Aqueous and anhydrous degradations of 6α-formamidopenicillins

Abstract

When an aqueous solution of the 6α-formamidopenicillin BRL 36650 (1) was set aside for 36 h, an essentially quantitative C(5)–C(6) cleavage resulted, yielding the α,α-bis(acylamino) acid (6) and N-formylpenicillamine (10). The unsubstituted phenyl compound (2) behaved analogously, but the 4-aminophenyl derivative (3) showed five-fold greater aqueous stability. Over a wider range of pH, the penicillin (1) was converted into the penillic acid (21) and/or the penicilloic acid (22) at 1 < pH < 7 and into the piperazine ring-opened diacid (23) at pH 10.

Both the 6β-aminopenicillin ester (15) and the urethane (24) yielded penicilloates (25) and (26) on base-catalysed methanolysis. However, while (15) was recovered in good yield after prolonged treatment with triethylamine, (24) underwent C(5)–C(6) cleavage, forming the dihydrothiazole (27). These results are interpreted in terms of initial oxazolone formation via the 6β-amido substituent, followed by C(5)–C(6) bond breaking.