GB1284974A - Novel diacyl penicillins and process for their production - Google Patents

Abstract

1284974 Diacyl penicillins TOYO JOZO KK 9 April 1970 [11 April 1969] 16961/70 Heading C2A Novel diacyl penicillins of formula wherein R is a carboxyl-protecting group and R 1 and R 2 are the same or different and are hydrogen or halogen, are prepared by reacting a benzylpenicillin ester in which the esterifying group is the group R as above, with a chlorinating agent in the presence of a tertiary organic base to give an imide chloride group-containing compound of formula wherein R is as above, and then reacting this compound with an isoxazole carboxylate of formula in which M is a metal atom and R 1 and R 2 are as above. Suitable carboxyl-protecting groups R are methyl, ethyl, t-butyl, p-methoxybenzyl, benzyl, p-nitrobenzyl, benzhydryl, phenacyl, p-bromophenacyl or trimethylsilyl. The preparation of the p-bromophenacyl and p-nitrobenzyl esters of benzylpenicillin by reacting the penicillin with the appropriate acyl bromide is described. The preferred chlorinating agent is PCl 5 , others suitable being PCl 3 , POCl 3 , COCl 2 or SOCl 2 ; the reaction is performed in an anhydrous organic solvent which is preferably water-immiscible, at about - 20‹ to 25‹ C. The tertiary organic base is preferably a weak base such as pyridine, quinoline or dimethylaniline. After the imide chloride preparation step, the reaction solution may be used for the next stage without further purification, or, if desired, may be filtered to remove any precipitated tertiary base hydrochloride, washed with dilute aqueous alkali to remove chlorinating agent derived compounds (e.g. POCl 3 and HCl) and then concentrated and redissolved in another reaction solvent. The isoxazole carboxylate salt may be that of K, Na, Li or Ag. The reaction may be effected by simply adding the salt to the imide chloride solution from the first stage, if necessary with heating to 40‹ to 50‹ C. The reaction mixture is then washed with water, aqueous acid and alkali, concentrated and chromatographed on a silica gel column using, e.g., benzene-ethyl acetate. The required diacyl penicillin may be isolated by freeze-drying the eluate. The diacyl penicillins may be de-esterified, to the corresponding penicillanic acid; dephenylacetylation of the latter provides a means for preparing useful isoxazolyl penicillins.