A Concise Process to Lenacapavir Sodium: Demonstration of One-Pot Sequential Heck/Suzuki-Miyaura Couplings in Lenacapavir API Synthesis

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 handling and simplifying Pd sequestration. The process affords lenacapavir API in up to 55% overall yield, with >99.9 wt % purity, and Pd content below 4.2 ppm.