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

A convergent nucleophilic aromatic substitution (SNAr) 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.