Synthesis of p38 MAP kinase inhibitor MK-0913 using naphthyridone N-oxide as a chemoselective control toward Grignard addition

ORGN 808

John Y. L. Chung, john_chung@merck.com1, Raymond J. Cvetovich, Raymond_Cvetovich@Merck.com2, Joseph S. Amato1, Fuh-Rong Tsay2, Mark McLaughlin, mark_mclaughlin@merck.com1, Steven Weissman2, Daniel Zewge3, and Mark Jensen1. (1) Department of Process Research, Merck Research Laboratories, PO Box 2000, R800-C369, Rahway, NJ 07065-0900, (2) Process Research, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, (3) Department of Process Research, Merck and Co., Inc, P.O. Box 2000, Rahway, NJ 07065
MK-0913 is a p38 MAP kinase inhibitor potentially useful for the treatment of rheumatoid arthritis and psoriasis. A novel 6-step synthesis suitable for large scale preparation was developed. The key steps include a tandem Heck-lactamization, N-oxidation and a highly chemoselective Grignard addition of 4-(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 dihydropyridine adduct was aromatized by treatment with iso-butylchloroformate and heating in pyridine. Syntheses of Grignard precursor, N-t-butyl-4-chloro-piperidine, were accomplished via a double retro-Michael-Michael-cyclization or via a methyl Grignard addition to the iminium ion. Utilizing this chemistry, multi-kg preparation of the crystalline MK-0913 was successfully demonstrated.

 

Total Synthesis, Materials, Molecular Recognition, Process R&D, and Physical Organic Chemistry
8:00 PM-10:00 PM, Wednesday, 13 September 2006 Moscone Center -- Hall D, Poster

Sci-Mix
8:00 PM-10:00 PM, Monday, 11 September 2006 Moscone Center -- Hall D, Sci-Mix

Division of Organic Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006