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 |
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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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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. 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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.</abstract><pub>American Chemical Society</pub><doi>10.1021/acs.oprd.9b00367</doi><tpages>16</tpages><orcidid>https://orcid.org/0000-0002-0438-5644</orcidid></addata></record> |
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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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