4,6-二氯-2-甲基嘧啶的合成工艺研究

4,6-二氯-2-甲基嘧啶是合成抗癌药物达沙替尼的重要中间体.以乙脒盐酸盐和丙二酸二甲酯为原料经过环化、三氯氧磷氯化合成4,6-二氯-2-甲基嘧啶.正交试验确定合成4,6-二羟基-2-甲基嘧啶的较优工艺条件为:以甲醇为溶剂,n(乙脒盐酸盐)/n(甲醇钠)=1∶3.4,温度20℃下反应4 h,收率85.76％;正交试验确定三氯氧磷氯化的较优工艺条件为:以三氯氧磷为溶剂和氯化试剂,反应温度105℃,N,N-二乙基苯胺用量为4,6-二羟基-2-甲基嘧啶物质的量的2倍下反应4h,收率69.55％;两步总收率59.65％.

Synthesis and Process Research of 4,6-Dichloro-2-methylpyrimidine

4,6-Dichloro-2-methylpyrimidine is an important intermediate of synthetic anticancer drug dasatinib.4,6-dichloro-2-methylpyrimidine was synthesized from acetamidine hydrochloride and dimethyl malonate via the cyclization and chlorination with phosphorus oxychloride.The optimal conditions of synthesis of 4,6-dihydroxy-2-methylpyrimidine were investigated by orthogonal test.They were: n(acetamidine hydrochloride)/n(sodium methoxide)=1∶3.4,in methanol at 20℃ for 4h,the yield of 4,6-dihydroxy-2-methylpyrimidine was 85.76%.The optimal conditions of chlorination with phosphorus oxychloride were investigated by orthogonal test.They were: n(N,N-diethyl-Benzenamine)/n(4,6-dihydroxy-2-methylpyrimidine)=2∶1,in phosphorus oxychloride at 105℃ for 4h,the yield of 4,6-dichloro-2-methylpyrimidine was 69.55%,the yield of two-steps was 59.65%.