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 intramolecula...

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Bibliographic Details
Published in:European journal of organic chemistry 2024-11, Vol.27 (41), p.n/a
Main Authors: Travagin, Fabio, Vladiskovic, Chiara, Giovenzana, Giovanni B., Mantegazza, Simone, Razzetti, Gabriele
Format: Article
Language:English
Subjects:
Anticonvulsants
Mechanism
NMR
Nuclear magnetic resonance
Oxime
Rearrangement
Stereochemistry
Sulfonamides
Sulfonic acid
Sultone
Zonisamide
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Summary: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. Zonisamide, an important anti‐epileptic drug, was prepared with a new and convenient synthesis. This process involves the preparation of a key hydroxyiminosultone intermediate, whose stereochemistry was characterized by powder XRD, and a rearrangement reaction, whose mechanism was investigated with a combination of techniques (NMR, HRMS and kinetic profiles).
ISSN:1434-193X
1099-0690
DOI:10.1002/ejoc.202400686