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

作　　者：陈道鹏[1,2] 金鑫 高梓真 杨相平[1,2] 许向阳 CHEN Daopeng;JIN Xin;GAO Zizhen;YANG Xiangping;XU Xiangyang(Jiangsu Nhwa Pharma.Corp.,Xuzhou 221116;Jiangsu Key Lab.of Central Nervous System Drug Research and Development,Xuzhou 221116)

机构地区：[1]江苏恩华药业股份有限公司,江苏徐州221116 [2]江苏省中枢神经药物研究重点实验室,江苏徐州221116

出　　处：《中国医药工业杂志》2023年第4期528-532,共5页Chinese Journal of Pharmaceuticals

基　　金：江苏省中枢神经药物研究重点实验室资助项目(BM2019004)。

摘　　要：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.

关 键 词：咪达唑仑 有关物质 合成 结构确证 

分 类 号：TQ460.6[化学工程—制药化工]