Synthesis of Lenacapavir Sodium: Active Pharmaceutical Ingredient Process Development and Scale-up

Lenacapavir sodium (GS-6207-02) is a first-in-class HIV capsid inhibitor. Process development of the four-step final assembly of lenacapavir sodium from four synthetic intermediates is described here. A bis-bromopyridine core is sequentially subjected to an alkynylation, an amide coupling with a chi...

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Bibliographic Details
Published in:Organic process research & development 2024-08, Vol.28 (8), p.3382-3395
Main Authors: Wagner, Anna M., Bonderoff, Sara A., Chang, Stanley, Deignan, Jeffrey, Esanu, Michelle M., Van Huynh, Huy, Niu, Tianmin, Ngo, Vinh, O’Keefe, B. Michael, Phoenix, Jenny, Rainey, Trevor J., Roberts, Benjamin J., Shen, Jinyu, Stewart, Craig, Vandehey, Amanda L., Wolckenhauer, Scott A., Wong, Chloe Y., Yarmuch, Brian H.
Format: Article
Language:English
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Summary:Lenacapavir sodium (GS-6207-02) is a first-in-class HIV capsid inhibitor. Process development of the four-step final assembly of lenacapavir sodium from four synthetic intermediates is described here. A bis-bromopyridine core is sequentially subjected to an alkynylation, an amide coupling with a chiral pyrazole carboxylic acid, and a Suzuki cross-coupling with an indazole boronic ester. The final step is a telescoped bis-methanesulfonylation and hydrolysis to yield the API. This report highlights experimental work on the final assembly sequence to establish robust processing conditions, minimize process mass intensity, control impurity formation, understand impurity purge, and enable large-scale manufacturing of lenacapavir sodium.
ISSN:1083-6160
1520-586X
DOI:10.1021/acs.oprd.4c00242