Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl‑xL Antagonist. 2. Manufacture of the 1,3-Diamine Moiety and Improvement of the Final Coupling Reaction

This paper describes the synthesis of kilogram quantities of the sulfonamide moiety 3 involved in a coupling reaction with acid moiety 2 to provide batches of drug candidate 1 for preclinical studies and first-in-human clinical trials. A first approach relying on a chiral separation furnished the de...

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Veröffentlicht in:Organic process research & development 2020-05, Vol.24 (5), p.670-685
Hauptverfasser: Hardouin, Christophe, Baillard, Sandrine, Barière, François, Craquelin, Anthony, Grandjean, Mathieu, Janvier, Solenn, Le Roux, Stéphane, Penloup, Christine, Russo, Olivier
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container_issue 5
container_start_page 670
container_title Organic process research & development
container_volume 24
creator Hardouin, Christophe
Baillard, Sandrine
Barière, François
Craquelin, Anthony
Grandjean, Mathieu
Janvier, Solenn
Le Roux, Stéphane
Penloup, Christine
Russo, Olivier
description This paper describes the synthesis of kilogram quantities of the sulfonamide moiety 3 involved in a coupling reaction with acid moiety 2 to provide batches of drug candidate 1 for preclinical studies and first-in-human clinical trials. A first approach relying on a chiral separation furnished the desired enantiomer of 1,3-diamine 20, precursor of sulfonamide 3. An enantiomeric synthesis of 20 using the Ellman’s chiral auxiliary coupled with an aza-Reformatsky reaction to control the stereochemistry is also discussed. Coupling conditions of the final step involving EDCI to provide 1 under a cGMP process are detailed. An alternative approach using N-(1-methanesulfonyl)­benzotriazole is also presented.
doi_str_mv 10.1021/acs.oprd.9b00367
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title Multikilogram Synthesis of a Potent Dual Bcl-2/Bcl‑xL Antagonist. 2. Manufacture of the 1,3-Diamine Moiety and Improvement of the Final Coupling Reaction
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