Efficient Stereoselective Synthesis of Vepdegestrant (ARV-471) via Ruthenium-Catalyzed Asymmetric Hydrogenation

Abstract

Vepdegestrant (ARV-471) is a novel estrogen receptor (ER) degrader currently under clinical evaluation for the treatment of ER-positive and HER2-negative breast cancer. We have developed an efficient catalytic stereoselective synthetic route to produce this important compound. The key step involves a Ruthenium-catalyzed asymmetric hydrogenation, which establishes the critical stereocenter with exceptional diastereoselectivity(>99% de). This method obviates the need for chiral chromatographic separation, thereby significantly improving the efficiency and scalability of the synthetic sequence compared to previously reported approaches.