A practical synthesis of an anti-methicillin resistant Staphylococcus aureus cephalosporin BMS-247243

A practical synthesis of the anti-methicillin resistant Staphylococcus aure us cephem (6R-trans)-E-7- [[[[2,5-dichloro-4- [3-[(carboxyethyl)amino]-3-ox o-1-propenyl]phenyl]-thio]-acetyl]amino]4-[[(2-carboxy-8-oxo-5-thia-1-azabi cyclo-[4.2.0]oct-2-en-3-yl)methyl]thio]-2,6-dimethyl-1-[3-(4-methylmorpholi no-4-yl)propyl]-1-pyridinium, hydroxide, inner salt (BMS-247243) was develo ped. A process was developed for the interchange of the iodide counterion i n 3a to chloride 3b that was essential for an efficient synthesis of the C- 3 side chain 4-mercaptopyridone 6b. Use of catalytic Bu4NCl in the reaction of chlorocinnamide 14 with the Li-salt of methylthioglycolate formed the m ethyl ester of the C-7 side chain 12b in high yield. Reaction with the dian ion of thioglycolic acid gave an increased level of the corresponding Micha el addition byproduct that led to lower quality thermodynamic product 12b b y the reverse reaction. Cephem nucleus 16 was acylated with the acid chlori de of acid 12b in a biphasic system to circumvent the cumbersome workup inv olved in reactions mediated by carbodiimdes DCC or EDAC for the synthesis o f diester 17. An unusual degradation product diacid 20 was obtained during the deprotection of diester 17 with TPA to amorphous diacid 19, Reaction of diacid 19 with 4-mercaptopyridone 6b formed BMS-247243 in moderate yield. Alternately, an efficient coupling of diester 17 with 4-mercaptopyridone 6b gave crystalline diester 21 with minimal(<1%) contamination of the double bond isomer 22. Double deprotection of diester 21 followed by crystallizati on furnished the double zwitterion BMS-247243 in high yield.