多替拉韦关键中间体的合成工艺优化

Optimized Process of Dolutegravir Intermediate

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.