- Synthesis of a naphthyridone p38 MAP kinase inhibitor
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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 enelactam. 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. American Chemical Society.
- Chung, John Y. L.,Cvetovich, Raymond J.,McLaughlin, Mark,Amato, Joseph,Tsay, Fuh-Rong,Jensen, Mark,Weissman, Steve,Zewge, Daniel
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p. 8602 - 8609
(2007/10/03)
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- Unique tandem heck-lactamization naphthyridinone ring formation between acrylanilides and halogenated pyridines
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The Heck coupling of acrylanilides with 4-bromo-2-chloro-3-iodo-pyridine using palladium acetate can produce bis-Heck products or undergo an unusual tandem Heck-lactamization ring formation to generate 5-chloro-1-aryl-1,6- naphthyridin-2(1H)-ones.
- Cvetovich, Raymond J.,Reamer, Robert A.,DiMichele, Lisa,Chung, John Y. L.,Chilenski, Jennifer R.
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p. 8610 - 8613
(2007/10/03)
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