Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl‑xL 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 o...

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Bibliographic Details
Published in:Organic process research & development 2020-05, Vol.24 (5), p.652-669
Main Authors: Hardouin, Christophe, Baillard, Sandrine, Barière, François, Copin, Chloé, Craquelin, Anthony, Janvier, Solenn, Lemaitre, Sylvain, Le Roux, Stéphane, Russo, Olivier, Samson, Sébastien
Format: Article
Language:English
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Summary: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.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.9b00364