Development of an Improved Route for the Synthesis of an Abemaciclib Intermediate

A new synthesis for an intermediate of abemaciclib is described. Keys to this route are the use of inexpensive starting materials, biphasic amine alkylation for mild C–N bond formation, anhydrous coupling of a 2-chloropyridine derivative with LiHMDS to avoid a hydroxy impurity, and neutral, fluoride-free conditions to affect desilylation. Scale-up of the optimized conditions are described on a kilogram scale.