A Concise Process to Lenacapavir Sodium: Demonstration of One-Pot Sequential Heck/Suzuki-Miyaura Couplings in Lenacapavir API Synthesis
Daryl Guthrie, Anand H. Shinde, Ramesh Vediyappan, Aline Nunes De Souza, Rama Krishna Sayini, John M. Saathoff, Nagaraju Sakkani, Naeem Asad, Samuel R. Hochstetler, Barrack Stubbs, Justina M. Burns, B. Frank Gupton, Ryan Littich, Limei Jin
TL;DR
This paper introduces a more efficient three-step process for synthesizing lenacapavir sodium, an HIV treatment, using a novel one-pot coupling method.
Contribution
The novel contribution is the first reported one-pot sequential Heck/Suzuki-Miyaura coupling in lenacapavir synthesis.
Findings
The new process achieves 55% overall yield with >99.9% purity.
Palladium content is reduced to below 4.2 ppm.
The method minimizes handling of atropisomers and simplifies Pd sequestration.
Abstract
This article presents a new three-step process for lenacapavir sodium, a first-in-class HIV capsid inhibitor developed by Gilead Sciences. Lenacapavir has received FDA approval for both the treatment of multidrug-resistant HIV (SunlencaⓇ, 2022) and PrEP (YeztugoⓇ, 2025). Previous medicinal chemistry synthetic routes relied on separate Pd-catalyzed couplings and involved atropisomeric intermediates, resulting in low efficiency. Gilead’s 2024 four-step process improved scalability but retained discrete Pd-catalyzed steps and early stage incorporation of the costly chiral pyrazole carboxylic acid (Frag C). Our streamlined approach begins with a chiral bromopyridine (Frag A) and features telescoped Heck/Suzuki-Miyaura coupling and late-stage amidation with Frag C. This marks the first reported one-pot Heck/Suzuki-Miyaura sequence in the synthesis of lenacapavir, minimizing atropisomer…
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Taxonomy
TopicsCatalytic Cross-Coupling Reactions · Synthetic Organic Chemistry Methods · Multicomponent Synthesis of Heterocycles