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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。
Cyclopropylmalonic acid followed by triethyl orthoformate and p-bromoaniline condensation, cyclization, nitration, chlorination to generate 3-nitro-4-chloro-6-bromoquinoline (7). The p-nitrophenylacetonitrile and iodomethane are alkylated to yield 2- (4-aminophenyl) -2-methylpropionitrile (10), which undergoes a substitution reaction with 7 to give 2- [4 - [(6 Nitro-quinol-4-yl) amino] phenyl] -2-methylpropionitrile, followed by reductive, cyclisation, methylation and Suzuki coupling reactions. PI3K / m TOR double inhibition NVP-BEZ235 was obtained in a total yield of 6% (calculated as cyclopropylmalonic acid) with a purity of 99.1% and confirmed by1H NMR and MS. The route of cheap raw materials, easy to operate, mild reaction conditions, suitable for large-scale preparation.