DK142174B - Process for the preparation of 7beta-acylamino-3-methyl-ceph-3-em-4-carboxylic acids or salts thereof. - Google Patents

Description

(11) SUBMIT G ELS ESS KR IN FT 14217U

DENMARK ln * C | S c 07 D 501/10 '(21) Application No 4Ο6Ο / 72 (22) Filed on 16 Aug. 1972 (24) Løbedsg 1 6. aUg. 1972 (44) The application presented and.

the presentation paper published on 15 · ββρ. 1 9θ0

DIRECTORATE OF

PATENT AND TRADEMARKET (3 °) P "" ** '»O» * h * den

Aug 17 1971 # 58637/71 # GB Dec 21 1971 # 59516/71, GB

W> GIST-BROCADES N.V., 1 Wateringsfiweg, Delft, NL.

(72) Inventor: Jan Verweij, 1 Moddermanstraat, Leiden, NL: Hong Sheng Tan, 94 BuizercTstraat, BleiBWijk, NL: Hermanus Jacobus Kooreman, 18 Wateringsevest, Delft, NL.

(74) Plenipotentiary in the proceedings:

International Patent Office.

(Μ) Process for Preparation of 7beta-aeylamino-3-methyl-ceph-3-em-4-carboxylic acids or salts thereof.

The invention relates to a particular process for the preparation of 7β-acylamino-3-methyl-ceph-3-em-4-carboxylic acids or their salts by conversion of corresponding 6β-acylamino-penicillanic acid sulfoxides.

Penicillins and cephalosporins are compounds which contain the "penam" and "cepham" structures, respectively, 1 1 6 5 / \ 2 7 6 / \ 2 - CH-CH CH_ -CH-CH CH0 II I 2 II I 2 0 = CN -CH + O- = CN CH? 7 4 3 8 5 \, η / 3 4 2

I · II

2,112,174 while "cephem" refers to the corresponding ring structure with a double bond, the position of which may be indicated by a leading "Δ" with the index at the top indicating the lowest atomic carbon from which the double bond is derived.

Recently, there has been great interest in the manufacture of 3. ...

Δ-Cephalosporins having antibiotic effect from penicillins. It is thus described in e.g. U.S. Patent No. 3,275,626 entitled "Penicillin conversion via Sulfoxide" states that 7-amino-cepham and cephem derivatives can be prepared by heating analog 6-aminopenicillanic acid-sulfoxide derivatives in solution to a temperature of ca. 80-175 ° C under acidic conditions, which reaction can be accelerated by e.g. acetic anhydride or toluene-p-sulfonic acid.

This known method of heating under acidic conditions results in a rearrangement of the heterocyclic ring structure, which leads to an expansion of the thiazolidine ring in the penicillanic acid sulfoxide. a thiazine ring which is a structural part of cephalosporin compounds. Several of these cepha-losporin compounds have useful antibiotic effects and are therefore very important as therapeutics.

When the ring expansion process described in the above-mentioned U.S. patent is carried out with a 6- (substituted amino) -penicillanic acid sulfoxide, i.e. a compound of structure 1 having an acylamino group R-CO- attached to the 6-position, wherein R represents essentially any organic group known in the penicillin chemistry, oxygen attached to the sulfur atom, two methyl groups attached to the 2-carbon atom, and a carboxy group attached to the 3-carbon atom, or with a salt of such an acid, it has been found that the 6-amino-penicillanic acid starting material is decarboxylated during formation of the cephalosporin, and the cephalosporin product consequently has no carboxy group attached to the 4-carbon atom in structure. II, as required for antibiotically useful cephalosporin compounds. However, when esters are used as starting materials, e.g. alkyl, cycloalkyl or phenyl esters, of such 6- (substituted amino) -penicillanic acid sulfoxides, the ring extension to cephalosporin compounds satisfactorily proceeds according to the U.S. Patent 3 disclosed and the Δ-cephem products have an esterified carboxy group attached to the 4-carbon atom. Thus, it is clear from the above-mentioned United States patent that when one wishes to obtain cephalosporins with a free carboxy group attached to the 4-carbon atom, the carboxy group in a 6- (substituted amino) -penicillanic acid sulfoxide starting material must first be esterified with a hydrocarbon group. in a first separate step, and the ester forming group in the cephalosporanoic acid product after the ring expansion reaction must then be removed by e.g. hydrolysis or by catalytic hydrogenation. This process first requires a separate formation of a hydrocarbon ester of the 6-amino-penicillic acid (i.e., an ester of the C00 group attached to a hydrocarbon group, for example, a methyl or 31A217 Λ benzhydryl group, or a substituted hydrocarbon group through a carbon atom), necessitates separation and isolation of at least one intermediate and is consequently disadvantageous in this regard.

According to the invention, there is now provided a process for the preparation of 78-acylamino-3-methyl-ceph-3-em-4-carboxylic acids from 66-acylamino-penticillanic acid sulfoxides, which avoids decarboxylation of the penicillanic acid sulfoxide and can eliminate the above drawback, enabling the entire reaction to be carried out in one step and in a single container, so that it is more convenient and easier to carry out than the previously known method 3 and which method can directly yield good yields of Δ-cephem compounds which are antibiotically useful.

The process of the invention is characterized in that: a) reacting a 68-acylamino-penicillanic acid sulfoxide with a halide of formula 3 R 3 wherein Hal represents a halogen atom and wherein R is an acid anhydride group having one of the following partial formulas V- VIII: R4

^ M1— V

wherein and R 1 are the same or different and each represents an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 5-8 carbon atoms, a phenyl group, a phenylalkyl group of 1 or 2 carbon atoms in the alkyl moiety, an alkoxy or alkylthio group having each 1-6 carbon atoms, a phenoxy group, a phenyl alkoxy group having 1 or 2 carbon atoms in the alkoxy group or a halogen atom, and M '*' represents a boron, aluminum or phosphorus atom, r *

R ° -t-T-VI

Wherein R, R and R are the same or different and each represents an optionally halo-substituted alkyl group of 1-6 carbon atoms, a cycloalkyl group of 5-8 carbon atoms, a phenyl group, a phenylalkyl group of 1 or 2 carbon atoms. the alkyl moiety, an alkoxy or alkylthio group having each 1-6 carbon atoms, a phenoxy group, a phenyl alkoxy group having 1 or 2 carbon atoms in the alkoxy group 456 or a halogen atom, or R (or R) and R taken together represent an oxygen atom 2 ...

(= 0) or a sulfur atom (= S), and M represents a silicon, sulfur, germanium, or tin atom, or a carbon atom when R and R together represent an oxygen or sulfur atom, r! R 3 and are the same or different and each represents a halogen atom, an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 5-8 carbon atoms, a phenyl group, a phenylalkyl group of 1 or 2 carbon atoms in the alkyl moiety, an alkoxy or alkylthio group having from 1 to 6 carbon atoms, a phenoxy group or a phenyl alkoxy group having 1 or 2 carbon atoms in the alkoxy group, and R 1 and R each represent a halogen atom or together represent an oxygen atom ( = 0) or sulfur atom (= S), 3 and M represent a phosphorus or tungsten atom

9 S

R * -S- VIII

8 g wherein R represents an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 5-8 carbon atoms, a phenyl group, a phenylalkyl group of 1 or 2 carbon atoms in the alkyl moiety, an alkoxy or alkylthio group of each 1-6 carbon atoms, a phenoxy group or a phenyl alkoxy group having 1 or 2 carbon atoms in the alkoxy group, wherein the phenyl groups or molecular moieties within the definitions of R 1, R 4 and optionally carry one or more substituents selected from halogen atoms, alkyl or alkoxy groups having 1-6 carbon atoms and dialkylamino groups having 1 -6 carbon atoms in each alkyl moiety, and b) heat the acid anhydride thus obtained to a temperature up to a maximum of 160 ° C in a dry, inert organic solvent with an anhydrous acid selected from hydrogen bromide, hydrogen chloride, toluene-p-sulfonic acid, concentrated sulfuric acid , hydrogen iodide, perchloric acid, periodic acid, nitric acid, chloric acid, iodic acid, selenic acid, bromoacetic acid, trichloroacetic acid, trifluoroacetic acid, trichloromethyl sulfonic acid, trifluoromethylsulfonic acid, naphthalenesulfonic acid, oxalic acid, picric acid, tris (ethylsulfonyl) methane, pentacyanopropene, tetracyanopropene, penta-cyanocyclopentadiene, tetracyanocyclopentadiene, tricyanocyclopentadiene an acid addition salt complex, in the presence of a silicon-containing compound selected from N, O-bis (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide, N, N-bis (trimethylsilyl) carbodiimide, N- (trimethylsilyl) ) acetamide, N-methyl-N- (trimethylsilyl) -acetamide, N-methyl-N- (trimethylsilyl) formamide, N- (trimethylsilyl) -2-pyrrolidone, N- (triethylsilyl) urea, N, N'-bis ( trimethylsilyl) urea, N- (triphenylsilyl) ethylcarbamate, trimethylsilyldimethylsulfoxymide, N-trimethylsilyl-N-methyltrifluoroacetamide, trimethylsilylimidazole, triphenylsilylamine, N-ethyltriethylsilyl-trimethyl, N-trimethyl, N-trimethylsilyl hexamethyldisilazane, hexamethylcyclotrisilane and octamethylcyclotetrasilazane, or a ^) react a 6g-acylamino-penicillanic acid sulfoxide directly according to b) and hydrolyze the compound formed in situ to separate the thus-formed 76-acylamino-3-methyl-ceph em-4-carboxylic acid as such or as a salt.

