吉美嘧啶的工业化合成工艺  

Industrial Synthetic Process of Gimeracil

作　　者：张乃华 马永杰 鲍广龙 孙彦云 张贵民 ZHANG Naihua;MA Yongjie;BAO Guanglong;SUN Yanyun;ZHANG Guimin(National Engineering and Technology Research Center of Chirality Pharmaceutical,Shandong New Time Pharmaceutical Co.,Ltd.,Linyi 273400)

机构地区：[1]山东新时代药业有限公司,国家手性制药工程技术研究中心,山东临沂273400

出　　处：《中国医药工业杂志》2022年第1期65-68,共4页Chinese Journal of Pharmaceuticals

摘　　要：以丙二腈(2)和原乙酸三甲酯为起始物料,先制得2-(1-甲氧基亚乙基)丙二腈(3)后再与原甲酸三乙酯反应生成1,1-二氰基-2-甲氧基-4-乙氧基-1,3-丁二烯(4),4经80%冰乙酸环合得3-氰基-4-甲氧基-2(1H)-吡啶酮(5),5经磺酰氯氯代生成5-氯-3-氰基-4-甲氧基-2(1H)-吡啶酮(6),最后6经30%硫酸水解得吉美嘧啶(1),液相纯度>99.88%,总收率62%(以2计)。其中,由化合物4制备5的方法未见文献报道。改进后的合成工艺收率稳定,操作简便,适合工业化生产。An improved synthetic process of gimeracil(1) was developed.Starting materials malononitrile (2) and trimethyl orthoacetate were condensed to deliver 2-(1-methoxyethylidene)malononitrile(3),which was in turn reacted with triethyl orthoformate to produce 1,1-dicyano-2-methoxy-4-ethoxy-1,3-butadiene(4).Intramolecular cyclization of 4 in 80% aqueous acetic acid proceeded smoothly to afford 3-cyano-4-methoxy-2(1H)-pyridone(5),which was subjected to sulfonyl chloride to generate 5-chloro-3-cyano-4-methoxy-2(1H)-pyridone(6).Finally,6 on exposure to 30% aqueous sulfuric acid was transformed into the target compound 1 with an overall yield of 62%(based on 2) and an HPLC purity of 99.88%.The synthetic method for 5 from 4 has not yet been reported in literature.The optimized synthetic process was more stable and operationally simpler,which was suitable for industrial production.

关 键 词：吉美嘧啶 二氢嘧啶脱氢酶抑制剂 合成工艺 

分 类 号：R979.19[医药卫生—药品] TQ463.54[医药卫生—药学]