Synthesis of a naphthyridone p38 MAP kinase inhibitor.
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 alpha 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.
Chung
John Y L
JY
Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07965, USA.
Cvetovich
Raymond J
RJ
McLaughlin
Mark
M
Amato
Joseph
J
Tsay
Fuh-Rong
FR
Jensen
Mark
M
Weissman
Steve
S
Zewge
Daniel
D
D003497:Cyclic N-Oxides / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D009287:Naphthyridines; D048051:p38 Mitogen-Activated Protein Kinases