JAK抑制剂Peficitinib的合成及工艺研究

Study on Synthesis and Optimization of Syn-thesis Technology of JAK Inhibitor Peficitinib

摘要: Peficitinib是由日本安斯泰来公司研发上市的一种新型JAK1 (Janus激酶)和JAK3抑制剂，主要治疗对甲氨蝶呤反应不充分的中重度类风湿性关节炎(RA)。目前Peficitinib的合成路线报道较少，本文首先设计出了完整的合成路线，然后对各步反应进行了研究和优化。以7-氮杂吲哚为起始原料，经过卤代，取代(上保护)，酯化，脱保护，酯水解，酰胺化，再取代七步反应得到目标化合物。利用提供催化剂或改变其他反应条件如溶剂、温度、反应物摩尔比等，成功得到一个路线合理、产率高、时间短、操作简单的Peficitinib合成工艺，使Peficitinib的合成可以达到工业化生产。目标化合物及中间体的结构经核磁共振氢谱确证，路线总产率为32.8%。

Abstract: Peficitinib is a novel Janus kinase 1 and Janus kinase 3 inhibitor developed by Astellas, a Japanese company. Peficitinib mainly treats the moderate or severe rheumatoid arthritis with inadequate response to methotrexate. At present, there are very few papers on the synthesis route of Pefi-citinib. In this paper, a complete synthesis route is designed, and then each step of the reaction is studied and optimized. Starting from 7-azindole, the target compound was obtained through seven steps including halogenation, substitution (upper protection), esterification, deprotection, ester hydrolysis, amidation and then substitution. By providing catalyst or changing other reaction con-ditions such as solvent, temperature and molar ratio of reactants, a reasonable route, high yield, short time and simple operation of Peficitinib synthesis process was successfully obtained, and the synthesis of Peficitinib can reach industrial production. The structures of the target compounds and intermediates were confirmed by 1H NMR, and the total yield of the route was 32.8%.