Mechanistic Insights on the Mechanosynthesis of Phenytoin, a WHO Essential Medicine.

Francesco Puccetti, Stipe Lukin, Krunoslav Užarević, Evelina Colacino, Ivan Halasz, Carsten Bolm, José G Hernández

Chemistry (Weinheim an der Bergstrasse, Germany) 2022 Mar 01

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In recent years, mechanochemistry has enriched the toolbox of synthetic chemists, enabling faster and more sustainable access to new materials and existing products, including active pharmaceutical ingredients (APIs). However, molecular-level understanding of most mechanochemical reactions remains limited, delaying the implementation of mechanochemistry in industrial applications. Herein, we have applied in situ monitoring by Raman spectroscopy to the mechanosynthesis of phenytoin, a World Health Organization (WHO) Essential Medicine, enabling the observation, isolation, and characterization of key molecular-migration intermediates involved in the single-step transformation of benzil, urea, and KOH into phenytoin. This work contributes to the elucidation of a reaction mechanism that has been subjected to a number of interpretations over time and paints a clear picture of how mechanosynthesis can be applied and optimized for the preparation of added-value molecules. © 2022 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.

Citation

Francesco Puccetti, Stipe Lukin, Krunoslav Užarević, Evelina Colacino, Ivan Halasz, Carsten Bolm, José G Hernández. Mechanistic Insights on the Mechanosynthesis of Phenytoin, a WHO Essential Medicine. Chemistry (Weinheim an der Bergstrasse, Germany). 2022 Mar 01;28(13):e202104409