PI3K/mTOR双重抑制剂NVP-BEZ235的合成  

Synthesis of PI3K/mTOR Dual Inhibitor NVP-BEZ235

作　　者：雷飞[1] 王林啸 欧阳宜强 郑鹏武[1] 朱五福[1] 

机构地区：[1]江西科技师范大学药学院,江西南昌330013

出　　处：《中国医药工业杂志》2016年第2期135-139,共5页Chinese Journal of Pharmaceuticals

基　　金：国家自然科学基金项目(81460527);江西省自然科学基金项目(20142BAB215020)

摘　　要：丙二酸环异丙酯依次与原甲酸三乙酯和对溴苯胺缩合、环合、硝化、氯代生成3-硝基-4-氯-6-溴喹啉（7）。对硝基苯乙腈与碘甲烷经烷基化、还原生成2-（4-氨基苯基）-2-甲基丙腈（10）,与7发生取代反应,得到2-[4-[（6-溴-3-硝基喹啉-4-基）氨基]苯基]-2-甲基丙腈,再经还原、环合、甲基化、Suzuki偶联反应制得PI3K/m TOR双重抑制剂NVP-BEZ235,总收率为6%（以丙二酸环异丙酯计算）,纯度为99.1%,并经~1H NMR、MS确证结构。该路线原料价廉易得、操作简便、反应条件温和,适合较大规模制备。6-Bromo-4-chloro-3-nitroquinoline（7） was synthesized from 2,2-dimethyl-1,3-dioxane-4,6-dione by substitution with triethoxymethane, condensation with 4-bromoaniline, cyclization, nitrification and chlorination. NVP-BEZ235, the PI3K/mTOR inhibitor, was synthesized from 2-（4-nitrophenyl）acetonitrile via alkylation with iodomethane and reduction to give 2-（4-aminophenyl）-2-methylpropanenitrile（10）, followed by substitution with 7 to obtain 2-[4-[（6-bromo-3-nitroquinolin-4-yl）amino]phenyl]-2-methylpropanenitrile, which was subjected to reduction, cyclization, alkylation and Suzuki-coupling reaction with an overall yield of 6%（based on 2,2-dimethyl-1,3-dioxane-4,6-dione） and purity of 99.1%. The structure of the target product was confirmed by ~1H NMR and MS. This method started with cheap raw materials was of simple experimental operation and mild reaction conditions. It was suitable for largescale pilot study.

关 键 词：PI3K/mTOR双重抑制剂 NVP-BEZ235 合成 工艺优化 

分 类 号：R979.19[医药卫生—药品]