Overcoming Product Inhibition in a Nucleophilic Aromatic Substitution Reaction
Diane N Le1, Mikhail Reibarkh2, Daniel A DiRocco1
1Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States.
Abstract:
The development of a nucleophilic aromatic substitution (SNAr) reaction for the synthesis of belzutifan and related analogues is disclosed. This classical transformation suffered from reaction stalling, despite prolonged reaction times. Through experimental and mechanistic studies, product inhibition was revealed and rationalized. Herein, we describe our efforts to overcome this synthetic challenge and demonstrate the importance of the judicious choice of the solvent to achieve reactivity.
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