Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 2─Development of a Scalable Nickel-Catalyzed Sulfonylation

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