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

Abstract

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.

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 1─Process History and Development Strategy

“…Inspired by these reports and in keeping our commitment to develop greener processes, we sought to develop a reductive sulfonylation utilizing an inexpensive earth-abundant metal (such as Ni) and that also takes advantage of the practical nature of K 2 S 2 O 5 as an SO 2 surrogate. With these intentions in mind, we successfully developed a one-pot catalytic synthesis of arylmethylsulfones using inexpensive NiCl 2 -dppe as a catalyst in the presence of K 2 S 2 O 5 and trimethyl phosphate (TMP) as a nontoxic methylating agent. , This new procedure allowed for the robust synthesis of arylsulfone 16 in good yield, most importantly avoiding the use of Pd or stoichiometric Cu and expensive SO 2 sources.…”

Diversification of Pharmaceutical Manufacturing Processes: Taking the Plunge into the Non-PGM Catalyst Pool

“…In 2024, researchers at Merck described their efforts in developing a robust, and scalable nickel-catalyzed sulfonylation of 29 to access intermediate 30 as a means to identify a more sustainable and cost-effective manufacturing process of the API Belzutifan ( Scheme 8 ). 70 The previous process had utilized copper catalysis and sodium methanesulfinate for the sulfonylation, but this reagent was costly for the overall synthesis. The inorganic sulfur salt, potassium metabisulfite, was chosen as an inexpensive source of SO 2 , however, the reagent introduced stirring challenges due to heterogeneity of the reaction.…”