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 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.

化合物1是一种p38丝裂原活化蛋白激酶（p38 MAP kinase）抑制剂，有望用于类风湿关节炎与银屑病的治疗。默克研究实验室（Merck Research Laboratories）为支持其药物开发项目，开发了一种适用于规模化制备的新型六步合成工艺。关键反应步骤包括串联Heck-内酰胺化反应、N-氧化反应，以及将4-(N-叔丁基哌啶基)氯化镁与萘啶酮N-氧化物进行的高化学选择性格氏加成（Grignard addition）反应。该N-氧化物通过螯合作用实现完全的化学选择性，引导格氏加成发生于α位，而非烯内酰胺上的1,4-加成。所得二氢吡啶基加成产物经氯甲酸异丁酯处理后，于吡啶中加热完成原位芳构化。格氏试剂前驱体N-叔丁基-4-氯哌啶（N-tert-butyl-4-chloro-piperidine）的合成可通过与季铵基哌啶酮的转胺反应，或是将氯化甲基镁加成至亚胺离子上来完成。利用该合成工艺，已成功实现化合物1的多千克级规模化制备。