ethyl acetate, covered with ethyl acetate, and the pH was adjusted to 1.5 by adding concentrated hydrochloric acid. The organic phase was separated, washed successively with water and a brine, dried <5 and evaporated to give an oily foam (584 mg). A solution of this foam in ethyl acetate was run in dropwise in stirred petroleum ether, bp 40-60 ° C, to give title dicarboxylic acid as an off-white solid (384 mg, 67%); [<x] d + 30.4 ° (c 1.0, acetone); so Xmax. (pH 6 phosphate buffer) 234 nm (e = 19,700) and 273 nm (e = 18,450); Vmax. (Nujol) 1784 cm-1 (β-lactam); the x (d6-DMSO values include 0.30 (d, J 8 Hz, NH), 4.07 (dd, J 8 and J 5 Hz, 7-H) and 8.50 [s, C (CH3) 2],

ss

Example 50

Pivaloxymethyl- (6R, 7R) -3-carbamoyloxymethyl-7- [2-carboxymethoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylate (syn isomer)

A stirred solution of 8.50 g of sodium (6R, 7R) -3- 60 (carbamoyloxymethyl-7- [2-tert-butoxycarbonylmethoxy-imino) -2- (fur-2-yl) -acetamido] -ceph- 3-em-4-carboxylate (syn isomer) in 100 ml of dimethylformamide was treated with 4.68 ml of chloromethyl pivalate. The solution was stirred at room temperature for 25 hours and partitioned between ethyl acetate and 6s water. The aqueous layer was further extracted with the ethyl acetate, and the combined extracts were washed successively with brine, saturated sodium bicarbonate and brine, and were then dried and evaporated to a small volume. The residue was slowly added to 1.5 l of stirred petroleum ether with a bp of 40 to 600 ° C. and the precipitate was collected, washed with petroleum ether and dried in vacuo, 8.32 g of a mixture of the tert-butyl ester of the title compound and its A2 Was obtained analogously (À2: A3 ratio ~ 3: 2, determined by NMR spectroscopy).

8.1 g of this isomer mixture, dissolved in 75 ml of methylene chloride, were cooled to -40 ° C. and stirred, while 2.41 g of m-chloroperbenzoic acid in 65 ml of methylene chloride were added dropwise. The solution was stirred at -40 ° C for 1.25 hours and a further 1.2 g of m-chloroperbenzoic acid in methylene chloride was added. After stirring for an additional 40 minutes, the solvent was evaporated and the residue partitioned between ethyl acetate and a brine. The ethyl acetate solution was washed with sodium bicarbonate solution and brine, dried over sodium sulfate and evaporated to 9.77 g of a yellow foam. This was triturated with ether and a yellow solid was filtered off, which was washed with ether and dried in vacuo to give 7.27 g of the 1-oxide of the title compound.

A solution of 7.07 g of this sulfoxide and 14.34 g of potassium iodide in 100 ml of dimethylformamide was surrounded by a salt-ice bath and stirred in 15 ml of dimethylformamide while the addition of 3.08 ml of acetyl chloride. The solution was stirred for 3.5 hours and an additional 1.54 ml of acetyl chloride in dimethylformamide was added. The solution was stirred for 1 hour and partitioned between a sodium metabisul-fit solution and ethyl acetate. The organic layer was washed with sodium metabisulfite solution and water and then dried and evaporated to a small volume. The resulting solution was slowly added to excess stirred petroleum ether, bp 40-60 ° C, and the solid obtained was collected, washed with petroleum ether and dried in vacuo to give 7 g of pivaloyloxy-methyl- (6R, 7R) -3-carbamoyloxymethyl -7- [2-tert-butoxy-car-bonylmethoxyimino-2- (fur-2-yl) -acetamido] -ceph-3-em-4-car-boxylate (syn-isomer) were obtained; Imax. (EtOH) 277 nm (e = 16,540); Xmax. (Nujol) 1782 (β-lactam), 1740 and 1720 cm-1 (CONH2); the t (ds-DMSO values include 0.25 (d, NH), 3.40 (s, NH2) and 8.8 [s, C (CH3) s].

