摘要
改进了抗肿瘤药物恩曲替尼的合成工艺。以4-氟-2-硝基苯甲酸为起始原料,经酯化反应、亲核取代、还原、亲核加成、三氟乙酰基保护、水解后得到4-(4-甲基哌嗪-1-基)-2-[2,2,2-三氟-N-(四氢-2H-吡喃-4-基)乙酰胺基]苯甲酸。2-氟-5-溴苯腈和硼酸三甲酯发生亲核取代,再与3,5-二氟苄溴发生Suzuki偶联反应,经成环后得5-(3,5-二氟苄基)-1H-吲唑-3-胺。4-(4-甲基哌嗪-1-基)-2-[2,2,2-三氟-N-(四氢-2H-吡喃-4-基)乙酰胺基]苯甲酸与5-(3,5-二氟苄基)-1H-吲唑-3-胺发生缩合反应,再经脱三氟乙酰基得到目标化合物,纯度99.12%,总产率26.0%(以4-氟-2-硝基苯甲酸计)。相比于文献路线,合成工艺缩短了酰胺的合成步骤,进行了原工艺中价格昂贵的原料(3-氰基-4-氟苯基)硼酸的合成,节约了成本,优化了多步反应的条件及后处理方法。改进后的合成路线具有原料易得、操作简便、产率高的特点,更适合工业化生产。
The synthesis process of the antitumor drug Entrectinib has been improved.Using 4-fluoro-2-nitrobenzoic acid as the starting material,4-(4-methylpiperazin-1-yl)-2-[2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido]benzoic acid was obtained after esterification,nucleophilic substitution,reduction,nucleophilic addition,trifluoroacetyl protection,and hydrolysis.The product obtained after nucleophilic substitution of 2-fluoro-5-bromobenzonitrile and trimethyl borate was then subjected to Suzuki coupling reaction with 3,5-difluorobenzyl bromide.The product underwent ring formation to give 5-(3,5-difluorobenzyl)-1H-indazol-3-amine.4-(4-Methylpiperazin-1-yl)-2-[2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido]benzoic acid and 5-(3,5-difluorobenzyl)-1H-indazol-3-amine underwent condensation reaction to obtain the product,and then the trifluoroacetyl group was removed to obtain the target compound,purity 99.12%,total yield 26.0%(based on 4-fluoro-2-nitrobenzoic acid).Compared with the literature route,the synthesis process shortens the synthesis steps of the amide and synthesizes(3-cyano-4-fluorophenyl)boronic acid,an expensive raw material in the original process,saving costs,optimizing the conditions and post-treatment of the multi-step reaction method.The improved synthetic route has the characteristics of easy availability of raw materials,simple operation and high yield,and is more suitable for industrial production.
作者
刘彦
范为正
冯柏年
LIU Yan;FAN Wei-zheng;FENG Bai-nian(School of Pharmacy,Jiangnan University,Wuxi 214122,China)
出处
《化学试剂》
CAS
北大核心
2020年第9期1102-1107,共6页
Chemical Reagents
基金
国家级大学生创新训练计划项目(201910295050Z)
江苏省前瞻性联合研究项目(BY2015019-25)。
关键词
恩曲替尼
酪氨酸激酶抑制剂
抗肿瘤药
合成
工艺优化
Entrectinib
tyrosine kinase inhibitors
antitumor drug
synthesis
process optimization
作者简介
刘彦(1993-),女,山东临沂人,硕士生,主要从事抗肿瘤药物的合成研究;通讯作者:冯柏年,E-mail:fengbainian@jiangnan.edu.cn。
