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.