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Designed ONE-FLOW System for the Synthesis of Rufinamide
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  • Chenyue Zhang,
  • Teresa de Martino,
  • Victor Bloemendal,
  • Floris Rutjes,
  • Can Jin,
  • Volker Hessel,
  • Jan van Hest
Chenyue Zhang
Technische Universiteit Eindhoven

Corresponding Author:[email protected]

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Teresa de Martino
University of Technology Eindhoven Department of Chemical Engineering and Chemistry
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Victor Bloemendal
University of Technology Eindhoven Department of Chemical Engineering and Chemistry
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Floris Rutjes
Radboud Universiteit Faculteit der Natuurwetenschappen Wiskunde en Informatica
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Can Jin
Zhejiang University of Technology
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Volker Hessel
The University of Adelaide
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Jan van Hest
University of Technology Eindhoven Department of Chemical Engineering and Chemistry
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Abstract

A nano-compartmentalized one-solvent (ONE-FLOW) procedure was developed for the two-step synthesis of Rufinamide, employing a combined simulation and experimental approach. Computer-aided solvent selection was combined with reagent/catalyst compartmentalization in a continuous flow set-up. The synthetic route encompassed azidation of benzyl chloride, followed by a Cu-catalyzed azide alkyne cycloaddition (CuAAC) reaction. A functional solvent was chosen via a COSMO-RS based method, which allowed a one-phase reaction while facilitating a thermally induced final product separation from the reaction mixture. To perform azidation and CuAAC reactions in a microfluidic system, both azidation reagent and Cu(I) catalyst were immobilized, on a packed bed and in the hydrophobic membrane of polymer vesicles, respectively, as this allowed a higher reaction efficiency, facile regeneration of azidation reagent, and recovery of the metal catalyst. This ONE-FLOW process has great benefits for the pharmaceutical industry in their quest to scalable, efficient and safe synthetic processes with minimal waste generation.