Cephalosporin derivatives containing a unique combination of lipophilic C-7 sidechains and polar C-3 thiopyridinium groups were synthesized and found to exhibit potent anti-MRSA activity in vitro and in vivo. The optimum C-7 sidechains utilized were 2,5-dichlorophenylthioacetamido and 2,6-dichloropyrid-4-ylthioacetamido. The C-3 thiopyridinium rings were substituted at nitrogen with amino acid and pyruvic acid groups that were designed to confer aqueous solubility as required for IV formulation. This paper describes the characteristics of these novel cephalosporins and highlights synthetic methods developed to allow their practical, large-scale syntheses.

A novel and highly efficient synthesis of [1S-(1 alpha,2 alpha,3 alpha,4 alpha)]-2-[[2-(3-methoxy-3-oxopropyl)phenyl]methyl]-7-oxabicyclo[2.2.1]-heptane-3-carboxylic acid (A), a key intermediate in the synthesis of ifetroban sodium, BMS-180291, is described. Reaction of chiral imides such as [2(S),3a alpha,4 beta,7 beta,7a alpha]-hexahydro-2-(1-phenylethyl)-4,7-epoxy-1H-isoindole-1,3(2H)-dione (B) with the Grignard reagent derived from 2-(2-bromophenyl)-1,3-dioxolane and subsequent in situ transformations give [2S-(2 alpha,3a alpha,4 beta,7 beta,7a alpha)]-2-(octahydro-3-oxo-4,7-epoxyisobenzofuran-1-yl)benzaldehyde, converted in two steps to A. Efficient syntheses of B from furan and maleic anhydride are described.