The above diester (1.0 g) was dissolved in 5 ml of trifluoroacetic acid and this solution was stirred at room temperature for 15 minutes and then diluted with ether, washed with water and evaporated. The residue was partitioned between ethyl acetate and a sodium bicarbonate solution and the organic layer was extracted again with sodium bicarbonate solution. The combined aqueous extracts were washed with ethyl acetate, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extracts were washed with water, dried and evaporated to give an oil. This was dissolved in a small volume of ethyl acetate and slowly added to excess stirred petroleum ether with a boiling point of 40 to 60 ° C. The gray-white precipitate was collected, washed with petroleum ether and dried in vacuo to give 0.645 g of the title ester; Xmax. (EtOH) 278 nm (s = 16,900); Lai. (Nujol) 1778 cm-1 (β-lactam); the x (d6-DMSO) values include 0.25 (d, NH), 2.16.3.26, 3.38 (fur-2-yl protons) and 4.10 (dd, 7-H) .

The sodium salt starting material for the above process was prepared as follows:

2.58 ml of triethylamine and 2 drops of dimethylformamide were added to a solution of 5 g of 2-tert-butoxycarbonylmeth-oxyimino-2- (fur-2-yl) acetic acid (syn isomer) in 200 ml of dry methylene chloride. The stirred solution

25th

was cooled to 0 ° C and 1.58 ml of oxalyl chloride was added. The solution was stirred for 1 hour and then evaporated. The residue was suspended in 150 ml of acetone and within half an hour to a stirred ice-cold solution of 5.08 g (6R, 7R) -3-carbamoyloxymethyl-s 7-aminoceph-3-em-4-carboxylic acid in 150 ml of acetone and 300 ml of water containing 3.74 g of sodium bicarbonate were added. The reaction mixture was stirred for 1 hour and evaporated to remove acetone. The aqueous residue was acidified to a pH of 1.8 using dilute hydrochloric acid and the layers were separated.

The aqueous layer was further extracted with ether and the combined extracts were washed with water and brine, dried and evaporated to give the (6R, 7R) -3- is carbamoyloxymethyl-7- [2-tert-butoxycarbonylmethoxyimino-2- ( fur-2-yl) -acetamido] -ceph-3-em-carboxylic acid (syn-isome-res) was obtained; Xmax. (pH 6 phosphate buffer) 274.5 nm (s = 17 520); Xmax. (CHBn) 1785 (β-lactam), 1686 and 1530 cm-1 (CONH); the x (d6-DMSO) values include 0.29 20 (d, NH), 4.19 (dd, 7-H) and 4.79 (d, 6-H).

A stirred solution of 9.02 g of the above acid in 40 ml of acetone was treated with a solution of 2.86 g of sodium 2-ethylhexanoate in 40 ml of acetone. The solution obtained was slowly added to 1600 ml of stirred petroleum ether of 25 bp. 40 to 60 ° C., and the precipitate was collected, washed and dried in vacuo, the sodium (6R, 7R) -3-carbamoyloxymethyl) -7- [2-tert-butoxy-carbonylmethoxyimino-2- (fur-2-yl) acetamido] ceph-3-em-4-carboxylate (syn isomer) (8.71 g) was obtained; Xmax. (pH 6-30 buffer) 274.5 nm (e = 17,650); Xmax. (Nujol) 1755 (β-lactam) and 1608 cm-1 (CO2-); the x (d6-DMSO) values include 0.4 (d, NH), 4.4 (dd, 7-H) and 4.98 (d, 6-H).

Example 51 35

(IR, 6R, 7R) -3-acetoxymethyl-7- [2- (2-carboxy-prop-2-yloxyimino) -2- (fur-2-yl) acetamido] -ceph-3-em-4- carboxylic acid l-oxide (syn isomer)