The process of the invention involves in step a) forming an anhydride of a 6B acylamino-penicillanic acid sulfoxide which is readily hydrolyzed by water alone, and then in step b) ring expansion of the penam ring under water. . 3 cleavage to a Δ-cephem-rmg under the action of said anhydrous acid. Hydrolysis of the first anhydride formed by the action of the water decomposed by the ring expansion is avoided due to the presence of the silicon-containing compound which is able to react rapidly with this water to form neutral or basic products. In other words, the silicon-containing compound is capable of removing water formed during the ring expansion quickly enough to prevent the water's hydrolysis of the acid anhydride present. At the same time, said acid is strong enough to not or not to be substantially silylated under the reaction conditions used. When the 7B-acylamino-3-methyl-ceph-3-enr-4-carboxylic acid formed during the final hydrolysis is separated from a salt, it is e.g. a sodium, potassium, calcium or amine salt.

By an anhydride of a penicillanic acid or a 3-methyl-ceph-3-em-4-carboxylic acid is meant such an acid whose carboxyl group is protected in such a way that the protecting group can be easily removed by hydrolysis in a neutral aqueous medium. .

If a 66-acylamino-penicillanic acid sulfoxide is reacted directly by step b) in the reaction variant a ^), the amount of silicon-containing compound added to the reaction mixture must be so large as to completely remove the water formed during the process and, moreover, in advance can silylate any free carboxy group in the 6B-acylamino-penicillanic acid sulfoxide.

From the disclosure of Danish Patent Application No. 726/71, a process for the preparation of 7β-acylamino-3-methyl-ceph-3-em-4-carboxylic acids or their salts, esters or amides is known by conversion of corresponding 66-acylamino acids. penicillanic acid sulfoxides, the process of heating the 6 (3-acylamino-penicillanic acid sulfoxide to up to 160 ° C under anhydrous conditions in the presence of at least 5 moles of a nitrogenous organic base per mole of penicillanic acid). sulfoxide and a silicon-halogen compound of the general formula γΐ 2 1

Y - Si - X

'3

Y

. Wherein Y, Y and Y each represent a halogen atom, an alkyl group of 1-4 carbon atoms, a phenyl group or a phenylalkyl group of 1 or 2 carbon atoms in the U2m6 alkyl moiety, and X represents a halogen atom. The process of the present invention is substantially different from this known process which is characterized by the use of an excess of a nitrogenous base and the presence of a silicon-halogen compound, while the process of the present invention is characterized by the use of anhydrous acid and presence of a silicon-containing compound selected from the above, all having a silicon-nitrogen bond in common. The process of the present invention generally yields higher yields of a cleaner product than the aforementioned known process.

The process of the invention can be used generally for the preparation of 7B-acylamino-3-methyl-ceph-3-em-4-carboxylic acids, which may be reproduced by the general formula / S \ acyl-NH-CH-CH 2 H 2 = C-LIX

C

I 3 COO-R

from the corresponding 6B-acylamino-penicillanic acid sulfoxides, optionally through 6β-acylamino-penicillanic anhydrides, which may be reproduced by the general formula 0 * acyl-NH-CH-CH C (CH 3) 2 Iv III 3

o = C-N-CH GOOR

. . 3 in which formulas R has the above meaning. The penicillanic anhydrides of formula IV are novel compounds.

3

Reagents R Hal which can be used to protect the carboxyl group of the starting compounds to form acidic anhydrides of general formula IV are

ISLAND

as will be seen, those wherein R is a group of one of the sub-formulas V, VI, VII and VIII. When these reagents react with the 6B-acylamino-penicillanic acid sulfide oxide, it gives rise to substitution of the hydrogen atom, which atom will be combined with the halogen atom of the reagent to form an acid. This acid can then serve as the acidic agent for the ring expansion reaction.

Examples of compounds containing the group of general formula V are compounds which can be considered as acid derivatives such as BCll, BBr₂, AlCl₂,

AlBr3 'PC13' PBr3 'C4H9BC12! (C4V2BC1 '(^ H ^ AlCl, (C4Hg) 2AlCl, C ^ PC ^, GH2 ° C6H5FBr2' C4H9PC12 'CH2O ^ PC1> 142174 7

f3 f2C1 r # 5'N (/ C ”2 \ CH, 0V

CHO-PCI, CHO-PCI, I PCI, CHoOPCl ,, CH OPCl2, 'PCI, I /' / 'v' / 3 2 2 5 2 CH.0 ^ C «2 ° *» 2 ° 3 C9H ° PCI , (C6H'5) 2PC1, C3H7OPCl2, C4HgOPCl2, c6h5opc 12, cich2ch2ch2opc 12, C2H5 ° C6H5CH2OPCl2, ClCH2CH (Cl) CH2OPCl2, CH3CH (C1) CH20PC12, ch3och2ch2opci2

Examples of compounds containing the group of general formula VI, and which may also be considered as acid derivatives, are compounds such as COC12> CSCl2, C2H5OCOBr, £ H 2 ^ CH0CO0Cl, C6H5OCOBr, C6H5CH2OCOCl, CH3COBr, BrCOCOBr, C 5

Cl , (CH30) 2SiCl2, (C2H50) 2SiCl2, (CH30CH2CH20) 2SiCl2, (C 2 O JgSICI 2 (C6H50) 2SiCl2 '(C ^^ SiBr, (C6H5CH20) 2SiCl2, (ClCH2CH20) 2SiCl2, [CH3CH (Cl) CH2o] ^ lCl2, (C ^ O ^ iCl, (C4Hg0) 3SiCl, (CH3) 3SiCl, (CH3 ) 3SiBr, (CgH ^ SiCl, CH3 ct3 \ ch3 \ CH, 0 - ^ SiCl, CHO - - iSiCl, CH = - - SiCl, Ctts-> SiCl, CH ^ - ^ SiCl, CH30 C2H5 ° ^ CH3 ° C2HsO C4Hg0

Cl (CH2 CH2 O) 3 SiCl, [CH3 CH (Cl) CH2 O] 3 SiCl, (C2 H5) 2GeC12 * (C4H9) 2GeG12 'GeBr4> SnC14' SnBr4, SOCl2, SOBr2, C2 OSOCl and Cg ^ OSOCl.

Examples of reagents containing the group of general formula VII are phosphoric acid derivatives such as PCIg, PBrg, POCl3 »B0Br3, PSBr3, CH = E ^ C1 '^ 3 ° 2 ^ 01' XX, / * 3 'c6h5poci2, ch3opoc12, c2h5opoci2, c3h7opoci2, c4HgoPoci2, cich2ch2opoci2, CH3OCH2CH2OPOCl2, C6H5OPOCl2, C2H5SP0Cg

Compounds containing the group of general formula VIII are acid derivatives such as C2H50SO2C1, C4Hg0SO2Cl, C3 St1 Cl, CH3C6H4S02C1, C2 OSO1 and U2174 δ

CgHjGHjOSOC1.

Among the preferred protective reagents, it is advantageous to use substances known and widely used in the chemistry, namely phosphorus trihalides, phosphorus pentahalides, tri- (C 1 -C 6 alkyl) halogen silanes, di-CC 1 -C 8 alkyl) -dihalogen silanes and carboxylic acid halides. The most preferred reagents are phosphorus-containing compounds such as phosphorus tribromide and phosphorus pentabromide, and silicon-containing compounds such as tri- (C 1 -C 4 alkyl) bromosilanes, e.g. trimethylbylbromosilane, di- (C 1 -C 4 alkyl) dibromosilanes, e.g. dimethyldibromsilan.

