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

A practical synthesis of the anti-methicillin resistant Staphylococcus aureus cephem (6R-trans)-E-7- [[[[2,5-dichloro-4- [3-[(carboxyethyl)amino]-3-oxo-1-propenyl]phenyl]-thio]-acetyl]amino]4-[[(2-carboxy-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-en-3-yl)methyl]thio]-2,6-dimethyl-1-[3-(4-methylmorpholino-4-yl)propyl]-1-pyridinium, hydroxide, inner salt (BMS-247243) was developed. A process was developed for the interchange of the iodide counterion in 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 methyl ester of the C-7 side chain 12b in high yield. Reaction with the dianion of thioglycolic acid gave an increased level of the corresponding Michael addition byproduct that led to lower quality thermodynamic product 12b by the reverse reaction. Cephem nucleus 16 was acylated with the acid chloride of acid 12b in a biphasic system to circumvent the cumbersome workup involved in reactions mediated by carbodiimdes DCC or EDAC for the synthesis of 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 crystallization furnished the double zwitterion BMS-247243 in high yield.