基于双溶剂法高效合成雷贝拉唑杂质B

Synthesis of Rabeprazole Impurity B by Double-solvent Method

以2-氯甲基-3-甲基-4-(3-甲氧丙氧基)吡啶盐酸盐为起始原料通过在二氯甲烷溶剂中用m-CPBA氧化得到2-氯甲基-3-甲基-4-(3-甲氧丙氧基)吡啶氮氧化物,不分离直接在二氯甲烷-水双溶剂体系中与巯基苯并咪唑钠盐反应,反应结束直接分出硫醚中间体所在的二氯甲烷相进行最后一步m-CPBA氧化反应;粗产物通过两次丙酮重结晶可获得纯度大于97%的杂质B。

The starting material of 2-chloromethyl-3-methyl-4-( 3-methoxypropoxy) pyridine hydrochloride was oxidized to 2-chloromethyl-3-methyl-4-( 3-methoxypropoxy) pyridine N-oxide in dichloromethane( DCM) with m-CPBA as the oxidant,which directly reacted with sodium 2-mercaptobenzimidazole in a DCM-water double-solvent system to afford the sulfide intermediate. The sulfide intermediate in DCM phase was separated from the double-solvent system and then subjected to the m-CPBA oxidation to give the target impurity B. The impurity B was obtained in a HPLC purity exceeding 97% simply by recrystallization twice in acetone.