Synthesis of Fragment A of Lenacapavir
Medicines for All Institute (M4ALL) demonstrated a 7-step route to make Fragment A (Frag A) that offers an overall raw material cost (RMC) reduction of 33-41%.
Key Assumptions
- Projected material cost reductions are significantly impacted by market dynamics for starting materials and reagents, and economies of scale related thereto. Please reach out to M4ALL for more information.
- The baseline route refers to the Gilead’s route described in the process development report below.
Scientific Highlights
- We demonstrate a chiral resolution-based approach to produce Frag A from 3,6-dibromo- 2-methylpyridine.
- The key transformations include an intensified two-step aldehyde synthesis, a telescoped three-step racemic amine synthesis, and a Gilead-pioneered dynamic kinetic resolution (DKR) with N-acetyl-D-leucine (NADL).
- Process development of this 7-step strategy enables the production of Frag A as a single enantiomer in 25-30% overall isolated yield, demonstrated at scales up to 200 grams.
Summary of Process Development Work on the Synthesis of Frag A of Lenacapavir