咪达唑仑原料药及其注射液中有关物质的发现和合成

Discovery and Synthesis of the Related Substances of Midazolam in the Bulk Drug and Its Injection

采用HPLC法检测出咪达唑仑原料药中的有关物质Ⅰ,且它在注射液中会逐渐转化为有关物质Ⅱ。根据LC/MS所测定的相对分子质量,推测有关物质Ⅰ为8-氯-4-乙氧基-6-(2-氟苯基)-1-甲基-4H-咪唑并[1,5-a][1,4]苯并二氮䓬,有关物质Ⅱ为1-[4-氯-2-(2-氟苯甲酰基)苯基]-2-甲基-1H-咪唑-5-甲醛,该发现为首次报道。以咪达唑仑为原料定向合成了这2个化合物,其结构均经过高分辨质谱、红外吸收光谱和核磁共振光谱确证。通过HPLC定位确认所制备的化合物即为咪达唑仑原料药和注射液中的有关物质Ⅰ和有关物质Ⅱ。

The related substanceⅠwas detected by HPLC in midazolam,and it was found that the related substanceⅠgradually transformed into the related substanceⅡin the injection.According to the relative molecular weight determined by LC/MS,it was speculated that the related substanceⅠshould be 8-chloro-4-ethoxy-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine,and the related substanceⅡshould be 1-[4-chloro-2-(2-fluorobenzoyl)phenyl]-2-methyl-1H-imidazole-5-carbaldehyde.This discovery was reported unprecedentedly.These two compounds were synthesized with midazolam as the starting material.Their structures had been confirmed by ESI-HRMS,IR and NMR.The prepared compounds were in consistence with the related substancesⅠandⅡin the midazolam bulk drug and its injection by HPLC.