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.
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