%0 Generic %A Y. L. Chung, John %A Cvetovich, Raymond J. %A McLaughlin, Mark %A Amato, Joseph %A Tsay, Fuh-Rong %A Jensen, Mark %A Weissman, Steve %A Zewge, Daniel %D 2006 %T Synthesis of a Naphthyridone p38 MAP Kinase Inhibitor %U https://acs.figshare.com/articles/dataset/Synthesis_of_a_Naphthyridone_p38_MAP_Kinase_Inhibitor/3051337 %R 10.1021/jo061618f.s001 %2 https://ndownloader.figshare.com/files/4756963 %K p 38 MAP kinase inhibitor %K iminium ion %K α position %K drug development program %K quaternary ammonium piperidone %K dihydropyridyl adduct %K Grignard addition %K Merck Research Laboratories %K chemoselective Grignard addition %K Grignard precursor %K compound 1 %K methylmagnesium chloride %K preparation %K Naphthyridone p 38 MAP Kinase InhibitorCompound 1 %X Compound 1 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel six-step synthesis suitable for large-scale preparation was developed in support of a 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 via chelation in directing the Grignard addition to the α position as opposed to 1,4-addition on the ene-lactam. The dihydropyridyl adduct was in situ aromatized with isobutylchloroformate followed by heating in pyridine. Syntheses of Grignard precursor, N-tert-butyl-4-chloro-piperidine, were accomplished via transamination with a quaternary ammonium piperidone or via addition of methylmagnesium chloride to an iminium ion. Utilizing this chemistry, multi-kilogram preparation of compound 1 was successfully demonstrated. %I ACS Publications