Multikilogram synthesis of a potent dual Bcl-2 / Bcl-xL antagonist. Part I. Manufacture of the acid moiety and development of some key reactions

Our efforts towards the process development of drug candidate 1 are described in a series of two papers. This manuscript focusses on the synthesis of kilogram quantities of acid precursor 2 originally followed 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.