莫洛替尼合成工艺研究

Study on synthetic process of momelotinib

目的优化莫洛替尼的合成工艺。方法以对氟硝基苯为起始原料,经亲核取代和还原反应得到4-吗啉基苯胺(3);以4-乙酰基苯甲酸甲酯为起始原料,经缩合、亲核取代、分子内环合和水解反应得到关键中间体4-(2-羟基嘧啶-4-基)苯甲酸(6),6经氯代、亲核取代反应得到中间体N-(氰基甲基)-4-(2-氯嘧啶-4-基)苯甲酰胺(8);中间体3与8经偶联反应得到莫洛替尼。结果与结论目标产物结构经核磁共振谱和质谱确证,总收率为42.9%(以4-乙酰基苯甲酸甲酯计),纯度为99.58%。该路线原料易得,生产成本低,反应条件温和,中间体易分离纯化,无需使用柱色谱,更适合大规模生产。

A synthetic process of momelotinib was optimized.The starting material 4-fluronitrobenzene underwent nucleophilic substitution and reduction to give 4-morpholinylaniline(3).The key intermediate 4-(2-hydroxypyrimidin-4-yl)benzoic acid(6)was synthesized from methyl 4-acetylbenzoate by condensation,nucleophilic substitution,intra-molecular cyclization and hydrolysis reactions.Then,intermediate 6 underwent chlorination,nucleophilic substitution to give N-cyanomethyl-4-(2-chloropyrimidin-4-yl)benzamide(8).Intermediate 8 was coupled with intermediate 3 to give momelotinib.The structure of momelotinib was confirmed by MS and NMR spectra.The total yield was 42.9%(from methyl 4-acetylbenzoate)with the purity of 99.58%.The improved process have the advantages of reduced cost,milder reaction conditions and convenient reaction operation,and is suitable for large-scale preparation.