Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl‑x_L Antagonist. 1. Manufacture of the Acid Moiety and Development of Some Key Reactions

Our efforts toward the process development of drug candidate 1 are described in a series of two papers. This manuscript focuses on the synthesis of kilogram quantities of acid precursor 2 to provide batches of material for preclinical studies and first-in-human clinical trials. Our approach relies on a chiral resolution to furnish the desired stereocenter, a cryogenic carboxylation, and N-alkylation of chloride derivative 26 prepared by a Suzuki coupling. Further efforts pursued to improve those key steps that could become issues on larger scale are also discussed.