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

• DOI: 10.1021/acs.oprd.3c00413
• Publication Date: 2024-02-05T22:29:03Z
• Authors: Diane N. Le; Timothy J. Wright; Embarek Alwedi; Clara Hartmanshenn; Hong Li; Jonathan P. McMullen; Daniel A. DiRocco
• Keywords: Reactivity; Process design; Manufacturing process

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.