LC-PDA-QTOF-MS联用法研究氯沙坦钾的未知工艺杂质

目的：采用LC-PDA-QTOF-MS对氯沙坦钾中工艺杂质进行结构确认及分析，并通过提高反应转化率，优化后处理操作，控制杂质含量，以提高产品质量。方法：对影响氯沙坦钾成品质量的RRT 1.12杂质，通过优化LC-MS的色谱条件，实现该杂质与主峰分离，比较其与主成分氯沙坦的一级质谱、二级质谱及紫外吸收光谱差异，结合对碎片峰进行解析和产生路径的推演，最终确认其化学结构，并通过在反应过程中加入相转移催化剂四丁基溴化铵，延长反应时间，后处理中增加碱洗操作对杂质加以控制。结果：通过LC-PDA-QTOF-MS确定氯沙坦钾成品质量的RRT 1.12杂质为氯沙坦羧酸衍生物，该杂质产生的主要原因是反应过程中关键原料氯腈进行四氮唑反应不完全，在后处理过程中水解产生的。通过添加相转移催化剂，延长反应时间，此杂质的含量明显下降，并低于最终产品的报告限度（≤0.02%）。结论：氯沙坦钾中的未知杂质源于生产工艺，应用LC-PDA-QTOF-MS方法可以快速地检测，通过在反应过程中加入相转移催化剂四丁基溴化铵，延长反应时间以及后处理中增加碱洗操作，可以控制杂质含量，提高氯沙坦钾成品的质量。

Objective: To identify and analyze the structure of the unknown process impurity by LC-PDA-QTOF-MS,and to improve the product quality by controlling the impurities with improving the reaction conversion rate and optimizing the post-treatment.Methods: The impurity with RRT 1.12 that affected quality of the final losartan potassium was well separated from the main peak by optimizing the LC-MS chromatographic conditions.The structure of impurity with RRT 1.12 was elucidated by comparing the differences between the main component losartan and impurity with RRT 1.12 using LC-MS/MS through analyzing the corresponding fragment ions and fragmentation pathways and by comparing their UV absorption spectra.The impurity was controlled by adding phase transfer catalyst,tetrabutylammonium bromide,prolonging the reaction time,and increasing the lye washing operation in the post-treatment.Results: The impurity with RRT 1.12 was identified as Losartan carboxylic acid by LC-PDA-QTOF-MS,the formation of which was due to incomplete conversion of the key raw material,the chloronitrile intermediate,to the corresponding tetrazole,followed by its hydrolysis in the post-processing.By adding phase transfer catalyst and prolonging the reaction time,this impurity was significantly decreased to lower than the reporting limit in the final product(≤ 0.02%).Conclusion: The unknown impurity with RRT 1.12 in losartan potassium is derived from the manufacturing process,which was quickly identified by LC-PDA-QTOF-MS.By adding phase transfer catalyst tetrabutylammonium bromide,prolonging the reaction time,and increasing the lye washing operation in the post-treatment,the generation of this impurity can be significantly reduced and the product quality of losartan potassium can be improved.