The adoption of and opportunities in continuous flow synthesis ('flow chemistry') have increased significantly over the past several years. Continuous flow systems provide improved reaction safety and accelerated reaction kinetics, and have synthesised several active pharmaceutical ingredients in automated reconfigurable systems. Although continuous flow platforms are commercially available, systems constructed 'in-lab' provide researchers with a flexible, versatile, and cost-effective alternative. Herein, we describe the assembly and use of a modular continuous flow apparatus from readily available and affordable parts in as little as 30 min. Once assembled, the synthesis of a sulfonamide by reacting 4-chlorobenzenesulfonyl chloride with dibenzylamine in a single reactor coil with an in-line quench is presented. This example reaction offers the opportunity to learn several important skills including reactor construction, charging of a back-pressure regulator, assembly of stainless-steel syringes, assembly of a continuous flow system with multiple junctions, and yield determination. From our extensive experience of single-step and multistep continuous flow synthesis, we also describe solutions to commonly encountered technical problems such as precipitation of solids ('clogging') and reactor failure. Following this protocol, a nonspecialist can assemble a continuous flow system from reactor coils, syringes, pumps, in-line liquid–liquid separators, drying columns, back-pressure regulators, static mixers, and packed-bed reactors.
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J.B. acknowledges A.-C. Bédard, J. Lummiss, T.A. McTeague, M.G. Russell, and R. Hicklin for their discussions during the preparation of the manuscript. J.B and T.F.J. thank the Defense Advanced Research Project Agency (DARPA) for support.
T.F.J. is a cofounder of Snapdragon Chemistry, Inc., and a scientific adviser for Zaiput Flow Technologies, Continuus Pharmaceuticals, Paraza Pharma, Inc., and Asymchem. J.B. declares no competing financial interests.
Supplementary Equations. Calculation of required reactor-coil length for a specific residence time and calculation of residence time. (XLSX 10 kb)
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Britton, J., Jamison, T. The assembly and use of continuous flow systems for chemical synthesis. Nat Protoc 12, 2423–2446 (2017). https://doi.org/10.1038/nprot.2017.102
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