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目的对ALK抑制剂brigatinib(AP-26113)的合成工艺进行优化。方法以5-氟-2-硝基苯甲醚为原料,依次经取代、还原胺化、还原反应得到中间体2-甲氧基-4-[4-(4-甲基哌嗪-1-基)哌啶-1-基]苯胺(5);以亚磷酸二乙酯为起始原料,依次经格氏反应、偶联、取代反应得到中间体2,5-二氯-N-(2-(二甲基亚膦酰基)苯基)嘧啶-4-胺(9);中间体5与9经取代反应得到目标产物brigatinib。结果与结论目标化合物的结构经MS、~1H-NMR和~(13)C-NMR确证。总收率为37.3%(以亚磷酸二乙酯计),纯度为99.9%(HPLC法)。优化后的工艺路线所用原料廉价易得、操作简便、条件温和、收率较高,可为工业化生产提供参考。
Objective To optimize the synthesis of ALK inhibitor brigatinib (AP-26113). Methods Starting from 5-fluoro-2-nitroanisole and subsequent reduction, reductive amination and reduction, the intermediate 2-methoxy-4- [4- Yl) piperidine-1-yl] aniline (5); Diethyl phosphite as the starting material, followed by Grignard reaction, coupling, substitution reaction to give the intermediate 2,5-dichloro-N- - (dimethylphosphono) phenyl) pyrimidin-4-amine (9); the intermediate 5 and 9 were substituted to give the target product brigatinib. Results and Conclusions The structures of the target compounds were confirmed by MS, 1H-NMR and 13C-NMR. The overall yield was 37.3% (as diethyl phosphite) with a purity of 99.9% (HPLC method). The optimized raw materials used in the process route are cheap, easy to operate, mild in conditions and high in yield, which can provide reference for industrialized production.