ES430117A1 - Process for rearranging 6-acylamidopenicillanic acid-1-oxides to 7-acyla mido-3-methyl-ceph-3-em-4-carboxylic acids - Google Patents

Abstract

An improved procedure for the preparation of hetacephalexin of the formula: **(See formula)** and non-toxic and pharmaceutically acceptable salts thereof, comprising the steps of: A) Oxidizing a penicillin produced by fermentation or a salt thereof to produce a penicillinsulfoxide of formula: **(See formula)** where R is the side chain of a penicillin produced by fermentation; B) transposing said penicillinsulfoxide to produce a cephalosporic acid compound of the formula: **(See formula)** where R is the one defined above; C) reacting said cephalosporanic acid compound with a silyl compound of formula **(See formula)** where R 2, R 3 and R 4 are hydrogen, halogen, lower alkyl, halo lower alkyl, phenyl, henyl, tolyl or dimethylaminophenyl, at least one of said groups R2, R3 and R4 being other than halogen or hydrogen; R1 is lower alkyl; m is an integer with a value of 1 or 2 and X is halogen or **(See formula)** where R5 is hydrogen or lower alkyl and R6 is hydrogen, lower alkyl or **(See formula)** where R2, R3 and R4 are as defined above, 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 cephalosporanic acid compound; D) reacting said 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 with said iminohalide an alcohol selected from aliphatic alcohols of 1 to 12 carbon atoms and phenylalkyl alcohols of 1 to 7 carbon atoms in the alkyl chain, to produce the corresponding iminoether; F) cleaving the imino junction of said iminoether by hydrolysis or alcoholysis to produce 7-amino deacetoxycephalosporanic acid; G) preparing the monosilyl or disilyl derivative of 7-amino deacetoxycephalosporanic acid; H) N-acylated said monosilyl or disilyl derivative with a phenylglycine derivative in the presence of acetone and I) separating by hydrolysis or alcoholysis any silyl group to form hetacephalexin or by subsequent conversion to form a non-toxic and pharmaceutically acceptable salt thereof; whose procedure is characterized in that: (1) the transposition step (B) is carried out by heating the free acid form of penicillinsulfoxide in a weakly basic solvent, in the presence of a catalyst that comprises a strong acid either alone or in combination with a nitrogenous base with a pKb not less than 4; (2) The monosilyl derivative of 7-amino deacetoxycephalosporanic acid is prepared by reacting the 7-amino deacetoxycephalosporinic acid product from step (F) with an approximately molar amount of a silyl compound as defined in step (C) or by carrying out the reaction of hydrolysis or alcoholysis of step (F) in the presence of at least about a molar excess of a silyl compound as defined in step (C) or subjecting in step (F) the imino bond of the iminoether to alcoholysis and thermal cleavage while in the presence of at least an approximately molar excess of a silyl compound as defined in step (C); (3) The disilyl derivative of 7-amino deacetoxycephalosporanic acid is prepared by reacting the 7-amino deacetoxycephalosporanic acid product from step (F) with at least 2 moles of a silyl compound as defined in step (C) per mole of acid 7 -amino deacetoxycephalosphanic agent or by carrying out the hydrolysis or alcoholysis reaction of step (F) in the presence of an excess of at least about double molar of a silyl compound as defined in step (C) or subjecting in step (F) the imino binding of the iminoether to alcoholysis and thermal cleavage while in the presence of at least about a double molar excess of a silyl compound as defined in step (C); and (4) the acylation reaction is carried out by reacting the monosilyl or disilyl derivative with phenylglycyl chloride hydrochloride in an inert, non-aqueous organic solvent system, in the presence of excess acetone, said acetone forming part of the mixture of acylation, in which case silylated hetacephalexin is produced in situ or, alternatively, by adding acetone after acylating and isolating the silylated cephalexin, in which case silylated hetacefalexin is formed in a new discrete step from silylated cephalexin. (Machine-translation by Google Translate, not legally binding)