PROCESS FOR MAKING CGRP RECEPTOR ANTAGONISTS

摘要

The disclosure encompasses a novel process for making piperidinone carboxamide indane and azainane derivatives, having less steps and improved yields as compared to previous synthetic methods for making these compounds, which are CGRP receptor antagonists, useful for the treatment of migraine. Conditions for an amide bond formation between an acid and amine include for example reacting the compounds of Formulae B (after salt break) and C with an amide coupling reagent and optionally an additive and an acid and/or a base in a non-reactive solvent.

主权项

1. A process for making a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein: X is selected from —C(R3)═ or —N═, wherein R3 is hydrogen, F or CN; Y is CH or N; R1 is selected from the group consisting of: C1-4alkyl, cyclopropylmethyl, cyclobutylmethyl and [1-(trifluoromethyl)cyclopropyl]methyl, each of which is optionally substituted with one or more substituents as allowed by valence independently selected from the group consisting of: F and hydroxy; and R2 is selected from hydrogen, methyl, F, Cl, or Br; comprising crystallizing the Formula A in the presence of an arylaldehyde derivative and a first acid in a first organic solvent to yield the compound of Formula B optionally as a salt, and coupling the compound of Formula B with a compound of Formula C or a salt thereof, under conditions for an amide bond formation between an acid and an amine to yield a compound of Formula I.