a) A solution of 1.21 g of (6R, 7R) -3-acetoxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) acetamido] -ceph-3 - 40 em-4-carboxylic acid (syn isomer) in 25 ml pyridine and 1 ml water was treated at - 45 ° C with 0.3 ml tert-butyl hypochlorite, with vigorous stirring. After 2 minutes, 1 ml of 2N sulfurous acid was added to the solution and the mixture was immediately poured into 100 ml of a 20% v / v 45% aqueous phosphoric acid solution. The aqueous solution was extracted with ethyl acetate, and the organic extracts were washed with 0.5N hydrochloric acid solution (50 ml), an aqueous sodium carbonate solution (50 ml) and water, then dried and concentrated in vacuo. The crude product was chromatographed on preparative silicon dioxide gel plates using ethyl acetate: petroleum ether at a temperature of 60 to 80 ° C. in a ratio of 4: 1 as the eluent. The slower running band was extracted with ethyl acetate to give 505 mg of the di-tert-ss butyl ester of the title compound; Xmax. (Nujol) 1798 (β-lactam), 1738, 1727, 1715 (acetate and C02.tBu), 1680 and 1542 cm "1 (CONH); the r (DMSO-de) values include 0.28 (d, j 8 Hz, NH), 4.19 (dd, J 5 and 8 Hz, 7-H), 5.02 (d J 5 Hz, 6-H), 5.71 and 6.38 (ABq, J 18 Hz, 2-H). Eo

0.38 g of the di-tert-butyl ester in 5 ml of trifluoroacetic acid, which contained a few drops of anisole, was stirred at room temperature for 15 minutes. The solution was concentrated in vacuo to a red oil, diluted with 2 ml of ethyl acetate and added dropwise to vigorously stirred petroleum ether of bp 60 to 80 ° (50 ml). The precipitated solid was collected, washed with 5 ml ether and dried to give 185 mg (60%) of the title acid; Xmax. (Ätha-

617703

noi) 276 nm (s = 16,600); A max. (Nujol) 1790 (β-lactam), 1730 (acetate), 1720 (ÇO2H), 1680 and 1523 (CONH) and 1040 cm-1 (S-> 0); the x (DMSO-d6) values include 0.21 (d, J 8 Hz, NH), 4.17 (dd, J 5 and 8 Hz, 7-H), 5.01 (d, J 5 Hz, 6-H), 5.71 and 6.32 (ABq, J 18 Hz, 2-H), 8.49 [s, C (CH3) 2].

The starting material for the above oxidation process was prepared as follows:

A solution of 1.05 g of tert-butyl- (6R, 7R) -7-amino-3-acetoxymethylceph-3-em-4-carboxylate in 10 ml of dry methylene chloride was added to a solution of 0.99 g of 2- ( 2-tert-Butoxycarbonylprop-2-yloxyimino) -2- (fur-2-yl) acetic acid (syn isomer) and 0.69 g of dicyclohexylcarbodiimide in IQ ml of dry methylene chloride were added and the mixture was stirred at room temperature for 1 hour . The solution was filtered and concentrated in vacuo. The crude product was passed through a column with silica gel [MFC, 2 X 20 cm, particle size 0.149 to 0.074 mm (100 to 200 mesh)] - using ethyl acetate: petroleum ether of bp 60 to 80 ° C in a ratio of 1: 1 as Eluent directed. The combination of the appropriate fractions, determined by thin layer chromatography, gave 1.29 g (6R, 7R) -3-acetoxymethyl-7- [2- (2-carboxyprop-2-yloxyimino) -2- (fur-2-yl) -acetamido] -ceph-3-em-4-carboxylic acid di-tert-butyl ester (syn isomer); Xmax. (CHBn) 1776 (β-lactam), 1725.1712 (acetate and C02.tBu), 1678 and 1512 cm "1 (CONH); the x (CDCb) values include 1.90 (d, J 8 Hz, NH) , 4.08 (dd, J 5 and 8 Hz, 7-H) and 4.98 (d, J 5 Hz, 6-H).

Example 52

(6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) - (l-carboxycyclopropyloxyimino) fur-2-ylacetamido] ceph-3-em-4-carboxylic acid 0.39 ml of oxalyl chloride became a solution at 0 ° C 1.1 g (lt-butyloxycarbonylcyclopropyl) oxyiminofur-2-yl-acetic acid in 25 ml dichloromethane containing 3 drops of N, N-dimethylformamide and 0.52 ml triethylamine were added. The solution was stirred at room temperature for 1 hour and then evaporated to dryness. The residue was dissolved in 20 ml dry acetone and to a solution of 1.035 g (6R, 7R) -3-carbamoyloxymethyl-7-aminoceph-3-em-4-car-bonic acid and 784 mg sodium bicarbonate in 25 ml water and 5 ml Acetone added. The mixture was stirred at room temperature for 4 hours, after which the acetone was removed under reduced pressure. The residue was diluted with water, washed with ethyl acetate and acidified with 2N hydrochloric acid while stirring with ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic solutions were washed with water, dried and evaporated. 1.95 g of (6R, 7R) -3-carbamoyloxymethyl-7 - [(Z) - (l-t-butyloxycarbonylcyclopropyloxyimino) fur-2-ylacetamido] ceph-3-em-4-carboxylic acid were obtained as a yellow foam. This compound was treated with 1.95 ml anisole and 5.07 ml trifluoroacetic acid for 20 minutes at room temperature. The solvents were then evaporated using toluene and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous phase was washed with ethyl acetate, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and evaporated to 1.789 g of a yellow foam. Two recrystallizations from ethanol provided 540 mg of the title compound as a white solid, [a] g = +35.3 (c 1.00, DMSO); W (pH 6.0 phosphate buffer) 276 nm (e = 18,400).

