Improving Zonisamide Manufacturing: Insights into Stereochemistry and Mechanisms for Continuous Optimization

Zonisamide is a heterocyclic sulfonamide widely employed as anticonvulsant. In this work, we report an efficient process for the preparation of zonisamide, obtained in a six-step synthesis from phenyl salicylate with an overall 31% yield. The key step is represented by a base-promoted intramolecular rearrangement of a β-ketosultone oxime, leading to the concomitant formation of the benzisoxazole ring and of the exocyclic sulfonic group. This intriguing transformation is investigated with a combination of analytical techniques (NMR, HRMS, PXRD), leading to a preliminary mechanistic proposal.