%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