Designed ONE-FLOW System for the Synthesis of Rufinamide
Chenyue Zhang +, a, b, M. Teresa De Martino+, a, Victor R. L. J. Bloemendal a, c, Floris P. J. T. Rutjes c, Can Jinb, d, Jan C. M. van Hest *,a, Volker Hessel *, b, e
a Bio-Organic Chemistry, Department of Chemical Engineering and Chemistry, Eindhoven University of Technology . P.O. Box 513 (Helix), 5600 MB Eindhoven, The Netherlands.
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.
c Institute for Molecules and Materials, Radboud University. Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands.
d College of Pharmaceutical Sciences, Zhejiang University of Technology. 310014 Hangzhou, China.
e School of Chemical Engineering and Advanced Materials, University of Adelaide. South Australia 5005 Adelaide, Australia.
+ These authors contributed equally to this work.
* Corresponding authors: J.C.M.v.Hest@tue.nl; volker.hessel@adelaide.edu.au
Significance: 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.
Keywords: microreactors, nanotechnology, self-assembly, solvent effects, sustainable chemistry.

Introduction

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.1,2{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.3-5Still, 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.1,2
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.6-8
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’).9 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.