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

## 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.

## Key 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 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.