利培酮的绿色合成工艺研究进展

Research Progress on Green Synthesis of Risperidone

归纳了目前利培酮的合成方法,通过对利培酮的逆合成分析,得到2种利培酮的分子断裂方式,在位置1断裂的2种分子结构更容易合成,而从位置2、3断裂的2种分子结构不易再进行拆分合成,且合成方案不适合工业生产。位置1断裂的合成路线主要有2条:路线1,由中间体3-(2-氯乙基)-6,7,8,9-四氢-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮和6-氟-3-(4-哌啶基)-1,2-苯并异噁唑盐酸盐缩合生成利培酮,总收率25.9%;路线2,由中间体2-(2-甲基-4-氧代-6,7,8,9-四氢-4H-吡啶基[1,2-a]嘧啶-3-基)乙醛和6-氟-3-(4-哌啶基)-1,2-苯并异噁唑还原胺化合成,总收率5.0%。因此,路线1较适合工业化生产。

The current synthesis methods of risperidone are summarized.Through the reverse synthesis analysis of risperidone,two molecular fracture modes of risperidone are obtained.The two molecular structures broken at position 1 are easier to synthesize,while the two molecular structures broken from position 2 and position 3 are not easy to be separated and synthesized,and the synthesis scheme is not suitable for industrial production.There are two main synthetic routes for the cleavage of position 1:route 1,Risperidone was synthesized by condensation of intermediate 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one and 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole hydrochloride,with an overall yield of 25.9%;route 2 was synthesized by reductive amination of intermediate 2-(2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyridyl[1,2-a]pyrimidin-3-yl)acetaldehyde and 6-fluoro-3-(4-piperidinyl)-1,2-benzoisoxazole with an overall yield of 5.0%.Therefore,route 1 is more suitable for industrial production.