ALK抑制剂brigatinib的合成工艺改进

Improved synthesis of ALK inhibitor brigatinib

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。

An optimal process has been developed after summarizing all the synthetic methods of brigatinib reported in literatures and combining with a large number of experiments explored by the authors. Starting from 5-fluoro-2-nitroanisole,the key intermediate 5 was synthesized by substitution,reductive amination and reduction reaction. The key intermediate 9 was prepared starting from diethyl phosphite,followed by Grignard reaction,coupling and substitution reaction. The intermediates 5 was condensed with 9,followed by substitution to obtain brigatinib. This paper emphasized on optimizing the synthesis process of intermediates 4and 7,which led to reducing the production cost greatly. The yield and purity of the target product had been improved significantly. The total yield of brigatinib was 37. 3%（ calculated from diethyl phosphite） and its purity was 99. 9% determined by HPLC. The structures of the target compound and some intermediates were characterized by ~1H-NMR,^（13）C-NMR and MS.