Development of a Leuckart–Wallach Reaction in Flow for the Synthesis of Abemaciclib

The development of a route for a key building block in the synthesis of abemaciclib is described. The route proceeds through a Leuckart–Wallach reductive amination in flow followed by an Ullmann amination with aqueous ammonia. Key to the Leuckart–Wallach reductive amination was the addition of trimethyl orthoformate for water removal, running the reaction continuously in a pipes-in-series reactor for rapid heat-up, and building a kinetic model to understand time and temperature parameters for the feed tank storage. The product of the Leuckart–Wallach reductive amination is forward processed in batch and telescoped with the Ullmann amination and subsequent workup. The development resulted in a robust process that has successfully been run on the production scale.