A Fit for Purpose Synthesis of Bruton’s Tyrosine Kinase Inhibitor GDC-0852

Abstract The development of an expedient synthesis to GDC-0852 (1), a reversible BTK inhibitor drug candidate, is described. The key starting material tricyclic lactam 5 was prepared by an annulation reaction of unprotected piperidine-2-carbaldehyde HCl salt (20) and N-Boc piperidine-2,4-dione 21 in a safe and scalable manner. A highly selective Pd-catalyzed C−N coupling of lactam 5 and linker 2a, followed by Suzuki−Miyaura coupling to fragment 8 subsequently provided a direct and convergent access to the penultimate 17. A simple NaBH4 aldehyde reduction completed the synthesis to GDC-0852 (1) in high yield (54% over 3 steps from 5) and purity (99.0 A% HPLC).