7β-Acylamino groups in the subject compounds are e.g. benzyloxycarbamoyl, phenylacetamido, phenoxyacetamido, 3-acetyl-ureido, (3,5-diehlorsalicyl) amino, 2-phenoxypropionamido, 2-phenoxybutyramido, 2-phenoxyphenylacetamido, 5-methyl-3-phenyl-4-isoxazole carboxamide -methyl-3- (o-chlorophenyl) -4-isoxazole carboxamido, 5-methyl-3- (2,6-dichlorophenyl) -4-isoxazole carboxamido, 2,6-dimethoxybenzamido, 2-ethoxy-1-naphthamido , 2- (o-Aminobenzamido) phenylacetamido-N-methyl, 2- (2-amino-5-nitrobenzamido) phenylacetamido-N-methyl, N-benzylformamido, N-methyl-2-phenoxyacetamido, N-methyl-2 phenylacetamido, N-ethyl-2-phenylacetamido, N-isobutyl-2-phenoxyacetamido, 2-benzylidene-4,5-dioxo-3-oxazolidinyl, 2-butylsuccinimido, 2,2-dimethyl-5-oxo-4- phenyl-1-imidazolidinyl, phthalimido, α-amino-α- (1-cyclohexa- 1,4-dienyl) acetamido, α-aminophenylacetamido, α-amino-2-thienylacetamido, 2-thienylacetamido, 3-thienylacetamido, 2 -furylacetamido, 4-chlorophenylacetamido, 3-bromophenylacetamido, 3-nitrophenylacetamido, 4-nitrophenylacetamido, 3-trifluoromethyl-phenylacet amido, 4-cyanophenylacetamido, 4-methylthiophenylacetamido, 3-chlorophenylthioacetamido, 2-benzofuranylacetamido, benzenesulfonamido, benzenesulfonylaminoacetamido, p-bromobenzenesulfonamido and 1-piperidinosulfonamido Preferred groups among these are phenylacetamido and phenoxyacetamido. When one wishes to obtain a 7B-acylamino-3-methyl-ceph-3-em-4-carboxylic acid of the general formula III, wherein the acylamino group, e.g. is α-aminophenylacetamido, the free amino group of the corresponding 6β-acylamino-penicillanic acid sulfoxide starting material must be protected during the ring expansion with e.g. a benzyloxycarbonyl group which can be easily removed afterwards to give the free amino group. A free carboxyl group in the 6-acyl side chain can be protected by e.g. esterification, preferably acid anhydride formation, thereby consuming an additional amount of the reagent responsible for the acid anhydride formation with the carboxyl group attached to the thiazolidine ring.

Among the silica-containing compounds used in the process of the invention, N, Q-bis (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide, N, N-bis (trimethylsilyl) carbodiimide, N- (trimethylsilyl) acetamide, N -methyl-N- (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) formamide, N- (trimethylsilyl) -2-pyrrolidone, N- (triethylsilyl) urea, N, N'-bis (trimethylsilyl) -reast, N- (triphenylsilyl) ethylcarbamate, trimethylsilyldimethylsulfoxime, N-U2m 9 trimethylsilyl-N-methyl-trifluoroacetamide and trimethylsilylimidazole in reaction with water form neutral compounds that do not affect the reaction process or interfere with the separation process.

The other silicon-containing compounds used, namely triphenylsilylamine, N-ethyl triethylsilylamine, N- (trimethylsilyl) diethylamine, hexamethyldisilazane, hexamethylcyclotrieilazane and octamethylcyclotetrasilazane, form by reaction with water basic compounds.

The most preferred silicon-containing compounds used in the process of the invention are N, O-bis (trimethylsilyl) acetamide and N, N'-bis (trimethylsilyl) urea, which can react extremely rapidly with anything formed during the ring expansion. to form neutral products, namely hexamethyldisiloxane and acetamide or urea, so as to avoid decomposition of the acid anhydride function during ring expansion due to the water formed.

As mentioned, the amount of silica-containing compound added to the reaction mixture must be so large that it completely removes the water formed during the process and, in addition, if necessary, it can pre-silylate any free carboxy group in the penicillin starting compound. Thus, when starting from a 6β-acylamino-peni-cillanic acid sulfoxide and using a silicon compound with two trimethylsilyl groups in the molecule, at least 11/2 mole-equivalent equivalent of silica compound is required. mole of penicillanic acid sulfoxide, namely 1/2 mole to act as silyldonor for the carboxy group and the residue to remove the water formed. However, when starting from an acid anhydride of the 6β-acylamino-penicillanic acid sulfoxide, at least 1 mole of the silicon compound is required to remove the water. Preferably, at least 2 to 4 mole equivalents of the silicon compound are used for each mole of penicillanic acid sulfoxide.

The acid used in the process of the invention to induce ring expansion of the pen amalgam can as such be incorporated into the reaction mixture. However, the acid is advantageously combined with a nitrogenous base to form an acid addition salt complex. Suitable bases are aliphatic, cycloaliphatic, aromatic or heterocyclic amines, e.g. hexamethylenetetramine, aniline, diphenylamine, N-methylaniline, dimethylaniline, pyridine and quinoline, and pyridine or quinoline substituted with e.g. one or more lower alkyl, aralkyl, aryl or mono or di (lower alkyl) amino groups such as the picolines, 2-ethylpyridine, 2-propylpyridine, 2,3-dimethylpyridine, 2,5-dimethylpyridine, 2, 6-dimethylpyridine, collidine and 2-dimethylaminopyridine, quinoline, isoquinoline, 3-methylisoquinoline, and in addition pyrazole, imidazole or N-methylimidazole. In order to obtain good yields, it is preferred that the base is pyridine, a substituted pyridine, quinoline, a substituted quinoline, imidazole or a substituted imidazole. Preferably, an excess base is used relative to the amount of acid.

142174 10

Complex compound of the acid and nitrogen-containing organic base can be formed in situ in the reaction mixture by first protecting a 60-acylamino-penicillanic acid sulfoxide starting material in solution in the dry, inert organic solvent by reaction with a compound R Hal, e.g. phosphorous trichloride, phosphorus pentachloride, acetyl bromide, propionyl bromide, trimethylchlorosilane, dimethyl dichlorosilane, trimethylbromosilane or triethylbromosilane. The hydrogen halide thus formed in this first step is preferably bonded by a base as the course of the acid anhydride formation will proceed smoother and as the penicillanic acid sulfoxide ring structure is very sensitive to the free strong acid. Preferably, nitrogenous bases are used which are soluble in the organic solvent used and have a pKa value between 4 and 10.

Initially, hydrogen halide formed can supplement or indeed constitute the acid necessary to effect ring expansion of the penicillin sulfoxide.

The presently preferred mole amounts of the substances introduced into the reaction mixture relative to each mole of 6S-acylamino-nenicillanic acid sulfoxide used are 1/4 to 4 moles of acid, (preferably about 1/3 to 1 mole), 1/4 to 4 equivalents of carboxyl protective reagent, (preferably 1/3 to 1 equivalent), at least 2 equivalents of silicon-containing compound (preferably 3 to 7 equivalents) or, when using a complex of acid and nitrogen-containing compound, 1/10 to 10 moles of acid base complex (preferably 1/4 to about 4 moles), 1/4 to 2 equivalents of carboxyl protective reagent (preferably 1/3 to 1 equivalent), at least 2 equivalents of silicon-containing compound (preferably 3 to 7 equivalents) and, preferably, an additional amount of the base itself on e.g. preferably from 1 to 10 moles, the amount of additional base being preferably directly proportional to the amount of acid-base complex used. By the term "one equivalent" is meant the number of moles of carboxyl protective reagent or silyl compound that is theoretically required to react with 1 mole of 6β-acylamino-penicillanic acid sulfoxide.

As mentioned, the acid anhydride formation and the ring expansion reaction are carried out in a dry, inert organic solvent. Suitable solvents are acetonitrile, chlorobenzene, toluene, diethylmethylsulfonamide, dimethylformamide, N, N-dimethylacetamide, 1,2-dimethoxyethane, dioxane, triethylene glycol diethyl ether, tetraethylene glycol diethyl ether, nitrobenzene acetate, benzylcyanide, benzylcyanide, benzylcyanide , carbon tetrachloride, dimethyl sulfoxide, methyl ethyl ketone, methyl or ethyl isobutyl ketone, and haloalkanes such as 1,2-dichloroethane, 1,1-dichloroethane, 1-bromo-1-chloroethane, 1,2,3-trichloropropane, methylene chloride and chloroform. A currently preferred solvent is dioxane.

The ring expansion process is generally carried out at a temperature above 50 ° C and, as mentioned, up to a maximum of 160 ° C, and advantageously at a temperature between 60 and 130 ° C. The reaction temperature must be kept below 160 ° C to reduce the formation of decomposition products. In order to obtain good yields within a reasonable reaction time, according to the invention, it is desirable that the temperature used during the ring expansion is between 70 and 110 ° C. Lower temperatures require slower reaction times, and higher temperatures require shorter reaction times, and at eg 80, 90 and 100 ° C, the reaction time can be approx. 24 hours, 10 hours and 6 hours.

In a preferred embodiment of the process according to the invention, whereby an advantageous combination of convenient embodiment and good yield is obtained, for each mole of penicillanic acid sulfoxide (e.g. benzylpenicillin sulfoxide) 1 to 4 moles of acid, preferably hydrogen bromide or hydrogen chloride, is used. 1.5 to 15 moles of nitrogenous base, preferably α-picoline, the base amount always exceeding the amount of acid, and 2 to 4 moles of N, O-bis (trimethylsilyl) acetamide, and the reaction is carried out at a temperature of 80 to 110 ° C in a dry , inert organic solvent, preferably dioxane.

