Synthesis of the Hypoxia-Inducible Factor-2 α (HIF-2 α) Inhibitor, 3-[(1 S,2 S,3 R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977, Belzutifan); Efficient Replication of Established Approaches

Khagendra B Hamal; Cyprian I Pavlich; Graham J Carlson; Yu Ching Wong; Fangzhou Zhao; Qing Zhang; Kevin K Klausmeyer; Kevin G Pinney

doi:10.1016/j.tetlet.2023.154691

Synthesis of the Hypoxia-Inducible Factor-2 α (HIF-2 α) Inhibitor, 3-[(1 S,2 S,3 R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977, Belzutifan); Efficient Replication of Established Approaches

Tetrahedron Lett. 2023 Sep 19:128:154691. doi: 10.1016/j.tetlet.2023.154691. Epub 2023 Aug 11.

Authors

Khagendra B Hamal¹, Cyprian I Pavlich¹, Graham J Carlson¹, Yu Ching Wong¹, Fangzhou Zhao², Qing Zhang², Kevin K Klausmeyer¹, Kevin G Pinney¹

Affiliations

¹ Department of Chemistry and Biochemistry, Baylor University, One Bear Place, No. 97348, Waco, Texas 76798-7348, United States.
² Department of Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, Texas 75390-9111, United States.

PMID: 38343394
PMCID: PMC10852213 (available on 2024-09-19)
DOI: 10.1016/j.tetlet.2023.154691

Abstract

A concise linear synthesis of hypoxia inducible factor-2α (HIF-2α) inhibitor, belzutifan was achieved by reproducing key components of previous synthetic approaches to this molecule as described in several publications and patents. Belzutifan is an orally bioavailable small-molecule (HIF-2α) inhibitor for the treatment of von Hippel-Lindau (VHL) disease-associated renal cell carcinoma (RCC) that received FDA approval in 2021. Herein, we report a 13-step synthesis of PT2977 that proceeded in good overall yield with high diastereoselectivity. Separation of diastereomeric mixtures at two different stages of the synthesis proved advantageous in ease of separation. The X-ray structure of belzutifan was determined.

Keywords: Belzutifan; Concise Synthesis of PT2977; Hypoxia Inducible Factor (HIF) inhibitor; MK-6482; Single Crystal X-ray Structure of PT2977; Welireg™.

Grants and funding

R01 CA244579/CA/NCI NIH HHS/United States