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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