In another preferred embodiment of the process according to the invention, whereby an advantageous combination of convenient embodiment and good yield is obtained, for each mole of penicillanic acid sulfoxide 1/3 to 1 equivalent of acetyl bromide or phosphorus tribromide, 1.5 to 15 moles of nitrogen-containing base, is used. preferably α-picoline, the base amount always exceeding the amount of the acid formed and 1.5 to 3 moles of N, O-bls (trimethylsilyl) acetamide or N, N N-bis (trimethylsilyl) urea.

After completion of the ring expansion reaction, the 7B-acylamino-3-methyl-ceph-3-em-4-carboxylic acid product is hydrolyzed in the reaction mixture and the 7β-acylamino-3-methyl-ceph-3-em-4-carboxylic acid obtained as such or as a salt is separated in any convenient manner, such as by extraction and / or crystallization. Thus, when the reaction is carried out in a water-immiscible organic solvent, the reaction mixture, after cooling, can be extracted with water to a pH of 7 which is adjusted with e.g. a dilute aqueous potassium hydroxide solution. From the aqueous solution, after washing with an organic medium such as butyl acetate, the 78-acylamino-3-methyl-ceph-3-em-4-carboxylic acid (e.g., 7β-phenylacetamido derivative) or a salt thereof can be obtained (a) by adding an aqueous solution of an acid and collecting the precipitated acid; (b) by extraction with an organic solvent having a pH below 4.5 and concentrating the extract to crystallize the acid; (c) By adding n-butanol, removing the water and crystallizing the potassium salt of the acid from the butanolic solution; (d) by extraction with an organic solvent having a pH below 4.5, then adding an alkali metal salt, e.g. potassium acetate, or a solution of an alkali metal salt, e.g. potassium 2-ethylhexanoate, or an amine, e.g.

Triethylamine or cyclohexylamine, in an organic solvent and collecting the precipitated alkali metal salt or amine salt of the acid, or (e) by extraction with an organic solvent having a pH below 4.5 and precipitating the acid by adding an apolar organic medium such as diethyl ether or cyclohexane.

When the reaction is carried out in a water-miscible organic solvent, the 7β-acylamino-3-methyl-ceph-3-em-4-carboxylic acid can be separated by pouring the reaction mixture into water and adding an organic solvent. Sufficient water is required. and organic solvent to achieve separation of the mixture into two layers. The organic layer is re-extracted with water at a pH of 7, and the combined aqueous layers are washed with an organic medium such as butyl acetate, and then treated as above under Method (a) to (e) to separate 7f3. acylamino-3-methyl-ceph-3-em-4-earboxylic acid or a salt thereof. Alternatively, after completion of the reaction, the organic solvent can be evaporated in vacuo, the amorphous residue dissolved in a water immiscible solvent and water added. After setting the pH to 7, the organic phase is discarded. The aqueous phase is washed with an organic medium and then treated as above in Methods (a) to (e). The reaction mixture can also be poured into an aqueous, acidic solution having a pH of approx. 2, with stirring, and the precipitated 78-acylamino-3-methyl-ceph-3-em-4-carboxylic acid is collected by filtration.

The yields of 7 $ -acylamino-3-methyl-ceph-3-em-4-carboxylic acids obtained by the process of the invention may vary according to the reagents and reaction conditions used, but conversion yields of more than 45% are generally obtained based on the amount of penicillanic acid sulfoxide, and the conversion yields can be as high as 70% and even above 90%.

The 6β-aeylamino-penicillanic acid sulfoxides used as starting materials in the process of the invention can be obtained by treating the corresponding 6β-acylamino-penicillanic acids with an oxidizing agent by known methods. For this purpose, the 68-acylamino-penicillanic acid derivative is treated in an inert organic solvent or water with an active oxygen-providing substance such as sodium periodate, a peracid, hydrogen peroxide or iodosobenzene, in a sufficient amount to oxidize the thiazolidine sulfur atom to a -SO- group. The sulfoxide obtained can easily be recovered from the reaction mixture by methods known per se.

It is preferred that the 68-acylamino-penicillanic acid sulfoxide used as a starting material is a sulfoxide obtained from a penicillin which can be readily prepared by fermentation such as benzylpenicillin or phenoxymethylpenicillin, but other semi-synthetically produced penicillins are also suitable. After the ring extension to the corresponding 76-acylamino-3-methyl-ceph-3-em-4-carboxylic acid compound, its 7B-acylamino group can be replaced by another desired acylamino group by deacylation and reacylation of the resulting amino group by methods known per se. .

The process according to the invention is further elucidated by the following examples. The starting material 6f5-phenyl-acetamido-penicillanic acid sulfoxide used in several cases is conveniently designated by the short term benzylpenicillin-sulfoxide, and correspondingly brief designation is used for other 6β-acylamino-penicillanic acid-sulfoxides. In the examples in which the yield of 76-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was determined by a microbiological sample, the acid can be obtained by treating the reaction mixture in a similar manner to that of Example 1.

Example 1

To 10.5 g (30 mmol) of benzylpenicillin sulfoxide was successively added 195 ml of dioxane, 25 ml (102 mmol) of N, O-bis (trimethylsilyl) acetamide, 6 ml (61 mmol) of α-picoline and 5.2 ml of a 5.8 M solution of α-picoline hydrobromide in dichloromethane (30 mmol α-picoline hydrobromide). The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After refluxing the reaction mixture for 6 hours (temperature: 102 ° C), it was cooled to 20 ° C and poured into 1500 ml of ice water. Then, 650 ml of ethyl acetate and 50 ml of butyl acetate were added and the pH was adjusted to 7 with 4 N potassium hydroxide solution. The mixture was allowed to separate and the organic layer was set aside. The aqueous layer was washed with 300 ml of ethyl acetate and 50 ml of butyl acetate. The obtained organic layer was combined with the previously obtained organic layer and the total organic layer was extracted with 200 ml of a 0.75 M aqueous potassium phosphate solution buffered to a pH of 7. The extract was added to the aqueous main solution. The total aqueous mixture contained 9.2 g of the potassium salt of 7 | 3-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid (yield: 83%), as determined by a microbiological sample using Escherichia coli as a sample microorganism.

After adding 500 ml of butyl acetate to the aqueous solution, the mixture was stirred and the pH was adjusted to 2 with 4N sulfuric acid. The mixture was allowed to stand and the organic extract was separated. The aqueous layer was re-extracted with 250 ml of butyl acetate. The combined butyl acetate extracts were filtered with a water repellent filter. The aqueous layer, which still contained a certain amount of 7β-phenyl-acetamido-3-methyl-ceph-3-em-4-carboxylic acid, was discarded. To the butyl acetate solution was then added with rapid stirring 2.65 g (27 mmol) of anhydrous, finely powdered potassium acetate. After stirring for 3 hours at room temperature, the precipitate was isolated by filtration, washed with a small amount of butyl acetate and dried in vacuo at 30 ° C to give 10.2 g of the potassium salt of 7 (3-phe. Nylacetamido-3-methyl-ceph-3-em-4-carboxylic acid with a purity of 85% as determined by a microbiological sample (yield: 23.5 mmol, 78%).

Imax (HoO): 262 nm. (E? - ^: 175).

2 cm

The structure was confirmed by IR and EMR spectra.

The analysis of the EMR spectrum was as follows: PMR (as the potassium salt in D2O, values in ppm.) $: 1.94 (s, 3); 2.99 (d, J = 18 Hz, 1); 3.44 (d, J = 18 Hz, 1); 3.62 (s, 2); 4.97 (d, J = 4.5 Hz, 1); 5.58 (d, J = 4.5 Hz, 1); 7.27 (s, 5).

The sodium salt of 2,2-dimethyl-2-silapentyl-5-sulfonate was used as internal reference.

Example 2 (a) 1.05 g (3 mmol) of benzylpenicillin sulfoxide was added to a mixture of 20 ml of a solution of 3.0 mmol of hydrogen bromide in dioxane and N, O-bis (trimethylsilyl) acetamide (2.5 ml , lo mmol). The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The reaction mixture was heated to 102 ° G. The reaction was followed by thin layer chromatography.

After 6 hours, no penicillin sulfoxide was left in the reaction mixture. Samples of 5 ml were taken and poured into 35 ml of a 0.75 M aqueous potassium phosphate solution buffered to pH 7. The aqueous solution was washed with 10 ml of ethyl acetate and diluted with water to 50 ml. The amount of potassium salt of 73-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid in the aqueous solution was determined by a direct microbiological sample using Escherichia coli as the sample microorganism. After 6 hours, the yield of 73-phenyl-acetamido-3-methyl-ceph-3-em-4-carboxylic acid was 47%.

