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

Article abstract of DOI:10.1021/acs.oprd.7b00234

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.