American Chemical Society
op9b00364_si_001.pdf (688.91 kB)

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

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journal contribution
posted on 2019-12-05, 01:13 authored by Christophe Hardouin, Sandrine Baillard, François Barière, Chloé Copin, Anthony Craquelin, Solenn Janvier, Sylvain Lemaitre, Stéphane Le Roux, Olivier Russo, Sébastien Samson
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.