目的:对格列美脲中间体4-[2-（3- 乙基-4- 甲基-2- 氧代-3- 吡咯啉-1- 甲酰胺基）乙基]- 苯磺酰胺（BHXA）在相对保留时间（RRT）1.08 和1.46 处的2 个较大杂质进行分离、鉴别。方法:采用高效制备型高效液相色谱（Prep-HPLC）对BHXA 的杂质进行分离, 通过核磁（1H-NMR、13C-NMR）和质谱（MS）进行结构分析和鉴定, 并进一步使用3-[2-（3- 乙基-4- 甲基-2- 氧代-3- 吡咯啉-1- 甲酰胺基）乙基]-苯磺酰胺和2-[2-（3- 乙基-4- 甲基-2- 氧代-3- 吡咯啉-1- 甲酰胺基）乙基]- 苯磺酰胺对照品进行了定性。结果:这2 个杂质为BHXA 合成过程中的异构副产物, 其化学名为3-[2-（3- 乙基-4- 甲基-2- 氧代-3- 吡咯啉-1- 甲酰胺基）乙基]- 苯磺酰胺（杂质Ⅰ）和2-[2-（3- 乙基-4- 甲基-2- 氧代-3- 吡咯啉-1- 甲酰胺基）乙基]- 苯磺酰胺（杂质Ⅱ）。结论:这2 个杂质与BHXA 结构极其相似, 根据其反应机理, 它们可以和BHXA 一起参与下一步反应, 得到格列美脲欧洲药典（EP）中的杂质D 和杂质I, 对格列美脲的药效和安全性会产生一定的影响。通过本研究, 可以在BHXA 合成过程中优化合成条件, 减少这2 个杂质的生成, 达到提前控制格列美脲成品中EP 杂质D 和杂质I 含量的目的, 以提高用药的安全性和有效性。
Objective：To separate and identify the two major impurities in glimepiride intermediate 4-[2-(3-ethyl-4-methyl-2-oxo-3-pyrrolin-1-formamido)ethyl]-benzene sulfonamide(BHXA), at the relative retention time(RRT)of 1.08 and 1.46. Methods：The impurities in BHXA were isolated by preparative high performance liquid chromatography(Prep-HPLC)and their structures were analyzed and identified by nuclear magnetic resonance(1H-NMR, 13C-NMR)and mass spectrometry(MS). The impurities were further identified by using the standard substance of 3-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzene sulfonamide and 2-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzene sulfonamide. Results：These two impurities were isomeric by-products in the synthesis of BHXA, and their structures were 3-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzene sulfonamide(impurity Ⅰ)and 2-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)ethyl]-benzene sulfonamide(impurity Ⅱ). Conclusion：These two impurities are very similar to the structure of BHXA. According to their reaction mechanism, these two impurities can participate in the next reaction together with BHXA to obtain the impurities D and I in glimepiride European Pharmacopoeia(EP), which will have a certain impact on the efficacy and safety of glimepiride. Through this study, the generation of these two impurities can be reduced by optimizing the synthesis conditions of BHXA, which can achieve the goal of controlling the content of EP impurities D and I in glimepiride in advance, so as to improve the safety and effectiveness of glimepiride.
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