To integrate both reaction steps in a ONE-FLOW set-up, the polymersomes and reagents were passed over the packed-bed of resin-N3(Scheme 1b). Initially, the synthesis of 2 was attempted as model reaction system. The conditions used were 65 °C, with a flow rate of 6 mL/h. 1 M 2,6-difluorobenzyl chloride, 2 M phenylacetylene, and 0.05 M Cu(I)-polymersomes were passed through the resin-N3 reactor (2 M). This process only led to 60% conversion of R1 and no product 2 was collected as a crystalline product upon cooling down. The reaction solution and resin-N3 were further characterized. From the SEM characterization (Figure S7, in the supporting information), product2 was present but Cu(I)-PLs could not be detected; we hypothesized that they were probably adsorbed on the resin-N3 . Therefore, a second one-flow process (Scheme 1c) was conducted. As depicted in Scheme 2a, the synthesis of azide was conducted at 80 oC and the reaction temperature for cycloaddition was set to 65 oC. The reaction solution after both steps was collected in a vial heated up to 40oC, to avoid uncontrolled product crystallization. Several flow experiments were performed to find the optimal conditions for both synthetic steps (Scheme 2b). Using a flow rate of 12 mL/h, resulting in a residence time of 15 min, yielded the desired triazole2 in 89% isolated yield. For the synthesis of Rufinamide, the concentrations of the starting compounds had to be lowered by a factor of three in order to achieve a homogeneous phase during the flow reaction. Using a flow rate of 192 mL/h and a residence time of 1 min, Rufinamide was obtained in a satisfactory 87% isolated yield. Although full conversions were not achieved, the ACN layer containing R1, P1, and P2 could be recycled after filtration. This was demonstrated with the outflow of the experiment, as performed under entry 2. The ACN layer containing the polymersome nanoreactors was collected after simple filtration and subsequently diluted twice by mixing it with the reactant solution (0.5 M R1) before being reintroduced in the flow reactor. 82% conversion could be achieved and 44% isolated yield of product2 were obtained (Scheme 2c). The possible reason of the decreased yield is the lower concentration of the final product, which makes the spontaneous recrystallization process less effective; however the recycling had no essential impact on the conversion.
Scheme 2. (a) Designed ONE-FLOW process of Rufinamide and product 2 preparations. (b) Optimization of the one-flow reaction conditions. (c) Reuse of the residues of ACN layer in a one-flow process (entry 2), exemplified by product 2 synthesis.
We have successfully introduced an integrated reactor-separator concept combining nano-compartmentalized polymersomes with a functional solvent system. The synthesis of Rufinamide was chosen as the model reaction and the conceptual approach of a ‘designed micro-nano ONE-FLOW system’ was verified via the selected functional solvent acetonitrile and the application of Cu(I) cross-linked polymersomes. In the future, we aim to extend this approach to other top-list drug syntheses. The final goal is to intensify multiple-step cascade reactions and separations by fully integrating them in an automatic and controllable one-flow process. This will increase the attractiveness of flow chemistry as a synthetic modality for scalable and cost-efficient pharmaceutical processes.

Acknowledgements

The authors acknowledge Paul van der Ven for the ICP-MS and Andrey Goryachev for the XPS measurements. The work is funded by the FET-Open EU project ONE-FLOW (Grant no. 737266).

Conflicts of interest

There are no conflicts to declare.

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