Synthesis of the Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitor, 3-[(1S,2S,3R)-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-2α (HIF-2α) Inhibitor, 3-[(1S,2S,3R)-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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	154691
Journal	Tetrahedron Letters
Volume	128
DOIs	https://doi.org/10.1016/j.tetlet.2023.154691
State	Published - Sep 19 2023

Keywords

Belzutifan
Concise synthesis of PT2977
Hypoxia Inducible Factor (HIF) inhibitor
MK-6482
Single crystal X-ray structure of PT2977
Welireg™

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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Hamal, K. B., Pavlich, C. I., Carlson, G. J., Ching Wong, Y., Zhao, F., Zhang, Q., Klausmeyer, K. K., & Pinney, K. G. (2023). Synthesis of the Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitor, 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977, Belzutifan); Efficient Replication of Established Approaches. Tetrahedron Letters, 128, Article 154691. https://doi.org/10.1016/j.tetlet.2023.154691

Synthesis of the Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitor, 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977, Belzutifan); Efficient Replication of Established Approaches. / Hamal, Khagendra B.; Pavlich, Cyprian I.; Carlson, Graham J. et al.
In: Tetrahedron Letters, Vol. 128, 154691, 19.09.2023.

Research output: Contribution to journal › Article › peer-review

Hamal, KB, Pavlich, CI, Carlson, GJ, Ching Wong, Y, Zhao, F, Zhang, Q, Klausmeyer, KK & Pinney, KG 2023, 'Synthesis of the Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitor, 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977, Belzutifan); Efficient Replication of Established Approaches', Tetrahedron Letters, vol. 128, 154691. https://doi.org/10.1016/j.tetlet.2023.154691

Hamal KB, Pavlich CI, Carlson GJ, Ching Wong Y, Zhao F, Zhang Q et al. Synthesis of the Hypoxia-Inducible Factor-2α (HIF-2α) Inhibitor, 3-[(1S,2S,3R)-2,3-Difluoro-1-hydroxy-7-methylsulfonylindan-4-yl]oxy-5-fluorobenzonitrile (PT2977, Belzutifan); Efficient Replication of Established Approaches. Tetrahedron Letters. 2023 Sep 19;128:154691. doi: 10.1016/j.tetlet.2023.154691

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

Abstract

Keywords

ASJC Scopus subject areas

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