IE36353L - Rearrangement of 6-acylamidopenicillanic acid sulfoxides - Google Patents

Abstract

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 R<SP>2</SP>, R<SP>3</SP> and R<SP>4</SP> are hydrogen, halogen, C 1 -C 7 alkyl, halo-(C 1 -C 7 alkyl), phenyl, benzyl, tolyl or dimethylaminophenyl, at least one of the R<SP>2</SP>, R<SP>3</SP> and R<SP>4</SP> groups being other than halogen or hydrogen; R<SP>1</SP> is C 1 -C 7 alkyl; m is 1 or 2; and X is halogen or wherein R<SP>5</SP> is hydrogen or C 1 -C 7 alkyl and R<SP>8</SP> 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 1-7 alkyl carbon atoms), to produce the corresponding imino ether; (F) splitting the imino bond of the imino ether by hydrolysis or alcoholysis, in the optional presence of a silylating agent as specified in step (C), to produce 7-amino-desacetoxycephalosporanic acid (7-ADCA) or, when the silylating agent is present, to produce the'mono- or-disilyi derivative of 7-ADCA; (G) if the mono-- or di-silyl derivative has not been prepared in step (F), then preparing such derivative by reacting the 7-ADCA with a silylating agent as specified in step (C); (H) N-acylating the silyl derivative with phenylglycyi chloride hydrochloride in an inert non-aqueous organic solvent; and (I) cleaving by hydrolysis or alcoholysis the silyl groups in the acylation product to form cephalexin, or, optionallly forming a nontoxic pharmaceutically acceptable salt of cephalexin. If the process is modified in one of the following'' ways, then the product is hetacephalexin instead of cephalexin: (1) in step (H) acetone is present in the N-acylation reaction mixture to provide silylated hetacephalexin, or (2) acetone is reacted with the product of step (H) to provide silylated hetacephalexin, the silylated material in each case then being cleaved as in step,. (I); or (3) acetone is reacted with the product of, step (I) to provide hetacephalexin or a non, toxic pharmaceutically acceptable salt thereof. [GB1391838A]