(b) The experiment described in (a) was repeated with the difference that instead of 20 ml of dioxane, 18 ml of toluene and 2 ml of a 1.5 M solution of hydrogen bromide in dioxane were used. The yield of 73-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 46% as determined by microbiological sample.

(c) The experiment described in (a) was repeated except that an amount of 0.9 ml (9 mmol) of α-picoline was further used. The yield of 73-phenyl-acetamido-3-methyl-ceph-3-em-4-carboxylic acid was 82% as determined by a microbiological sample.

Example 3

To 1.05 g (3 mmol) of benzylpenicillin sulfoxide was successively added 20 ml of dioxane, 3.2 ml (13 mmol) of N, O-bis (trimethylsilyl) acetamide and 0.57 g (3 mmol) of p-toluenesulfonic acid. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After heating the reaction mixture for 6 hours to 101 ° C, no sulfoxide was left. After working up the reaction mixture as in Example 2, the yield of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 41%, as determined by a microbiological sample.

Example 4 (a) A mixture of 2.1 g (6 mmol) of benzylpenicillin sulfoxide, 20 ml of chloroform, 20 ml (200 mmol) of α-picoline, 8 ml (33 mmol) of N, O-bis (trimethylsilyl) acetamide and 1.6 ml (5.8 mmol) of concentrated sulfuric acid were heated to 83 ° C. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ.

After 24 hours, the yield of 7B-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 12% as determined by a microbiological sample using the method described in Example 2 * (b) described experiments were repeated with the exception that 6.4 ml (26 mmol) of N, O-bis (trimethylsilyl) acetamide and 1.14 g (6 Hanoi) of p-toluenesulfonic acid were used instead of 1.16 ml of concentrated sulfuric acid. The yield of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid after 24 hours heating to 83 ° C was 15% as determined by microbiological test using the method described in Example 2.

(c) The experiment described in (a) was repeated with the difference that 5 ml (20 mmol) of N, O-bis (trimethylsilyl) acetamide and 2 ml of a 3.3 M solution of α-picoline hydrochloride were used. (6.6 mmol) in dichloroethane instead of 1.6 ml of sulfuric acid. After heating for 24 hours to 85 ° C, the yield of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 53% as determined by microbiological test using the method described in Example 2.

Example 5

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 10 ml of benzyl cyanide, 10 ml (100 mmol) of α-picoline, 3 ml of a 3.3 M solution of α-picoline hydrochloride (10 mmol) in U2 -dichloroethane and 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide were heated to 95 ° C. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After 6 hours, the yield of 7 {3-phenylacetamido-3-methyl-ceph-3-enr-4-carboxylic acid was 48% as determined by microbiological test using the method described in Example 2.

Example 6

The experiment described in Example 5 was repeated with the difference that 15 ml of benzyl cyanide and 5 ml (50 mmol) of α-picoline were used. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of 7 | 3-phenylacetate

14-217 A

16 amido-3-methyl-eeph-3-em-4-carboxylic acid after 6 hours heating to 95 ° C was 48% as determined by microbiological test using the method described in Example 2.

Example 7

The experiment described in Example 5 was repeated with the difference that 17.5 ml of benzyl cyanide, 2.5 ml (25 mmol) of α-picoline and 2 ml of a 3.3 M solution of o-picoline hydrochloride (6) were used. , 6 mmol) in 1,2-dichloroethane. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of 73-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid after 6 hours heating to 95 ° C was 48% as determined by microbiological test using the method described in Example 2.

Example 8

A mixture of 1 g (3 mmol) benzylpenicillin sulfoxide, 15 ml benzyl cyanide, 7.2 ml (72 mmol) pyridine, 2.5 ml (10 mmol) N, O-bis (trimethylsilyl) acetamide and 0.27 ml ( 1 mmol) of a 3.3 M solution of α-picoline hydrochloride was heated to 90 ° G. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After 6 hours, the yield of 70-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 38% as determined by microbiological test using the procedure described in Example 2.

Example 9

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 20 ml of benzyl cyanide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide and 0.24 g (1.5 mmol) of pyridine hydrobromide heated to 90 ° C. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After 10 hours, the yield of 70-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 54% as determined by microbiological test.

Example 10

The experiment described in Example 9 was repeated using 0.48 g (3 mmol) instead of 0.24 g pyridine hydrobromide and with the addition of 0.3 ml (3 mmol) of α-picoline. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After heating for 10 hours to 90 ° G, the yield of 73-phenyl-acetamido-3-methyl-ceph-3-em-4-pharboxylic acid was 59% as determined by microbiological sample.

142174 17

Example 11

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 20 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.48 g (3 mmol) of pyridine hydrobromide and 0 , 3 ml (3 mmol) of α-picoline was heated to 85 ° C. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After 22 hours, the reaction mixture was poured into 150 ml of a 0.75 M aqueous potassium phosphate solution buffered to pH 7 and washed with 50 ml of chloroform. The pH of the aqueous layer was adjusted to 2 in the presence of 50 ml of ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. Evaporation of the ethyl acetate gave 1 g of 7 (3-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid with a purity of 56% as determined by PMR using 2,6-dichloroacetophenone as internal reference.

Example 12

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 20 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.5 ml (3 mmol) of a 6 M solution of α -Picoline hydrobromide in dichloromethane and 0.6 ml (6 mmol) of α-picoline was heated to 102 ° G with stirring. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After 6 hours, the reaction mixture was poured into a mixture of 200 ml of a 0.75 M aqueous potassium phosphate solution buffered to pH 7 and 50 ml of ethyl acetate. The buffered aqueous layer was washed with 50 ml of ethyl acetate and after adjusting the pH to 2, the aqueous layer was extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulfate, the ethyl acetate was evaporated under reduced pressure. The residue, which was 1.07 g, contained 70% 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid as determined by UV and PMR (yield 2.25 mmol, .75%).

Example 13 0.64 g (3.3 mmol) of triethylbromosilane was added to a mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 20 ml of dioxane and 0.9 ml (9 mmol) of α-picoline.

After stirring for 1/2 hour, the triethylslyl derivative of benzylpenicillin sulfoxide was formed in situ, its presence being confirmed by PMR. Then, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide was added and the mixture containing α-picoline hydrobromide was heated to 102 ° C for 4 hours. After treatment of the reaction mixture as described in Example 2, the yield of 73 ~ phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 73% as determined by microbiological sample.

142174 18

Example 14 (a) To a mixture of 20 ml of a 0.15 M solution of hydrogen chloride (3 mmol) in dioxane and 2.5 ml (10.2 mmol) of N, O-bis (trimethylsilyl) acetamide was added 1, 05 g (3 mmol) of benzylpenicillin sulfoxide. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After refluxing for 6 hours (102 ° C), the reaction mixture was treated as described in Example 2. The yield of 7 (3-phenylacetamido-3-methyl-eeph-3-em-4-carboxylic acid was about 10% as determined by microbiological sample.

(b) To a mixture of 2 ml (3 mmol) of a 1.5 M solution of hydrogen chloride in benzyl cyanide, 2.5 ml (10 mmol) N, 0-bis (trimethylsilyl) acetamide and 0.9 ml (9 mmol) oricoline in 19 ml of benzyl cyanide was added 1.05 g (3 mmol) of benzylpenicillin sulfoxide. The mixture was heated to 95 ° C for 6 hours and the yield of formed 7β-ρ1ΐθ ^ 1ηοβί3ΐηίάο-3-methyl-ceph-3_em-4-carboxylic acid was determined to 48% by the procedure described in Example 2.

Example 15 (a) To 1.05 g (3 mmol) of benzylpenicillin sulfoxide was added 18 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide and 0.9 ml (9 mmol) of a -picolin.

After a few minutes, 2 ml of a 1.5 M solution of hydrogen bromide (3 mmol) in dioxane was added and the mixture obtained was heated to 101 ° C for 6 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. Treatment of the reaction mixture as described in Example 2 yielded a 97% yield of 7β-phenylacetamido-3-methyl-ceph-3β-4-carboxylic acid as determined by microbiological test.

(b) A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.3 ml (3 mmol) of α-picoline, and 0, 25 ml (1.5 mmol) of a 6 M solution of α-picoline hydrogen bromide in 20 ml of dioxane was refluxed for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of 73-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 82% as determined by microbiological test.

(c) The experiment described in (b) was repeated with the difference that 0.9 ml (9 mmol) was used instead of 0.3 ml of α-picoline and 420 mg (3 mmol) of bromoacetic acid instead of α-picoline. picoline hydrobromide. The trimethylsilyl derivative of benzyl-penicilLine sulfoxide was formed in situ. The yield of 73-phenylacetamido ~ 3-methyl-ceph-3-em ~ 4-carboxylic acid was 32% as determined by microbiological sample.

(d) The experiment described in (c) was repeated with the exception that 700 mg (3 mmol) of picric acid was used instead of bromoacetic acid. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of 7β-19 1A 2 1 7 Λ phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 47% as determined by microbiological sample.

