阿托吉泮的合成研究进展

Research progress in synthesis of atogepant

阿托吉泮是一种降钙素基因相关肽受体拮抗剂,也是全球首个用于预防性治疗成人偏头痛的口服药物。阿托吉泮由氨基哌啶酮衍生物(2)和羧酸化合物(3)两个关键手性中间体经缩合反应制备。根据起始原料和合成工艺的不同分别综述了这2个中间体的合成路线。已报道的合成路线均是以手性拆分的方法来分别得到2和3,其中中间体2的5种合成路线中,较优的路线Ⅴ以手性拆分试剂进行拆分,中间体3的3种合成路线中,较优的路线III虽原料廉价易得,反应收率较高,但多次使用格氏反应对设备和操作条件要求较高。中间体2和3的不对称合成方法和合成工艺研究,以及阿托吉泮连续流合成工艺研究将是提高该药物合成工艺的安全性和收率的重要研究方向。

Atogepant,a calcitonin gene-related peptide receptor antagonist,is the first oral drug in the world for the prophylactic treatment of migraines in adults.It is prepared by the condensation reaction of two key chiral intermediates,an amino-piperidone derivative(Intermediate 2)and a carboxylic acid(Intermediate 3).The synthetic routes of these two intermediates are reviewed based on different starting materials and synthetic processes.All reported synthetic routes use chiral resolution methods;among the five synthetic routes of Intermediate 2,the optimal route V uses chiral resolution reagents;among the three synthetic routes of Intermediate 3,although the optimal route III uses cheap and readily available raw materials and has a high yield,the repeated use of the Grignard reaction requires more robust equipment and harsh operating conditions.The asymmetric synthesis methods and synthetic process research of these two intermediates,as well as the continuous flow synthesis process research of atogepant,will be important directions to improve the safety and yield of the synthetic process of this drug.