In good agreement with the COSMO-RS results, ACN proved to be a selective solvent for reactants and product at room temperature (r.t.), as it dissolved both reactants, but not the product. Moreover, the solubility of the product Rufinamide increased with increasing temperature. At r.t., the solubility was <1.5 g/L; when heating up to 65 °C, the product dissolved in ACN at a concentration of 5 g/L, which guaranteed homogeneous reaction conditions. Upon cooling down spontaneous precipitation happened at this concentration (Figure S1, in supporting information). Notably, the selected solvent ACN also dissolved the benzyl azide, the intermediate product (P1) synthesized from benzyl chloride (R1). ACN was also a favorable solvent and showed similar solubility selectivity for the synthesis of Rufinamide analogue2 . In ACN at r.t. the reagent phenylacetylene R2 was soluble whereas 2 was not; however at 65 °C analogue 2 totally dissolved (> 10 g/L) in ACN as well.
The synthesis of Rufinamide and 2 consists of two parts. First, the benzyl chloride (R1) is azidated, followed by a [3+2] Huisgen cycloaddition reaction catalyzed by Cu(I) (CuAAC). For the first part of the reaction, the synthesis of 2,6-difluorobenzyl azide in a continuous flow process, an azide-functional resin (resin-N3) was prepared using an ion-exchange resin-Cl (Amberlite IRA-400 chloride) in a batch reaction with sodium azide for 6 hours, resulting in an azide loading of 3.9 mmol/g.22 Then, a designed packed-bed was made of the resin-N3 in a flow device (Figure 1a), and the synthesis of 2,6-difluorobenzyl azide from 2,6-difluorobenzyl chloride was executed. With flow rates of 6 mL/h, at 80 °C the resin-N3 reactor reached 97% conversion from R1 (1 M); and at 65 °C, an average conversion of 87 % was reached. The resin could be recovered easily and regenerated by azidation up to at least 3 times with similar conversions (Figure 1b). Therefore, 6 mL/h (residence time 1 min) and 80 °C were defined as optimal conditions for the azidation step.