jo061618f_si_001.cif (17.78 kB)
Synthesis of a Naphthyridone p38 MAP Kinase Inhibitor
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posted on 2006-10-27, 00:00 authored by John Y. L. Chung, Raymond J. Cvetovich, Mark McLaughlin, Joseph Amato, Fuh-Rong Tsay, Mark Jensen, Steve Weissman, Daniel ZewgeCompound 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.
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p 38 MAP kinase inhibitoriminium ionα positiondrug development programquaternary ammonium piperidonedihydropyridyl adductGrignard additionMerck Research Laboratorieschemoselective Grignard additionGrignard precursorcompound 1methylmagnesium chloridepreparationNaphthyridone p 38 MAP Kinase InhibitorCompound 1
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