Synthesis of a Naphthyridone p38 MAP Kinase Inhibitor

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• 作者：John Y. L. Chung ; Raymond J. Cvetovich ; Mark McLaughlin ; Joseph Amato ; Fuh-Rong Tsay ; Mark Jensen ; Steve Weissman ; Daniel Zewge
• 刊名：Journal of Organic Chemistry
• 出版年：2006
• 出版时间：October 27, 2006
• 年：2006
• 卷：71
• 期：22
• 页码：8602 - 8609
• 全文大小：253K
• 年卷期：v.71,no.22(October 27, 2006)
• ISSN：1520-6904

文摘

Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritisand psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support ofa drug development program at Merck Research Laboratories. The key steps include a tandem Heck-lactamization, N-oxidation, and a highly chemoselective Grignard addition of 4-(N-tert-butylpiperidinyl)magnesium chloride to a naphthyridone N-oxide. The N-oxide exerted complete chemoselectivity viachelation in directing the Grignard addition to the position as opposed to 1,4-addition on the ene-lactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heatingin pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished viatransamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride toan iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfullydemonstrated.