FORFARANDE FOR FRAMSTELLNING AV CEFALEXIN

1391838 Penicillins and cephalosporins BRISTOL MYERS CO 11 May 1972 [11 May 1971] 22164/72 Heading C2C [Also in Division C3] A process for the rearrangement of a 6- acylamidopenicillanic acid sulphoxide of Formula I wherein R is the side chain of a fermentation produced penicillin into a 7-acylamido-3- methylceph-3-em-4-carboxylic acid of Formula II comprises heating the penicillanic acid sulphoxide (free acid form) in a weakly basic solvent in the presence of a catalyst comprising a strong acid either alone or in combination with a nitrogen base having a pKb of not less than 4. R may be hexyl, heptyl, thiophene-2-methyl, phenylmethyl, phenyl, phenoxymethyl or phenylmercaptomethyl. Alternatively, when R is one of the specified phenyl-containing groups. the phenyl radical may be substituted so that it is expressed by the formula in which Z is H, Cl, CH 3 , CH 3 0 or N0 2 . The above-mentioned rearrangement process may be employed in the preparation of cephalexin or hetacephalexin or non-toxic pharmaceutically acceptable salts thereof, and such antibiotic substances, thus obtained, may be formulated into pharmaceutical compositions together with an inert pharmaceutically acceptable carrier. Thus, a process for the preparation of cephalexin or a non-toxic pharmaceutically acceptable salt thereof comprises (A) oxidizing a fermentationproduced penicillin or a salt thereof to prqduce a 6-acylamido penicillanic acid sulphoxide of Formula I above; (B) converting the sulphoxide to a 7-acylamido-3-methylceph-3-em-4-carboxylic acid by the above-mentioned rearrangement process; (c) reacting the 4-carboxylic acid with a silylating agent of the formula or wherein R2, R3 and R4 are hydrogen, halogen, C 1 -C 7 alkyl, halo-(C 1 -C 7 alkyl), phenyl, benzyl, tolyl or dimethylaminophenyl, at least one of the R2, R3 and R4 groups being other than halogen or hydrogen; R1 is C 1 -C 7 alkyl; m is 1 or 2; and X is halogen or wherein R5 is hydrogen or C 1 -C 7 alkyl and R8 is hydrogen, C 1 -C 7 alkyl or under anhydrous .conditions in an inert solvent, and in the presence of an acid-deactivating tertiary amine to form the corresponding silyl ester of the 4-carboxylic, acid; (D) reacting the silyl ester with an excess of a halogenating agent under anhydrous conditions, in an inert solvent and in the presence of an acid-deactivating tertiary amine, to form the corresponding imino halide; (E) reacting the imino halide with a C 1 -C 12 aliphatic alcohol or with a phenylalkyl alcohol (of