Development of a Scalable Strategy for the Synthesis of PI3Kδ Inhibitors: Selective and Efficient Functionalization of Purine Derivatives

The first-generation development route used to prepare the PI3K delta inhibitor GNE-293 (3) for early toxicology studies is described. Through the use of a metal-free SNAr reaction in place of a Pd-catalyzed C-N coupling, the synthesis was both simplified and made more reproducible in preparation for scale-up by reducing the number of operations required for purification and eliminating the need for column chromatography. The utility of the recently developed reagent TMPZnCl center dot LiCl is highlighted by a novel method of iodination to access the key aryl halide intermediate.