Anna M. Wagner*, Sara A. Bonderoff, Stanley Chang, Jeffrey Deignan, Michelle M. Esanu, Huy Van Huynh, Tianmin Niu, Vinh Ngo, B. Michael O’Keefe, Jenny Phoenix, Trevor J. Rainey, Benjamin J. Roberts, Jinyu Shen, Craig Stewart, Amanda L. Vandehey, Scott A. Wolckenhauer, Chloe Y. Wong and Brian H. Yarmuch,
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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 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.
期刊介绍：
The journal Organic Process Research & Development serves as a communication tool between industrial chemists and chemists working in universities and research institutes. As such, it reports original work from the broad field of industrial process chemistry but also presents academic results that are relevant, or potentially relevant, to industrial applications. Process chemistry is the science that enables the safe, environmentally benign and ultimately economical manufacturing of organic compounds that are required in larger amounts to help address the needs of society. Consequently, the Journal encompasses every aspect of organic chemistry, including all aspects of catalysis, synthetic methodology development and synthetic strategy exploration, but also includes aspects from analytical and solid-state chemistry and chemical engineering, such as work-up tools，process safety, or flow-chemistry. The goal of development and optimization of chemical reactions and processes is their transfer to a larger scale; original work describing such studies and the actual implementation on scale is highly relevant to the journal. However, studies on new developments from either industry, research institutes or academia that have not yet been demonstrated on scale, but where an industrial utility can be expected and where the study has addressed important prerequisites for a scale-up and has given confidence into the reliability and practicality of the chemistry, also serve the mission of OPR&D as a communication tool between the different contributors to the field.
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