多替拉韦关键中间体的合成工艺优化  

Optimized Process of Dolutegravir Intermediate

作　　者：樊印波 韩永飞 苏枫 冯祥龙 王世辉 FAN Yin-bo;HAN Yong-fei;SU Feng;FENG Xiang-long;WANG Shi-hui(Ningbo Nuobai Pharmaceutical Co.,Ltd.,Ningbo 315000,China;Zhejiang Langhua Pharmaceutical Co.,Ltd.,Taizhou 318000,China)

机构地区：[1]宁波诺柏医药有限公司,浙江宁波315000 [2]浙江朗华制药有限公司,浙江台州318000

出　　处：《精细化工中间体》2021年第1期15-18,22,共5页Fine Chemical Intermediates

摘　　要：以4-甲氧基乙酰乙酸甲酯为起始原料,经N,N-二甲基甲酰胺-二甲基羧醛(DMF-DMA)缩合、氨基乙醛缩二甲醇取代后,与草酸二甲酯在甲醇钠催化下环合,最后在氢氧化锂甲醇溶液中经单酯水解得多替拉韦关键中间体1-(2,2-二甲氧基乙基)-5-甲氧基-6-甲氧羰基-4-氧代-1,4-二氢吡啶-3-羧酸粗品,经乙酸乙酯/正庚烷重结晶纯化后纯度达到99.9%,优化后的4步总收率为60.5%。同时制备了工艺中产生的双水解杂质A,并对其进行了MS、NMR确证。The key intermediate of Dolutegravir,1-(2,2-dimethoxyethyl)-5-methoxyl-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid was prepared through a four-step process including DMF-DMA condensation reaction,substitution reaction with 2,2-dimethoxyethylamine,cyclization with dimethyl oxalate,and finally mono-hydrolysis using Li OH,recrystallization from EA/heptane system with a purity of 99.9%and a total molar yield of 60.5%.Meanwhile,the impurity IMP-A from hydrolysis was identified using MS and NMR.

关 键 词：多替拉韦关键中间体 工艺优化 合成 杂质 

分 类 号：TQ460.6[化学工程—制药化工]