Synthesis of a Naphthyridone p38 MAP Kinase Inhibitor

• Published in: Journal of organic chemistry Vol. 71; no. 22; pp. 8602 - 8609
• Main Authors: Chung, John Y. L, Cvetovich, Raymond J, McLaughlin, Mark, Amato, Joseph, Tsay, Fuh-Rong, Jensen, Mark, Weissman, Steve, Zewge, Daniel
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.10.2006; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Organic; Cyclic N-Oxides - chemistry; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with only one n hetero atom and condensed derivatives; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Molecular Structure; Naphthyridines - chemical synthesis; Naphthyridines - chemistry; Naphthyridines - pharmacology; Organic chemistry; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; Physical Sciences; Preparations and properties; Science & Technology; QUINOLINE N-OXIDES; CROSS-COUPLING REACTIONS; ALKYL; RING; REGIOSELECTIVE SYNTHESIS; PYRIDINES; SALTS; GRIGNARD-REAGENTS; ACRYLANILIDES; Organic cation; Chemoselectivity; Nitrogen heterocycle; Nitrone; Lactam; Heck reaction; Transamination; Pyridine derivatives; Piperidine derivatives; Chelation; Dihydropyridine derivatives; Oxidation; Naphtyridine derivatives; Chemical synthesis; Drug; Enzyme; Iminium compounds; Mitogen-activated protein kinase; Magnesium chloride; Tandem reaction; Organic chlorine compounds; Piperidone derivatives; Quaternary ammonium compound; Inhibitor; Ethylenic compound
• DOI: 10.1021/jo061618f
• ISSN: 0022-3263

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.