艾司奥美拉唑钠两种砜类杂质的一锅法合成研究

One-pot synthesis of two sulfone impurities in esomeprazole sodium

目的合成艾司奥美拉唑钠两个砜杂质,加强其质量控制。方法以2-氯甲基-3,5-二甲基-4-甲氧基吡啶盐酸盐和2-巯基-5-甲氧基苯并咪唑为起始原料,通过一锅法同时合成艾司奥美拉唑钠的两个砜类杂质:5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-2-吡啶基)甲基]磺酰基]-1H-苯并咪唑(收率为49%)和5-甲氧基-2-[[(4-甲氧基-3,5-二甲基-1-氧代-2-吡啶基)甲基]磺酰基]-1H-苯并咪唑(收率为46%),总收率为95%。结果与结论两个杂质的结构经质谱、核磁共振氢谱确证,纯度均高于99.8%,可作为艾司奥美拉唑钠原料药和制剂研究质量控制的标准品。本工艺采用一锅法同时合成两种砜类杂质,该法操作简单、条件温和、纯度高、收率高、成本低。

Esomeprazole sodium is a new generation of proton pump inhibitor drugs.To enhance the quality control of esomeprazole products,two high purity impurities synthesized by one-pot method were studied.The 2-chloromethyl-3,5-dimethyl-4-methoxy pyridine hydrochloride and 2-mercapto-5-methoxy benzimidazole were used as raw materials to synthesize 6-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfonyl]-1H-benzimidazole(1)and 6-methoxy-2-[(4-methoxy-3,5-dimethyl-1-oxidopyridin-1-ium-2-yl)methylsulfonyl]-1H-benzimidazole(2).The structure of the two impurities was confirmed by ESI-MS and 1H-MNR with purity higher than 99.8%,which can be used as a standard for the quality control of esomeprazole sodium.In this experiment,one-pot method was used to synthesize two impurities with high purity at the same time.The method has the advantages of simple operation,mild conditions,high yield,high purity and low cost.