6-氟-3-(4-哌啶基)-1,2-苯并异唑盐酸盐合成工艺改进

An Improved Process of 6-Fluoro-3-(piperidin-4-yl)-1,2-benzoisoxazole Hydrochloride

本研究改进了利培酮关键中间体6-氟-3-(4-哌啶基)-1,2-苯并异唑盐酸盐的合成工艺。(2,4-二氟苯基)(4-哌啶基)-甲酮盐酸盐和盐酸羟胺加热回流12 h得(Z)-(2,4-二氟苯基)(4-哌啶基)甲酮肟,收率97%;再和氢氧化钾在水/甲苯两相溶剂中反应后,与氯化氢成盐得目标化合物。水/甲苯两相溶剂的使用,可以使终产品中二聚体杂质的含量降低至约1%。改进后的工艺操作简捷,总收率高(约80%),纯度99%,适合放大生产。

The synthesis of 6-fluoro-3-(piperidin-4-yl)-1,2-benzoisoxazole hydrochloride,a key intermediate of risperidone was improved.(2,4-Difluorophenyl)(piperidin-4-yl)methanone hydrochloride reacted with hydroxylamine hydrochloride in ethanol/H2O at reflux for 12h to afford (Z)-(2,4-difluorophenyl)(piperidin-4-yl)-methanone oxime with a yield of 97%.Then the latter was subjected to an intramolecular nucleophilic substitution with KOH in toluene/ H2O followed by a salification to produce the target compound.The result showed that,the content of dimer impurity in the final product could be reduced to 1%by using two-phase solvent (toluene/H2O).The improved process has some advantages such as simple operation,high total yield (about 80%)with a purity of 99%,which is suitable for industrial production.