Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 6─Development of a Nucleophilic Aromatic Substitution in Water

Abstract

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

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

“…Heating aryl fluoride 17 with phenol 18 in in the presence of K 2 CO 3 at 90 °C provides 89% assay yield of the desired drug substance (Scheme ). After cooling to room temperature and adding 2-propanol, the crude drug substance can be isolated by simple filtration in high yield (87%) and good purity . Beyond the benefits that water provides for reaction performance and isolation, it also serves as a rare example of an S N Ar that does not require the use of dipolar aprotic solvents, many of which carry health and safety risks.…”

Evolution of a Green and Sustainable Manufacturing Process for Belzutifan: Part 5─Chemoenzymatic Diastereoselective Fluorination/DKR

“…The current commercial process successfully met the aggressive program timelines; however, opportunities to improve the manufacturing route led to the development of an improved commercial process that is more concise, efficient, and atom economical . The electrophilic fluorination/dynamic kinetic resolution (DKR) sequence that sets two of three stereocenters was viewed as a strategic sequence to form the syn -1,2-fluoroalcohol substructure, and this disconnection was retained in the improved commercial process (Figure ).…”

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

“…Thus, belzutifan ( 3 ) represents a breakthrough treatment for those who suffer or will suffer from this disease. We acquired the compound from Peloton Therapeutics in 2019, whereupon a campaign to establish a manufacturing route was initiated . As part of that effort, the preparation of sulfone 2 from aryl bromide 1 was explored (Scheme ).…”