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.
GAO Xiu-rui, WANG Yi-yun, XU Hao-jie, XU You-wei, SHANG Yan-mei, MENG Zi-hui
. Study on impurities in intermediate BHXA of glimepiride[J]. Chinese Journal of Pharmaceutical Analysis, 2021
, 41(8)
: 1408
-1416
.
DOI: 10.16155/j.0254-1793.2021.08.15
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