Example 53

a) (6R, 7R) -3-acetoxymethyl-7 - [(Z) - (l-carboxy-cyclopropyloxyimino) fur-2-ylacet-amido] ceph-3-em-4-carboxylic acid 1.05 ml of oxalyl chloride was added a solution of 2.95 g (1-

617703

t-Butyloxycarbonylcyclopropyloxyimino) fur-2-ylacetic acid in 70 ml dichloromethane containing 10 drops N, N-dimethylformamide and 1.4 ml triethylamine, added and stirred at 0 ° C. The mixture was stirred for 1 hour without further cooling and then evaporated to dryness. The residue was treated with 60 ml of acetone and the mixture in a solution of 2.72 g (6R, 7R) -3-acetoxymethyl-7-aminoceph-3-em-4-carboxylic acid and 2.1 g of sodium bicarbonate in 70 ml of water and 15 ml of acetone filtered. The mixture was stirred at room temperature overnight and then the acetone was removed under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The extracts were extracted again with 5% aqueous sodium bicarbonate and discarded. The combined aqueous solutions were acidified with 2N hydrochloric acid while stirring under ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic solutions were washed with water, dried and evaporated. 5.08 g of (6R, 7R) -3-acetoxymethyl-7 - [(Z) - (1-t-butyloxycarbonylcyclopropyloxyimino) fur-2-ylacetamido] ceph-3-em-4-carboxylic acid were obtained as a light brown foam. This compound was treated with 5.1 ml of anisole and 13.3 ml of trifluoroacetic acid at room temperature for 20 minutes. The solvents were evaporated using toluene and the remaining brown resinous substance was triturated with ether. The solution was evaporated to give 4.48 g of the title compound as a light brown foam, vmax. (Nujol) 3260-2200 (CH), 1788 (β-lactam), 1720 (CChH), 1680 and 1536 cm-1 (CONH); x (DMSO-d6) 0.37 (1 H, d, J 8 Hz, NH) 2.09 (1H, s, 5'-H), 3.22 (1 H, d, J 3 Hz, 3 ' -H), 3.33 (1H, dd, J 2 and 3Hz, 4'-H), 4.09 (1H, dd, J 5 and 8 Hz 7-H), 4.75 (1 H, d, J5 Hz 6-H), 4.94 and 5.28 (2 H, ABq, J 12 Hz, -CH2OAC), 6.38 (2 H, d, J 6 Hz, -S-CH2-), 7, 93 (3H, s, OCOCH3), 8.4-8.8 (4H, m, cyclopropyl protons).

b) (6R, 7R) -3-acetoxymethyl-7 - [(Z) - (l-carboxy-cyclopropyloxyimino) fur-2-ylacetamido] ceph-3-em-4-carboxylic acid disodium salt 984 mg (6R, 7R) -3-Acetoxymethyl-7 - [(Z) - (l-carboxy-cyclopropyloxyimino) fur-2-ylacetamido] ceph-3-em-4-carboxylic acid in 15 ml acetone were added in portions with a solution of 700 mg sodium octoate in 10 ml of acetone treated. The mixture was stirred for 20 minutes, the precipitate obtained was collected under nitrogen and washed with acetone. The wet filter cake was dried under vacuum. It was pulverized and stirred with 50 ml acetone for 30 minutes, then collected to give 738 mg of the title compound, Xmax. (pH 6.0 phosphate buffer) 276 (e = 19,300) and 233 nm (e = 10,600); Vmax. (Nujol) 3190 (NH), 1765 (β-lactam), 1740 (acetate) and 1680 cm-1 (carboxylate).

