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.
出处
《中国医药工业杂志》
CAS
CSCD
北大核心
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)