依匹哌唑的合成工艺研究  

Study on The Synthetic Process of Brexpiprazole

作　　者：彭子祥 刘丹 王瑶琼 刘进兵 PENG Zixiang;LIU Dan;WANG Yaoqiong;LIU Jinbing(School of Food and Chemical Engineering,Shaoyang University,Shaoyang 422099,China)

机构地区：[1]邵阳学院食品与化学工程学院,湖南邵阳422099

出　　处：《合成化学》2022年第11期902-908,共7页Chinese Journal of Synthetic Chemistry

基　　金：湖南省教育厅项目(19C1632);邵阳学院-华润双鹤校企合作项目(2021hx43)。

摘　　要：依匹哌唑是首个治疗精神分裂症的多巴胺、部分5-HT1A受体激动剂和5-HT2A受体拮抗剂类化合物,然而其目前的生产路线存在成本高、收率低等缺点。本文在文献方法的基础上,设计了一条合成依匹哌唑的新路线:以4-取代丁腈和7-羟基喹啉-2-(1H)酮为起始原料,经氧烃基化反应得醚化物1,将醚化物1氰基还原得到氨基物2,氨基物2与Boc-双氯乙基亚胺关环得环合物3,环合物3经脱保护得化合物4,化合物4与4-溴苯并噻吩反应得到目标产物依匹哌唑。采用核磁共振和质谱确证了中间体和目标产物的结构,目标产物纯度高达99.30%,且此合成路线具有操作简单、反应易控、原料易得、产物易分离以及环境友好等优点。Brexpiprazole is the first dopamine, partial 5-HT1A receptor agonist and 5-HT2A receptor antagonist for the treatment of schizophrenia. However, the current production route of Brexpiprazole has defects such as high cost and low yield. In this paper, on basis of literature methods, a new synthetic route of Brexpiprazole was designed: Compound 1 was synthesized by the etherification reaction of 4-substituted nitrile with 7-hydroxyquinoline-2-(1H) ketone. The cyano group of compound 1 was reduced to obtain amino compound 2, then compound 2 was cyclized with Boc-dichloroethyl imine to get the cyclic compound 3. The cyclic compound 3 was deprotected to obtain the compound 4. The Brexpiprazole was obtained by the reaction of compound 4 with 4-bromobenzothiophene. Structures of intermediates and target compound were confirmed by NMR and MS. The purity of target product reached 99.3%. The synthetic route has advantages such as simple operation, easy control, commercially availability of starting materials, easy separation, environmental friendliness.

关 键 词：依匹哌唑 精神分裂症 合成 工艺改进 丁腈 喹啉 关环反应 

分 类 号：R914.5[医药卫生—药物化学]