filgotinib合成工艺的改进  

Improvement of filgotinib synthesis

作　　者：黄林峰 梁妍 钟山裕 董开心 陈梦雅 许军[1] 刘燕华[1] HUANG Lin-feng;LIANG Yan;ZHONG Shan-yu;DONG Kai-xin;CHEN Meng-ya;XU Jun;LIU Yan-hua(School of Pharmacy y Jiangxi UniversUy of Traditional Chinese Medicine,Nanchang 330004,China;School of Pharmacy,Hubei University of Science and Technology,,Xianning 437100,China)

机构地区：[1]江西中医药大学药学院,南昌330004 [2]湖北科技学院药学院,咸宁437100

出　　处：《中国新药杂志》2020年第19期2239-2243,共5页Chinese Journal of New Drugs

基　　金：国家自然科学基金项目(81573344)。

摘　　要：目的:改进filgotinib的合成工艺。方法:以2-氨基-6-溴吡啶为原料,依次经缩合、环合、酰胺化反应得到中间体N-(5-溴-[1,2,4]三唑并[1,5-a]吡啶-2-基)环丙基甲酰胺(3);以4-(4,4,5,5-四甲-1,3,2-二氧杂硼烷-二基)甲苯为起始原料,依次经溴化、亲核取代反应得到中间体4-[4-(4,4,5,5-四甲基[1,3,2]二氧硼杂环戊烷-2-基)苄基]硫代吗啉-1,1-二氧化物(5);中间体3和中间体5通过Suzuki反应合成目标化合物filgotinib。结果:目标产物结构经核磁共振氢谱(1H nuclear magnetic resonance,1H-NMR)和电喷雾电离质谱(electrospray ionization mass spectrometry,ESI-MS)确证,总收率为57.4%(以6-氨基-2-溴吡啶计),纯度达98%。结论:优化后的合成工艺成本低廉、操作简便、总收率高,可为工业化生产提供参考。Objective:To improve the synthesis process of filgotinib.Methods:Starting from 2-amino-6-bromopyridine,the key intermediate N-(5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropyl carboxamide(3)was synthesized by condensation,cyclization and amidation reaction.The key intermediate 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)thiomorpholine-1,1-dioxide(5)was prepared starting from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)toluene by bromination and nucleophilic substitution reaction;The filgotinib was synthesized using intermediates 3 and 5 via Suzuki reaction.Results:The structure of the target product and some intermediates were verified by^1H-NMR and ESI-MS.The overall yield was 57.4%(calculated from 6-amino-2-bromopyridine),and its purity was 98%.Conclusion:The improved synthetic process is cost-effective,convenient with higher yield,which can provide the foundation for commercial production.

关 键 词：2-氨基-6-溴吡啶 filgotinib 合成 工艺改进 

分 类 号：R914.5[医药卫生—药物化学]