title: Synthesis development of a naphthyridinone p38 kinase inhibitor.
abstract: In this review the development of a viable large-scale synthesis of a p38 kinase inhibitor is discussed. Multiple strategies have been explored in devising syntheses to the intermediates containing the p38 kinase inhibitor's naphthyridinone core to allow the appendage of difluorophenyl and 4-N-tert-butylpiperidine fragments. A novel Heck lactamization reaction was discovered upon reacting 2,6-dichloroacrylanilide with a trihalo-substituted pyridine leading to the rapid synthesis of the naphthyridinone core. Investigations led to the development of two syntheses of 4-N-tert-butyl-chloropiperidine, including a novel methyl Grignard addition to an acetone iminium intermediate to build the tert-butyl group. The chemoselective addition of a 4-N-tertbutyl-chloropiperidine Grignard reagent to a pyridine oxide intermediate followed by re-aromatization using isobutylchloroformate and pyridine as solvent completed the synthesis of this potentially important p38 kinase inhibitor.
authors.affiliation: Process Research, Merck & Co Inc., Rahway, NJ 07065, USA.
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chung
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Cvetovich
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D009287:Naphthyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010601:Pharmacology, Clinical / Q000379:methods* / Q000639:trends; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D004791:Enzyme Inhibitors; D009287:Naphthyridines; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases