A Practical Synthesis of an Anti-Methicillin Resistant Staphylococcus aureus Cephalosporin BMS-247243

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• 作者：Janak Singh ; Oak K. Kim ; Thomas P. Kissick ; Kenneth J. Natalie ; Bo Zhang ; Gerard A. Crispino ; Dane M. Springer ; John A. Wichtowski ; Yunhui Zhang ; Jason Goodrich ; Yasutsugu Ueda ; Bing Y. Luh ; Brian D.
• 刊名：Organic Process Research & Development
• 出版年：2000
• 出版时间：November 2000
• 年：2000
• 卷：4
• 期：6
• 页码：488 - 497
• 全文大小：395K
• 年卷期：v.4,no.6(November 2000)
• ISSN：1520-586X

文摘

A practical synthesis of the anti-methicillin resistant Staphylococcus aureus cephem (6R-trans)-E-7-[[[[2,5-dichloro-4-[3-[(carboxymethyl)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 ofthe iodide counterion in 3a to chloride 3b that was essentialfor 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 formedthe methyl ester of the C-7 side chain 12b in high yield. Reactionwith the dianion of thioglycolic acid gave an increased level ofthe corresponding Michael addition byproduct that led to lowerquality thermodynamic product 12b by the reverse reaction.Cephem nucleus 16 was acylated with the acid chloride of acid12b in a biphasic system to circumvent the cumbersome workupinvolved in reactions mediated by carbodiimdes DCC or EDACfor the synthesis of diester 17. An unusual degradation productdiacid 20 was obtained during the deprotection of diester 17with TFA to amorphous diacid 19. Reaction of diacid 19 with4-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 thedouble zwitterion BMS-247243 in high yield.