来氟米特合成工艺的改进  

Improvement in Synthesizing Technology of Leflunomide

作　　者：苏国栋[1] 姜永悦[2] 吕延文[1] 

机构地区：[1]衢州学院化学与材料工程学院,浙江衢州324000 [2]上海化工研究院,上海200062

出　　处：《化工时刊》2011年第4期11-14,共4页Chemical Industry Times

基　　金：浙江省自然科学基金项目(No.Y2100908)

摘　　要：以乙酰乙酸乙酯与原甲酸三乙酯为原料,经缩合、环合得中间体5-甲基-4-异噁唑甲酸乙酯,不精馏直接将其碱水解15 min生成5-甲基-4-异噁唑甲酸,三步收率高达63.8%;再经氯化,不精制直接与对三氟甲基苯胺在乙酸乙酯溶剂中反应生成来氟米特粗品,粗品以乙酸乙酯为溶剂进行精制得高品质产品,经HPLC测量产品含量达99.97%,异构体含量小于0.01%;全程总收率达41.0%,收率提高了8.7%。同时,各步反应的投料比得到优化,反应时间大大缩短,合成更安全环保,成本更低。5-Methylisoxazole-4-carboxylic acid ethyl ester,a drug intermediate of leflunomide,was synthesized from ethyl acetoacetate and triethoxy methane from ate by condensation and cyclization,and the ester was hydrolyzed by alkali without rectify to 5-Methylisoxazole-4-carboxylic acid,the yield was 63.8%;The acyl chloride of the acid reacted with p-trifluorom ethylaniline to leflunomide,the crude product was refined by acetic ether to high quality leflunomide,which content is 99.97%,and the content of isomer was less than 0.01%;The total yield was 41.0%,and improved 8.7%.At the same time,the mole ratio was optimized,the reaction was shorted,the synthesis was more safe and more Environment Protection,and the cost was lower.

关 键 词：来氟米特 乙酰乙酸乙酯 原甲酸三乙酯 合成 改进 

分 类 号：TQ463[化学工程—制药化工]