Enantio- and Diastereoselective Total Synthesis of Belzutifan Enabled by Rh-Catalyzed Hydrogenation DOI
Diane N. Le, Heather C. Johnson, Yu‐hong Lam

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(19), P. 4059 - 4064

Published: May 6, 2024

Herein, we report a nine-step synthesis of belzutifan enabled by novel Rh-catalyzed asymmetric hydrogenation to install the contiguous fluorinated stereocenters with high enantioselectivity. Moreover, final ketone reduction in proceeds diastereoselectivity, leading expedient assembly stereotriad. In contrast original 16-step synthesis, this route avoids lengthy bromination–oxidation sequence and introduces sulfone functionality via nucleophilic aromatic substitution, obviating need for transition metal catalysis.

Language: Английский

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 1─Process History and Development Strategy DOI
Daniel A. DiRocco, Yong‐Li Zhong, Diane N. Le

et al.

Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(2), P. 404 - 412

Published: Feb. 5, 2024

An improved synthesis has been developed for belzutifan, a novel HIF-2α inhibitor the treatment of Von Hippel–Lindau (VHL) disease-associated renal cell carcinoma (RCC). The efficiency previous supply and commercial routes was encumbered by lengthy 5-step sequence, needed to install chiral benzylic alcohol traditional methods. Identification directed evolution FoPip4H, an iron/α-ketoglutarate dependent hydroxylase, enabled direct enantioselective C–H hydroxylation simple indanone starting material. While this enabling transformation set stage greatly synthesis, several other key innovations were made including development base-metal-catalyzed sulfonylation, KRED-catalyzed dynamic kinetic resolution, facile SNAr reaction in water. Together, these improvements resulted significantly shorter (9 steps) versus route (16 75% reduction process mass intensity (PMI), while also removing reliance on third-row transition metals toxic solvents.

Language: Английский

Citations

10
Stereodivergent Synthesis of the Vicinal Difluorinated Tetralin of Casdatifan Enabled by Ru-Catalyzed Transfer Hydrogenation DOI Creative Commons
Guillaume Mata,

Artur K. Mailyan,

Jeremy Fournier

et al.

Organic Letters, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

We disclose a stereodivergent strategy to prepare vicinal difluorinated tetralins from γ-substituted tetralones via combination of catalyst-controlled transfer hydrogenation and substrate-controlled fluorinations. This process is easily scalable amenable highly functionalized substrates, as demonstrated here in the late-stage synthesis casdatifan, clinical-stage inhibitor hypoxia-inducible factor-2α. Analysis physicochemical properties which features cis-vicinal difluoride, revealed higher level facial polarization compared its trans-vicinal difluoride isomers.

Language: Английский

Citations

1
Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 2─Development of a Scalable Nickel-Catalyzed Sulfonylation DOI
J. Caleb Hethcox, Jungchul Kim, Heather C. Johnson

et al.

Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(2), P. 413 - 421

Published: Jan. 30, 2024

A nickel-catalyzed sulfonylation reaction was discovered and developed into a robust process for the manufacturing of belzutifan, an FDA-approved treatment Von Hippel-Lindau disease-associated renal cell carcinoma. The proceeds via reductive sulfinylation utilizing two insoluble salts (potassium metabisulfite potassium formate), followed by methylation with nontoxic methylating reagent (trimethylphosphate). doubly heterogeneous nature proved difficult to scale due mixing particle size issues. Controlled addition solution formate in ethylene glycol found mitigate all scaling issues, mechanistic studies revealed this be control catalyst speciation. demonstrated on multikilogram kinetics between scales. Reaction discovery, development, multikilogram-scale demonstration, insights are detailed within.

Language: Английский

Citations

7
Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 6─Development of a Nucleophilic Aromatic Substitution in Water DOI
Diane N. Le,

Timothy J. Wright,

Embarek Alwedi

et al.

Organic Process Research & Development, Journal Year: 2024, Volume and Issue: 28(2), P. 451 - 459

Published: Feb. 5, 2024

A convergent nucleophilic aromatic substitution (SNAr) was developed as the final step in an improved manufacturing process to belzutifan. The reaction performed water enable a reactive crystallization and direct isolation of drug substance toward green sustainable process. Due sensitivity vapor phase composition, engineering controls around headspace pressure sweep rate were tuned balance reactivity selectivity maximize product yield purity. Ultimately, our investigation resulted robust process, which successfully demonstrated at pilot plant scale.

Language: Английский

Citations

4
Enantio- and Diastereoselective Total Synthesis of Belzutifan Enabled by Rh-Catalyzed Hydrogenation DOI
Diane N. Le, Heather C. Johnson, Yu‐hong Lam

et al.

Organic Letters, Journal Year: 2024, Volume and Issue: 26(19), P. 4059 - 4064

Published: May 6, 2024

Herein, we report a nine-step synthesis of belzutifan enabled by novel Rh-catalyzed asymmetric hydrogenation to install the contiguous fluorinated stereocenters with high enantioselectivity. Moreover, final ketone reduction in proceeds diastereoselectivity, leading expedient assembly stereotriad. In contrast original 16-step synthesis, this route avoids lengthy bromination–oxidation sequence and introduces sulfone functionality via nucleophilic aromatic substitution, obviating need for transition metal catalysis.

Language: Английский

Citations

1