Synthesis and biological evaluation of 3-chloro-1-carbacephem compounds.

Abstract

The 3-chloro-1-carbacephem uncleus was prepared for the first time from a 3H-1-1carbacephem compound through a sequence of reactions involving addition of thiophenol, oxidation of sulfide to sulfoxide, and α-chlorination of the sulfoxide, followed by elimination of phenylsulfinic acid. The 2-β-methyl analog was similarly prepared, but the 2α-methyl analog was not obtained.Optical resolution of the 3-chloro-1-carbacephem compound was achieved by the employment of penicillin acylase. That is, the 7-phenylacetamide derivative was enantioselectively hydrolyzed to afford the optically active 7-amino-3-chloro-1-carbacephem compound. Carbacefaclor, the carbacephem analog of cefaclor, was directly and efficiently prepared by enzymatic phenylglycylation of the recemic 7-amino-3-chloro-1-carbacephem compound by using immobilized penicillin acylase. Carbacefaclor thus prepared exhibited comparable antibacterial activity against most gram positive bacteria tested and higher activity against typical gram negative bacteria as compared with cefaclor. Moreover, carbacefaclor possessed remarkably high chemical stability.