(e) The experiment described in (c) was repeated with the difference that 875 mg (3 mmol) of tris (ethylsulfonyl) methane was used in place of bromacetic acid, i.e. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of 70-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 28% as determined by microbiological test.

Example 16 (a) 530 mg (1.5 mmol) of benzylpenicillin sulfoxide was suspended in 10 ml of dioxane. After the addition of 0.45 ml (4.5 mmol) of ot-picoline, the clear solution was cooled to 0 ° C. Phosphorous tribromide (v05 ml (0.5 mmol) was added with vigorous stirring. The mixture was stirred for 30 minutes at 0 ° C. The anhydride of benzylpenicillin sulfoxide and phosphorous tribromide was formed in situ. Then 0.9 ml (3 ml) was added). After 5 hours of reflux, the amount of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid formed was 85% as determined by microbiological test.

(b) The experiment described in (a) was repeated with the difference that 0.05 ml (0.5 mmol) of acetyl bromide was used in place of phosphorus tribromide. The intermediate formed in this case was the acetyl anhydride of benzylpenicillin sulfoxide. The yield of 70-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 87% as determined by microbiological test.

(c) The experiment described in (b) was repeated with the difference that the acetyl bromide was added while the mixture was at room temperature. The yield was 83% of 70-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid as determined by microbiological sample.

(d) The experiment described in (b) was repeated with the difference that instead of α-picoline 0.36 ml (4.5 mmol) of pyridine was used. The yield of 70-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 94%.

(e) The experiment described in (d) was repeated with the difference that 0.07 ml (1.0 mmol) was used instead of 0.05 ml of acetyl bromide. The yield of 70-phenyl-acetamido-3-methyl-ceph-3-em-4-carboxylic acid was 92%.

(f) The experiment described in (d) was repeated with the difference that 0.14 ml (2.0 mmol) was used instead of 0.05 ml of acetyl bromide. The yield of 70-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 93%.

(g) The experiment described in (d) was repeated with the difference that 0.05 ml of oxalyl bromide was used instead of acetyl bromide. The intermediate formed in this case was the oxalyl anhydride of benzylpenicillin sulfoxide. The yield of 7 {3-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 69%.

(h) The experiment described in (e) was repeated with the difference that instead of dioxane, 10 ml of toluene was used as the solvent. The acetyl anhydride of benzylpenicillin sulfoxide was formed in situ. The yield of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 76%.

(i) The experiment described in (e) was repeated with the exception that 10 ml of butyl acetate was used instead of dioxane. The yield of 73-phenylacetamido-3-methyl-eeph-3-em-4-carboxylic acid was 78%.

Example 17

A solution of 10.5 g (30 mmol) of benzylpenicillin sulfoxide in 150 ml of dioxane and 7.2 ml (90 mmol) of pyridine was cooled to 6 ° C. After adding a solution of 1.4 ml (18.5 mmol) of acetyl bromide in 50 ml of dioxane, the mixture was stirred for 30 minutes at 5 ° C. The acetyl anhydride of benzylpenicillin sulfoxide was formed in situ. Then 18 ml (70 mmol) of N, O-bis (trimethylsilyl) acetamide was added and the reaction mixture was refluxed for 4.5 hours. After cooling, the mixture was poured into 1 liter of a 0.2 M aqueous potassium phosphate solution buffered to pH 7. After adjusting the pH of 7 with 4N potassium hydroxide solution, 600 ml of butyl acetate was added. The mixture was shaken, and then the two layers were separated into a separatory funnel. The aqueous layer was washed with 400 ml of butyl acetate. The combined butyl acetate layers were extracted with 500 ml of a 0.75 M aqueous potassium phosphate solution buffered to pH 7 and the extract was added to the main aqueous solution.

The combined aqueous solutions contained 9.1 g of the potassium salt of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid (yield 82%) as determined by U.V. and by microbiological sample using Escherichia coli as the sample microorganism.

The potassium salt of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was isolated as in Example 1 to give 11.1 g with a purity of 67% as determined by microbiological sample (yield 75%),

Example 18 (a) 530 mg (1.5 mmol) of benzylpenicillin sulfoxide was suspended in 10 ml of dioxane.

After the addition of 0.45 ml (4.5 mmol) of α-picoline, the clear solution was cooled to 0 ° C. With vigorous stirring, 0.05 ml (0.7 mmol) of acetyl bromide was added and the mixture was stirred for 30 minutes at 0 ° C. The acetyl anhydride of benzylpenicillin sulfoxide was formed in situ. Then 1.35 g (6.6 mmol) of N, N, bis (trimethylsilyl) urea was added and after 4.5 hours of reflux the amount of 73-phenylacetamido-3-methyl-ceph-3-em carboxylic acid by microbial 21 U 2m sample. The yield was 54%.

(b) The experiment described in (a) was repeated with the exception that 0.05 ml (0.5 mmol) of phosphorus tribromide was used in place of acetyl bromide. The intermediate formed in this case was the anhydride of benzylpenicillin sulfoxide and phosphorus tribromide. The yield of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 33% as determined by microbiological test.

(c) The experiment described in (a) was repeated with the difference that 10 ml of butyl acetate was used instead of dioxane and 0.12 ml (1.5 mmol) of acetyl bromide instead of 0.7 mmol. The yield of 7β-J-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 54%.

(d) The experiment described in (a) was repeated with the difference that 0.36 ml (4.5 mmol) of pyridine was used instead of α-picoline and 0.22 ml (2.5 mmol) of trimethyl bromosilane instead. for acetyl bromide.

The intermediate formed was the trimethylsilyl derivative of benzylpenicillin sulfoxide. The yield of 73-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 80%.

(e) 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 760 mg (3.7 mmol) of N, N'-bis (trimethylsilyl) urea were suspended in 10 ml of toluene. Then 0.12 ml (1.5 mmol) of pyridine and 0.12 ml (1.0 mmol) of benzoyl bromide were added and the mixture was heated to 100 ° C for 5 hours. The benzoyl anhydride of benzylpenicillin sulfoxide was formed as an intermediate. The yield of 7 (3β-phenylacetaraido-3-methyl-ceph-3-em-4-carboxylic acid was 57% as determined by microbiological test.

(f) The experiment described in (e) was repeated with the difference that several other acid derivatives were used instead of benzoyl bromide. The results are given in the following table: Amount of yield of 70-phenyl

Acid derivative reversed acid acetamido-3-methyl derivative (mmol) ceph-3-em-4-earboxylic acid (%) 1. Trichloroacetyl bromide 1.0 67 2. Trichloroacetyl chloride 1.0 67 3. Propionyl bromide 1.0 75 4 Phosgene 0.5 31 5. Thionyl chloride 0.55 32 6. Thionyl bromide 0.65 67 7. p-Tolylsulfonyl chloride 1.0 21 8. Boron tribromide 0.37 81 9. Aluminum tribromide 0.34 40 22 142t74

Table (continued)

Acid derivative Amount of yield Yield of 7β-phenyl-turned-acid-acetamido-3-methyl-derivative (mmol) ceph-3-em-4-carboxylic acid (%) 10. Silicon tetrabromide 0.25 73 11. Germanium tetrabromide 0 , 25 82 12. Tintetrabromide 0.25 26 13. Phosphorus pentabromide 0.2 82 14. Phosphorus oxybromide 0.33 75 15. Phosphorothiobromide 0.37 .74 16. Tungsten pentabromide 0.2 56

It is clear that the trichloroacetyl (1, 2), propionyl (3), carbonyl (4), thionyl (5, 6) and p-tolylsulfonyl anhydride (7) of benzylpenicillin sulfoxide and the anhydride of benzylpenicillin sulfoxide and boron tribromide (8), aluminum tribromide (9), silicon tetrabromide (10), germanium tetrabromide (11), tin tetrabromide (12), phosphorus pentabromide (13), phosphorus oxybromide (14), phosphorothiobromide (15) and tungsten pentabromide (16) .

Example 19 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.4 g (7 mmol) of Ν, ′'-bis (trimethylsilyl) urea were suspended in 10 ml of dioxane. 0.35 ml (2 mmol) of a 6 M solution of α-picoline hydrobromide in dichloromethane was added and the mixture was heated to 100 ° C for 4 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The amount of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid formed was determined to be 80% using the procedure described in Example 2.

Example 20 (a) 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.05 g (5 mmol) of Ν, ′'-bis (trimethylsilyl) urea were suspended in 10 ml of dioxane. 0.25 ml (3 mmol) of pyridine and 0.15 ml (1.6 mmol) of trimethyl bromosilane were added and the mixture was heated to 100 ° C for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The amount of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid formed was 85% as determined by microbiological test.

(b) The experiment described in (a) was repeated with the difference that 0.16 ml (1.6 mmol) of α-picoline was used instead of pyridine. The yield was 85%.