Example 54

(6R, 7R) -7 - [(Z) -2- (l-carboxycycloprop-l-yloxyimino) -2- (fur-2-yl) -acetamido] -3 - [(5-methyl-l, 3, 4-thia-diazol-2-yl) -thiomethyl] -ceph-3-em-4-carboxylic acid To a solution of 298 mg of 2- (lt-butoxycarbonylcyclo-prop-l-yloxyimino) -2- (fur-2- yl) acetic acid in 3.5 ml dichloromethane, 0.14 ml triethylamine and then 0.09 ml oxalyl chloride and 1 drop N, N-dimethylformamide were added at 0 ° C. The mixture was stirred at 0 ° to 5 ° C for one hour and then evaporated to dryness. The residue was taken up in 10 ml of acetone and the filtered solution for 30 minutes to a stirred solution of 346 mg (6R, 7R) -7-amino-3 - [(5-methyl-l, 3,4-thiadiazol-2-

yl) thiomethyl] ceph-3-em-4-carboxylic acid and 210 mg sodium bicarbonate in 20 ml water and 10 ml acetone at 0 ° C. The solution was stirred at 0 ° C and then the temperato was allowed to rise to 10 ° C over 15 minutes. The solution was then washed with ether, covered with 100 ml ether / ethyl acetate (1: 1), acidified with concentrated hydrochloric acid and filtered. The organic layer was washed with concentrated saline, dried and evaporated. 574 mg (6R, 7R) -7 - [(Z) -2- (lt-butoxycarbonylcycloprop-l-yloxyimino) -2- (fur-2-yl) -acet-amido] -3 - [(5- methyl-l, 3,4-thiadiazol-2-yl) thiomethyl] ceph-3-em-4-carboxylic acid as a yellow foam. 509 mg of this compound were treated with 0.1 ml of anisole and 2 ml of trifluoroacetic acid at 24 ° C for 5 minutes. The solvents were evaporated using ethyl acetate and the residue was partitioned between 3% sodium bicarbonate solution and ethyl acetate. The aqueous phase was washed with ethyl acetate, then covered with ether / ethyl acetate (1: 1) and acidified with concentrated hydrochloric acid. The organic phase was washed with concentrated saline, dried and evaporated to 438 mg of a light brown foam which, after trituration with ether / petroleum ether (1: 3), gave 354 mg of the title compound as an off-white solid, [a] g = -103 ° ( c 0.81, acetone), Xmax. (pH 6.0 phosphate buffer) 279 nm (e = 25 200).

Example 55

(6R, 7R) -7 - [(Z) -2- (l-carboxycycloprop-l-yloxyimino) -2- (fur-2-yl) acetamido] -3- (l-methyltetrazol-5-ylthiomethyl) ceph -3-em-4-carboxylic acid A solution of 296 mg of 2- (lt-butoxycarbonyl-cyclo-prop-l-yloxyimino) -2- (fur-2-yl) acetic acid in 3.5 ml of dichloromethane was added at 0 ° C 0.14 ml of triethylamine and then 0.09 ml of oxalyl chloride and then 1 drop of N, N-dimethylformamide. The mixture was then stirred at 0 ° to 5 ° C. for one hour and then evaporated to dryness. The residue was taken up in 12 ml of acetone and the filtered solution for 30 minutes to a stirred solution of 330 mg (6R, 7R) -7-amino-3- (l-methyltetra-zol-5-ylthiomethyl) ceph-3-em -4-carboxylic acid and 210 mg sodium bicarbonate in 20 ml water and 10 ml acetone added at 0 ° C. The solution was stirred at 0 ° C and then at 20 ° C for 15 minutes and then concentrated to about half its volume by evaporation. The mixture was overlaid with 100 ml ether / ethyl acetate (1: 1), acidified with 0.2 ml concentrated hydrochloric acid and filtered. The organic layer was washed with concentrated saline, dried and evaporated. 552 mg (6R, 7R) -7 - [(Z) -2- (lt-butoxycarbonylcycloprop-l-yloxy-imino) -2-fur-2-yl) -acetamido] -3- (l-methyltetrazole- 5-ylthio-methyl) ceph-3-em-4-carboxylic acid as a light yellow foam. 453 mg of this compound were treated with 0.1 ml of anisole and 2.0 ml of trifluoroacetic acid at 25 ° C. for 5 minutes. The solvents were then evaporated using ethyl acetate and the residue was partitioned between 2% aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was washed with ethyl acetate, then overlaid with ethyl acetate / ether (1: 1) and acidified with concentrated hydrochloric acid. The organic phase was washed with concentrated saline, dried and evaporated to 417 mg of a light brown foam which was triturated with ether / petroleum ether (1: 3) and gave 315 mg of the title compound as an off-white solid, [a] g -72 ° ( c 0.67, acetone), Âmax. (pH 6.0 phosphate buffer) 278 nm (e = 23,300).

