雷贝拉唑钠混合体系合成工艺的研究

Study on the Synthesis Process of Rabeprazole Sodium Mixed System

目的建立混合体系合成雷贝拉唑钠的新方法并对新方法进行优化。方法以2-氯甲基-4-(3-甲氧基丙氧基)-3-甲基吡啶盐酸盐(简称SM1)和2-巯基苯并咪唑(简称SM2)为原料,依据Williamson醚的合成工艺,首先将SM2与氢氧化钠溶液反应得到2-巯基苯并咪唑钠,增强其化学反应活性,接着将SM1与2-巯基苯并咪唑离子在水-乙醇、乙酸乙酯的混合系统中进行化学反应,制得雷贝拉唑硫醚,然后将雷贝拉唑硫醚用二氧化氯氧化制得雷贝拉唑钠粗品,再用重结晶法制备出高纯度的雷贝拉唑钠。结果制备得到的雷贝拉唑钠纯度大于99.7%,收率超过85%,有关物质的总量不大于0.2%,单个杂质不超过0.1%。结论本工艺生产步骤相对较少,减少了其他溶剂的使用,明显降低了生产成本,适合工业化生产,所得产物收率更高,纯度也更高,质量稳定性更好。

Objective:To establish a new one-step synthesis process for rabeprazole sodium and optimize the new process.Methods:The 2-chloromethyl-4-(3-methoxypropoxy)-3-methyl pyridine hydrochloride(SM1 for short)and 2-mercaptobenzimidazole(SM2 for short)are the raw materials.According to the synthesis process of Williamson ether,SM2 was first reacted with sodium hydroxide solution to obtain 2-mercaptobenzimidazole sodium,which enhanced its chemical reactivity,and then SM1 was chemically reacted with 2-mercaptobenzimidazole ion in a mixed system of water ethanol and ethyl acetate to prepare rabeprazole sulfide.Raw rabeprazole sodium was prepared by oxidizing rabeprazole sulfide with chlorine dioxide,and then high-purity rabeprazole sodium was prepared by recrystallization method.Results:The purity of the prepared rabeprazole sodium was over 99.7%,the yield was over 85%,the total amount of related substances was not more than 0.2%,and the single impurity was not more than 0.1%.Conclusion:This method with relatively fewer production steps,reduces the use of other solvents,and significantly reduces production costs.It is suitable for industrial production.The obtained products have higher yield,purity,and quality stability.