(C) The experiment described in (a) was repeated with the difference that 0.83 ml (3.4 mmol) of N, O-bis (trimethylsilyl) acetamide was used instead of Ν, Ν'-bis. (trimethylsilyl) urea. The yield of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 69% as determined by microbiological test.

Example 21 525 mg (1.5 mmol) of benzylpenicillin sulfoxide and 1.05 g (5 mmol) of Ν, ′'-bis (trimethylsilyl) urea were suspended in 10 ml of butyl acetate. 0.23 ml (2.3 mmol) of α-picoline and 0.2 ml (2.2 mmol) of trimethylbromosilane were added. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. After heating to 100 ° C for 4.5 hours, the yield of 73-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 78 L as determined by microbiological test.

Example 22

A mixture of 1.05 g (3 mmol) of benzylpeniillin sulfoxide, 3.1 ml (15 mmol) of hexamethyldisilazane, 6 ml of a 0.5 M solution of hydrogen bromide in dioxane and 14 ml of dioxane was heated to 100 ° C for 4 hours. 5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of formed 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was determined at 48% by the procedure described in Example 2.

Example 23 (a) A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 18 ml of dioxane, 0.9 ml (9 mmol) of α-picoline, 2.6 g (10 mmol) of N, O-bis ( trimethylsilyl) trifluoroacetamide and 2 ml of a 1.5 M solution of hydrogen bromide in dioxane was refluxed for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of formed 7β-phentlacetamido-3-methyl-ceph 3-em-4-carboxylic acid was determined to 73% by microbiological test.

(b) The experiment described in (a) was repeated with the difference that 1.8 g (10 mmol) of NjN'-bisitrimethylsilylcarbodiimide was used in place of N, O-bis (trimethylsilyl) trifluoroacetamide. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of 73-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 14% as determined by microbiological test.

Example 24 1.05 g (3 mmol) of benzylpenicillin sulfoxide was suspended in 15 ml of dioxane.

2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 1.2 ml (9 mmol) of 2-methylquinoline and 6 ml of a 0.5 M solution of hydrogen bromide in dioxane were added and the mixture was heated to 100 ° C for 4.5 hours. The trimethylsilyl derivative of benzyl penicillin sulfoxide was quenched in situ. The amount of 7β-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid formed was determined by the microbiological test method described in Example 2 using Escherichia coli as the sample microorganism. The yield was 49%.

The experiment was repeated with bases other than 2-methylquinoline. The results are given in the following table.

Table Amount of base Yield (%) of 7β-Base (mmol) phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid 1. diphenylamine 3 54 2. aniline 9 58 3. N-methylaniline 9 53 4 hexamethylenetetraamine 2.25 73 5. 3-methylpyridine 9 75 6. 4-methylpyridine 9 32 7. 2,3-dimethylpyridine 9 30 8. 2,6-dimethylpyridine 9 52 9. 2-ethylpyridine 9 33 10. 2-propylpyridine 9 35 11. 4-benzylpyridine 9 75 12. 4-phenylpyridine 9 31 13. 2-dimethylaminopyridine 9 34 14. 1,3,5-collidin 9 84 15. quinoline 9 84 16. isoquinoline 9 89 17. 3-methylisoquinoline 9 72 18. pyrazole 9 54 19. imidazole 3 69 20. N-methylimidazole 3 87

Example 25 (a) A mixture of 525 mg (1.5 mmol) of benzylpenicillin sulfoxide, 10 ml of toluene, 0.12 ml (1.5 mmol) of pyridine, 1.45 ml (9 mmol) of N-methyl-N trimethylsilyl acetamide and 0.35 ml of a 6 M solution of α-picoline hydrobromide in dichloromethane were heated to 100 ° C for 5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The yield of 73-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid formed was 58% as determined by microbiological test.

(B) The previous experiment was repeated with the exception that 1.7 ml (9.2 mmol) of N-methyl-N-trimethylsilyltrifluoroacetamide 1 was used instead of N-methyl-N-trimethylilylacetamide. The yield of 78.-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 86%.

Example 26

A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.6 ml (6 mmol) of α-picoline and 0.5 ml of a 6 M solution of α-picoline hydrobromide in methylene chloride in 20 ml of dioxane is refluxed for 4.5 hours. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ.

The amount of 73-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was determined as described in Example 2 by microbiological test. The yield was 82%.

The experiment was repeated in solvents other than dioxane. The results are given in the following table.

Table

Yield (%) of 7 (3-phenyl-solvent acetamido-3-methyl-ceph-3-em-4-carboxylic acid 1,2,3-trichloropropantoluene 40 toluene 41 N, N-dimethylacetamide 44 diethylmethylsulfonamide 49 chlorobenzene 52 isoamyl acetate 60 butyl acetate 64 diethyl oxalate 82 anisole 81 1,2-dimethoxyethane 58 ether aethyethyl lyco 1 - dimethyl ether 81 triethylene glyco1-dimethyl ether 64

Example 27 1.3 g (3 mmol) of 2-ethoxynaphthylpenylcillin sulfoxide, 2.5 ml (10 mmol) of N, C-bis (trimethylsilyl) acetamide, 0.3 ml (3 mmol) of α-picoline and 0.25 ml (1.5 mmol) of a 6 M solution of α-picoline hydrobromide in methylene chloride was dissolved in 20 ml of dioxane. The trimethylsilyl derivative of 2-ethoxynaphthylpenicillin sulfoxide was formed in situ. The mixture was refluxed for 4.5 hours and then poured into a cold mixture of 200 ml of a 0.75 M aqueous potassium phosphate solution buffered to pH 7 and 50 ml of ethyl acetate. After adjusting the pH of 7 with 4N potassium hydroxide solution, the mixture was transferred to a separatory funnel, shaken and allowed to stand. The aqueous layer was washed with 50 ml of ethyl acetate and, after adjusting the pH of 2 with a 4N sulfuric acid solution, was extracted twice with 100 ml of ethyl acetate. After drying over magnesium sulfate, the ethyl acetate was evaporated under reduced pressure. The dried residue, constituting 490 mg, contained 80% 7 & - (2-ethoxynaphthamido) -3-methyl-ceph-3-enr4-carboxylic acid determined by PMR using 2,6-dichloroacetophenone as internal reference. The yield was 31%.

Example 28

The experiment described in Example 27 was repeated with 1.1 g (3 mmol) of phthalimidopenicillin sulfoxide except that the 0.25 ml of α-picoline hydrobromide solution and 0.3 ml of α-picoline were replaced with 0 , 5 ml (3 mmol) of a 6 M solution of α-picoline hydrobromide in methylene chloride. The trimethylsilyl derivative of phthalimi-dopenicillin sulfoxide was formed in situ. The reaction mixture was treated in the same manner as described in Example 27 to obtain 880 mg of 73 ~ phthalimido-3-methyl-ceph-3-em-4-carboxylic acid with a purity of 84%. The yield was 72%.

Example 29

The experiment described in Example 27 was repeated with 1.3 g (3 mmol) of benzene sulfonamidomethylpenicillin sulfoxide. The trimethylsilyl derivative of benzenesulfone amidomethylpenicillin sulfoxide was formed in situ. 1.3 g of 73-benzir sulfonamidomethyl-3-methyl-ceph-3-em-4-carboxylic acid with a purity of 63% were obtained.

The yield was 66%.

Example 30 (a) To 1.1 g (3 mmol) of phenoxymethylpenicillin sulfoxide were added 20 ml of dioxane, 2.5 ml (10 mmol) of N, O-bis (trimethylsilyl) acetamide, 0.6 ml (6 mmol) picoline and a 6 M solution of α-picoline hydrobromide in methylene chloride (0.5 ml, 3 mmol). The trimethylsilyl derivative of phenoxymethylpenicillin sulfoxide was formed in situ. The mixture was refluxed for 4.5 hours and then treated as described in Example 2. The yield of 7β-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid was 71% as determined by a direct microbiological sample using Escherichia coli as a sample microorganism.

(b) The experiment described in (a) was repeated with the difference that the reaction mixture was worked up as described in Example 27 to give 860 mg of 7β-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid with a 85% purity as determined by its PMR spectrum using 2,6-dichloroacetophenone 1A 217 / s 27 as internal reference. The yield was 70%.

Example 31

To a suspension of 1.35 g (3 mmol) of the cyclohexylammonium salt of benzyl-penicillin sulfoxide in 15 ml of dioxane was added 2.8 ml (11 mmol) of N, O-bis (trimethylsilyl) acetamide and 6 ml of a 0 , 5 M solution of hydrogen bromide in dioxane. The trimethylsilyl derivative of benzylpenicillin sulfoxide was formed in situ. The mixture was refluxed for 4.5 hours and the yield of 7 (3-phenylacetamido-3-methyl-ceph-3-em-4-carboxylic acid was determined at 55% by microbiological sample.

Example 32

Preparation of the mixed anhydride of phenoxymethylpenicillin sulfoxide and acetic acid.

