<div>Designed ONE-FLOW System for the Synthesis of Rufinamide</div><div>Chenyue Zhang <sup>+, a, b</sup>, M. Teresa De Martino<sup>+, a</sup>, Victor R. L. J. Bloemendal <sup>a,
c</sup>, Floris P. J. T. Rutjes <sup>c</sup>, Can Jin<sup>b, d</sup>, Jan C. M. van Hest *<sup>,a</sup>, Volker
Hessel *<sup>, b, e</sup></div><div>a Bio-Organic Chemistry, Department of Chemical Engineering and
Chemistry, Eindhoven University of Technology . P.O. Box 513 (Helix),
5600 MB Eindhoven, The Netherlands.</div><div>b Micro Flow Chemistry and Synthetic Methodology, Department of Chemical
Engineering and Chemistry, Eindhoven University of Technology. P.O. Box
513 (Helix), 5600 MB Eindhoven, The Netherlands.</div><div>c Institute for Molecules and Materials, Radboud University.
Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.</div><div>d College of Pharmaceutical Sciences, Zhejiang University of Technology.
310014 Hangzhou, China.</div><div>e School of Chemical Engineering and Advanced Materials, University of
Adelaide. South Australia 5005 Adelaide, Australia.</div><div>+ These authors contributed equally to this work.</div><div>* Corresponding authors:
J.C.M.v.Hest@tue.nl;
volker.hessel@adelaide.edu.au</div><div><b>Significance:</b> Herein we describe the first designed
nano-compartmentalized micro-flow process for the synthesis of
Rufinamide by combining a computer-aided functional solvent selection
with catalyst compartmentalization in polymeric nanoreactors. Product
purification, reactant and catalyst recovery are achieved via
spontaneous separation in flow, due to the specific features of the
functional solvent and the nanoreactors. This generic concept of
integrated reactor and separator units (ONE-FLOW) using micro and
nanostructured reaction conditions can greatly simplify multiple-step
cascade reactions.</div><div><b>Keywords:</b> microreactors, nanotechnology, self-assembly, solvent
effects, sustainable chemistry.</div><h2 data-label="introduction" class="ltx_title_subsection">Introduction</h2><div>The process design of pharmaceutical synthesis has attracted much
attention over the years. One of the more intriguing developments has
been the end-to-end processing of medicines from raw materials in one
run, which even involved the connection with compounding/formulating
equipment to deliver ready-to-use pills
continuously.<sup>1,2</sup>{Adamo,
2016 #237} Chemists have in the past two decades expanded the concept
of continuous micro-flow reactors, initially employed for a plethora of
single chemical reactions, to a much broader choice of chemistries
involving multi-step reactions in continuous-flow, which has been coined
flow chemistry.<sup>3-5</sup>Still, this process chain commonly needs to incorporate work-up steps in
between the flow reactors, due to compatibility issues, which leads to a
high number of reactor and separator units and complicated controller
tasks, i.e. high system
complexity.<sup>1,2</sup></div><div>To simplify this complicated and expensive production process, an
alternative approach might be to employ an integrated reactor-separator
unit which can cope with these issues. For this approach, it is
important to think of another way of combining the reaction with
separation spaces, which are traditionally not integrated. This separate
chain of reactors and separators – one after the other − is what we
call the ‘vertical’ alignment of a series of flow equipment. The
inspiration for alternative multistep synthetic processes can be found
in nature, in particular in living cells. Nature did not choose for a
‘vertical’ series of cells, each being unique to one kind of operation.
Rather, all is done in one cell which internally is hierarchically
compartmentalized (with its membranes and organelles) and which is
modular, meaning different cells refer to the same building principle.
That approach, of conducting diverse chemistries at the same time and
virtually the same place, may be termed ‘horizontally’ in order to
distinguish it from the aforementioned traditional
approach.<sup>6-8</sup></div><div>Learning from nature and in order to turn a microfluidic reactor into a
soft-matter structured operating unit, an entirely new reactor concept
for multi-step organic reactions involving catalytic conversions is
presented based on micro-flow continuous processing. This work describes
the development of functional solvent and nanoparticle combinations to
provide a compartmentalized flow reactor/separator system with
‘horizontal hierarchy’ – as opposed to the ‘vertical hierarchy’ of
common multi-step flow syntheses (or batches) with their consecutive
reactors-separators. The solvent plays a dual role, since it provides a
homogeneous solution for the reaction to take place, while it enables a
spontaneous separation of the final product from the reaction mixture.
Concerning the design of the catalyst, the choice of immobilizing it in
nanosized compartments combines the benefits of homogeneous catalysis,
i.e. high accessibility, with ease of separation from the product flow.
Such flow cascade processing ideally needs just one reactor passage
(‘ONE-FLOW’).<sup>9</sup> The
‘ONE-FLOW’ process will fluidically open and close interim reaction
compartments with the aims to facilitate (a) orthogonality during the
reaction, (b) recycling of catalysts and reactants, (c) purification of
products, (d) high-c processing, and (e) ensured activity and stability
of the catalysts.</div>