多替拉韦手性杂质的合成与结构确证

Synthesis and identification of dolutegravir chiral impurities

目的为了对多替拉韦原料药及制剂产品进行质量控制,合成了3个多替拉韦手性杂质。方法以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-羧酸为起始原料,经水解、环合、缩合、脱甲基反应制备出对映异构体杂质A;经缩合、水解反应制备关键中间体9,采用不同构型的氨基丁醇试剂,经环合、水解、缩合、脱甲基反应分别制备得到非对映异构体杂质B和C。结果与结论合成的3个手性杂质的结构经过ESI-MS、^(1)H-NMR谱确证,纯度大于98%,手性ee值为96%-99%,可满足多替拉韦手性杂质的分析方法开发要求,为多替拉韦原料药的手性杂质研究和质量控制策略提供了科学依据。

To improve the quality control upon substance and product of dolutegravir, three chiral impurities should be obtained.Starting with 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid, the enantiomer impurity A was obtained after hydrolysis, cyclization, condensation and methyl removal reactions.Key intermediate 9 could be prepared by condensation and hydrolysis, then cyclizaiton, hydrolysis, condensation and methyl removal reactions to give two diastereoisomer impurities B and C with different amino butanol reagents.Three impurities were all confirmed with MS and NMR.The purities were all above 98%,and the values of ee were in the range of 96%-99%.Those impurities met the requirement of analysis method development, and provided scientific support for impurity study and control strategy of dolutegravir.