(a) A solution of 0.28 ml (3 mmol) of acetyl bromide in 5 ml of 1,2-dichloroethane was added to a solution of 1.1 g (3 mmol) of phenoxymethylpenicillin sulfoxide and 0.72 ml (9 mmol) of pyridine in 20 ml of 1,2-dichloroethane. After stirring for 1 hour at 0 ° C, the mixture was filtered and evaporated to dryness. The residual abrasive product which was 1.08 g (2.6 mmol) was the mixed anhydride of phenoxymethylpenicillin and acetic acid.

Analysis of IR spectrum (in CHCl3): 1820; 1800 and 1758 cm "" '*'.

Analysis of the FMR spectrum (in CDCl3), δ: 1.35 (s, 3); 1.74 (s, 3); 2.32 (s, 3); 4.55 (s, 2); 4.67 (s, 1); 5.17 (d, 1, J = 4.5 Hz); 6.12 (q, 1, J = 11 Hz and J = 4.5 Hz); 6.98 (s, 5).

(b) 2.2 g (5 mmol) of the anhydride of phenoxymethylpenicillin sulfoxide and acetic acid were dissolved in 30 ml of dioxane. After addition of 3 ml (11.7 mmol) of N, O-bis (trimethylsilyl) acetamide, 1.1 ml (15 mmol) of pyridine and 0.6 ml of dichloromethane containing 3.6 nmol of α-picoline hydrobromide, the mixture was heated to reflux for 4.5 hours. The reaction mixture was cooled to room temperature and poured into a stirred mixture of 400 ml of a 0.75 M aqueous potassium phosphate solution buffered to pH 7 and 100 ml of ethyl acetate. After adjusting the pH of 7 with 4n potassium hydroxide, the mixture was transferred to a separatory funnel, shaken and allowed to stand. The aqueous layer was separated, washed with 100 ml of ethyl acetate and, after adjusting the pH to 2 with a 4N sulfuric acid solution, was extracted twice with 200 ml of ethyl acetate. After drying the reaction mixture over anhydrous magnesium sulfate, the ethyl acetate was evaporated under reduced pressure. The dried residue, constituting 1.28 g, contained 86% 70-phenoxyacetamido-3-methyl-ceph-3-em-4-carboxylic acid as determined by its PMR spectrum using 2,6-dichloroacetophenone as internal reference. The yield was 63%.

This example shows that the anhydride formed as an intermediate can

Claims (5)

Is separated from the reaction mixture and, in the case where the anhydride is formed in situ, can be used for ring expansion. Example 33 A mixture of 1.05 g (3 mmol) of benzylpenicillin sulfoxide, 0.9 ml (9 nmol) of α-picoline and a solution of 3.0 mmol of hydrogen bromide in dioxane was refluxed for 4.5 hours with various amounts of N , O-bis (trimethylsilyl) acetaraide as detailed below. The total volume was always 2.4 ml. The yield of 7β-phenyl-acetamido-3-methyl-eeph-3-em-4-carboxylic acid was determined by microbiological test and the results are given in the following table. Amount of N, O- Yield of 7 (3-phenylacetis bis (trimethylsilyl) - amido-3-methyl-ceph-3-em-acetamide (mmol) 4-carboxylic acid (%) 4.5 0 6 56 7.5 82 9 85 The table shows that, under the above conditions, the highest yield was 85 7 'and was obtained with an amount of about 9 to 10 mmol of N, O-bis (trimethylsilyl) acetamide. A process for the preparation of 7β-acylamino-3-methyl-ceph-3 “-em-4-carboxylic acids or their salts by conversion of corresponding 6β-acylamino-peni-cillanic acid sulfoxides, characterized in that a) a 60-acylamino-penicillanic acid sulfoxide having a halide of formula 3. 3 R Hal, wherein Hal represents a halogen atom and wherein R is an acid anhydride group having any of the following partial formulas V-VIII: R4 M1 - V R5 ^ 29 142 m wherein R4 and R3 are the same or different and each represents an alkyl group having 1 -6 carbon atoms, is a cycloalkyl group having 5-8 carbon atoms, a phenyl group, a phenylalkyl group having 1 or 2 carbon atoms in the alkyl moiety, an alkoxy or alkylthio group having each 1-6 carbon atoms, a phenoxy group, a phenyl alkoxy group having 1 or 2 carbon atoms in the alkoxy group or a halogen atom, and represents a boron, aluminum or phosphorus atom, R 5 - ^ - M 2 - VI wherein R 4, R 3 and R 2 are the same or different and each represents an optionally halogen substituted alkyl group of 1-6 carbon atoms, a a cycloalkyl group having 5-8 carbon atoms, a phenyl group, a phenylalkyl group having 1 or 2 carbon atoms in the alkyl moiety, an alkoxy or alkylthio group having each 1-6 carbon atoms, a phenoxy group, a phenylalkoxy group having 1 or 2 carbon atoms in the alkoxy group or a halogen atom, or R (or R "*) and together represent an oxygen atom (= 0) 2 or a sulfur atom (= S), and M represents a silicon, sulfur, germanium or 4,6 tin atom, or a carbon atom when R and R together represent an oxygen or sulfur atom, R 4 - VII 4 wherein R and R are the same or different and each represents a halogen atom, an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 5-8 carbon atoms, a phenyl group, a phenylalkyl group having 1 or 2 carbon atoms in the alkyl moiety, an alkoxy or alkylthio group having from 1 to 6 carbon atoms, a phenoxy group or a phenyl-alkoxy group having 1 or 2 carbon atoms in the alkoxy group, and R and R each represent a halogen atom or together represent a halogen atom oxygen atom (= O) or sulfur atom («S), 3 and M represents a phosphorus or tungsten atom 0 9 II 'VIII R * -S- I! 0. Wherein R represents an alkyl group of 1-6 carbon atoms, a cycloalkyl group of 5-8 carbon atoms, a phenyl group, a phenylalkyl group of 1 or 2 carbon atoms in the alkyl moiety, an alkoxy or alkylthio group of each 1-6 carbon atoms, a phenoxy group or a phenylalkoxy group with 1 or 2 carbon atoms in the alkoxy group, wherein the phenyl groups or molecular moieties within the definitions of R \, R ^ and R ^ optionally carry one or more substituents selected from halogen atoms, alkyl or alkoxy groups of 1-6 carbon atoms and dialkylamino group b) having 1-6 carbon atoms in each alkyl moiety, and b) heating the acid anhydride thus obtained to a temperature up to a maximum of 160 ° C in a dry, inert organic solvent with an anhydrous acid selected from hydrogen bromide, hydrogen chloride, toluene-β- sulfonic acid, concentrated sulfuric acid, hydrogen iodide, perchloric acid, periodic acid, nitric acid, chloric acid, iodic acid, selenic acid, bromoacetic acid, trichloroacetic acid, trifluoroacetic acid R base to form an acid addition salt complex, in the presence of a silicon-containing compound selected from N, O-bis (trimethylsilyl) acetamide, N, O-bis (trimethylsilyl) trifluoroacetamide, N, N-bis (trimethylsilyl) carbodiimide, N- (trimethylsilyl) acetamide, N-methyl — N— (trimethylsilyl) acetamide, N-methyl-N- (trimethylsilyl) formamide, N- (trimethylsilyl) -2-pyrrolidone, N- (triethylsilyl) urea, Ν, Ν -bis (trimethylsilyl) urea, N- (triphenylsilyl) ethylcarbamate, trimethylsilyldimethylsulfoxymide, N-trimethylsilyl-N-methyl-trifluoroacetamide, trimethylsilylimidazole, triphenylsilylamine, N-ethyltriethylsilylamine ylamine, hexamethyldisilazane, hexamethylcyclotrisilane and octamethylcyclotetrasilazane, or a ^) react a 6β-acylamino-penicillanic acid sulfoxide directly according to b) and hydrolyze the compound formed in situ to separate the 7.6-acylamino-3 thus formed ceph-3-em-4-carboxylic acid as such or as a salt. Process according to claim 1, characterized in that the base is pyridine, a substituted pyridine, quinoline, a substituted quinoline, imidazole or a substituted imidazole. Process according to claim 1 or 2, characterized in that the temperature used during the ring expansion is between 70 and 110 ° C. Process according to claim 1, characterized in that for each mole of penicillanic acid sulfoxide, 1 to 4 moles of acid, preferably hydrogen bromide or hydrogen chloride, 1.5 to 15 moles of nitrogen-containing base, preferably α-picoline, are used, the base amount always exceeding and 2 to 4 moles of N, O-bis (trimethylsilyl) acetamide, and the reaction is carried out at a temperature of 80-110 ° C in a dry, inert organic solvent, preferably dioxane. Process according to claim 1, characterized in that for each mole of penicillanic acid sulfoxide, 1/3 to 1 equivalent of acetyl bromide or phosphorus tribromide, 1.5 to 15 moles of nitrogen-containing base, preferably α-picoline, is used.