溴夫定有关物质的制备与结构鉴定

Preparation and structure identification of related substances of brivudine

目的对溴夫定合成过程中产生的两个有关物质A(5-(2,2-二溴乙烯基)-2′-脱氧尿苷)和B((E)-5-(2-碘乙烯基)-2′-脱氧尿苷)进行制备与结构鉴定。方法通过LC-MS分析,推测有关物质A和B的分子结构与产生途径。以2′-脱氧尿苷为起始原料,经碘代、偶联、水解反应制得(E)-5-(2-羧基乙烯基)-2′-脱氧尿苷,再经脱羧二溴代反应得到有关物质A;以(E)-5-(2-羧基乙烯基)-2′-脱氧尿苷经脱羧碘代反应得到有关物质B;结合HPLC定位,确定所得化合物为目标物质,进一步经LC-MS和 ^(1)H-NMR、^(13)C-NMR谱对有关物质A和B的分子结构进行确证。结果制备了2种溴夫定有关物质,其结构得到确证。结论溴夫定有关物质的制备与结构鉴定为其原料药的合成工艺优化提供方向,为原料药的质量研究提供物质基础。

Two related substances were produced during the synthesis of the antiviral drug brivudine, namely 5-(2,2-dibromo-vinyl)-2′-deoxyuridine(A) and(E)-5-(2-iodo-vinyl)-2′-deoxyuridine(B).Related substance A was obtained via iodination, coupling, hydrolysis and decarboxylation dibromide reaction from 2′-deoxyuridine, Related substance B was obtained via iodination, coupling, hydrolysis and decarboxylative Iodination reaction from 2′-deoxyuridine.The structures of A and B were characterized by LC-MS,^(1)H-NMR,^(13)C-NMR and 2D-NMR.The sources and control methods of these related substances had been studied, which provided direction for process optimization and quality controlling of brivudine API.