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Claims (9)

617703 2nd PATENT CLAIMS 1. Process for the preparation of the syn isomer or a mixture of syn and anti isomer, the proportion of the syn isomer being at least 90%, of new antibiotic 7ß-acylamido-ceph-3-em-4-carboxylic acids of formula I. r-c-co-nh cooh '° - (CH2> m - ?; (CH2) n-C00H R wherein B> S or> S-> 0; R thienyl or furyl; Ra and Rb, which are the same or different, are hydrogen, Ci-Gt-alkyl, C2-C4-alkenyl, C3-C7-cycloalkyl, phenyl, naphthyl, thienyl, furyl, carboxy, C2-Cs-alkoxycarbonyl or cyano; or Ra and Rb together with the carbon atom to which they are attached, C3-C7-cycloalkylidene or C3-C7-cycloalkenylidene; m and n are each zero or 1, the sum of m and n being zero or 1; and Z is a bridge connecting the nuclear sulfur atom and the carbon atom in the 4-position with 2 carbon atoms, which can carry substituents, and wherein there is a double bond between the C3 and Gt atoms of the bridge, or of their non-toxic derivatives, thereby characterized in that a compound of formula V Mixture of syn and anti isomers condensed, existing carboxyl protecting groups split off and, if one started from a ceph-2-em compound, the resulting ceph-2-em compound isomerized to the corresponding ceph-3-em compound. 2. The method according to claim 1, characterized in that a compound of the formula I obtained, in which B> S-> 0, is reduced to the corresponding compound in which B> S is reduced. 3. The method according to claim 1, characterized in that an acid halide of an acid of the formula VI is used as the acylating agent. (I) 5 4. The method according to claim 3, characterized in that the condensation is carried out in the presence of an acid-binding agent, wherein a tertiary amine, an inorganic base or an oxirane is used as the acid-binding agent. 5. The method according to claim 1, characterized in that an acid of the formula VI 20 is used and the condensation is carried out in the presence of a condensing agent, a carbodiimide, a carbonyl compound, for. B. carbonyldi-imidazole, or an isoxazolinium salt used. 6. The method according to claim 1, characterized in that a compound of formula I obtained is converted with inorganic or organic bases into its non-toxic base salts. 7. The method according to claim 1, characterized in that having a compound of formula I obtained 3 »Converts inorganic or organic acids into their non-toxic acid addition salts. 8. The method according to claim 1, characterized in that a compound of formula I, wherein the 7β-acyl group of a group of the formula 35 R.C.CO— N Rc 40 ND.C.COOH I. Rd (v), cook" wherein R19 is hydrogen or a carboxyl protecting group; and Z 'is a carbon bridge corresponding to Z, with the difference that the double bond can also be arranged in such a way that a ceph-2-em compound is present, mean, or an acid addition salt or a silyl derivative of this compound with a, an acid of formula VI R-C-COOH worm 45 Rc methyl, ethyl, propyl, allyl or phenyl; Rd is hydrogen, carboxy or Rc; or Rc and Rd together with the carbon atom to which they are attached so represents a cyclobutylidene, cyclopentylidene or cyclohexylidene group. 9. A process for the preparation of non-toxic esters of compounds of the formula I, characterized in that a compound of the formula I is prepared by the process according to claim 1 and this is used accordingly. 55 esters. 10. The method according to claim 9, characterized in that one produces a metabolically labile acyloxymethyl ester. N R £ 0- (CH2) m-C- (CH2) II-COOR20 From (VI), wherein R20 is a carboxyl protecting group, corresponding acylating agent in the form of the syn isomer or one