Development and Industrialization of New Intermediate 3-Chloromethyl- Δ³-cephems for Cephalosporin Antibiotic Synthesis

Abstract

Synthesis as well as characteristic features of 3-chloromethyl-Δ ³-cephems (GCLE), a new potent intermediate for the synthesis of a wide variety of antibiotics of cepbalosporin family, are described. The synthetic scheme of GCLE starting from penicillin G consists of pyrolytic cleavage of penicillin sulfoxide leading to 4-(phenylsulfonylthio) azetidin-2-one derivatives, electrochemical ene-type chlorination of the N-substituent (3-methyl-3-butenoate) of the azetidinones, and subsequent construction of the cephem framework by ammonia-promoted recyclization. The phenylsulfonyl moiety works eectively for trapping the in situ generated sufenic acid in the rst step, as a protecting group in the ene-type chlorination, and as a good leaving group in the nal recyclization step. Our continuing eorts on the improvement of each of the sequen tial processes upto the level feasible for industrial production of GCLE deal with (1) elucidation of active chlorine species generated in the electrochemical chlorination, in turn, leading to the innovation of ene-type chlorination with molecular chlorine associated with particular hetero atom compounds, (2) recovery and recycle use of the phenylsulfonyl moiety, and (3) optimization of the cyclization of the azetidinones into GCLE with ammonia. Deprotection of p-methoxybenzyl and diphenylmethyl ester moietyin a phenol matrix, which is an essential stage for the synthesis of antibiotic drugs, as well as demonstrations of the synthetic utility of GCLE are also described.