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The assembly and use of continuous flow systems for chemical synthesis

Abstract

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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Figure 1: Continuous flow equipment and its use in the multistep continuous flow synthesis of active pharmaceutical ingredients.
Figure 2: Outline of the equipment constructed in this protocol.
Figure 3: Reactor coil assembly.
Figure 4: Stainless-steel syringe assembly.
Figure 5: Pressurization of the back-pressure regulator.
Figure 6: Continuous flow system assembly.
Figure 7: Assembly of a static mixer.
Figure 8: Packed-bed reactor assembly.
Figure 9: Assembly of a liquid–liquid separator and its incorporation into a continuous flow system.
Figure 10: Assembly of a drying unit.
Figure 11: Synthesis of N,N-dibenzyl-4-chlorobenzenesulfonamide (3) from dibenzylamine (1) and 4-chlorobenzenesulfonyl chloride (2).
Figure 12: Continuous flow reactor setup for the synthesis of sulfonamide (3).

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Acknowledgements

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.

Author information

Authors and Affiliations

Authors

Contributions

J.B. and T.F.J. wrote the manuscript.

Corresponding author

Correspondence to Timothy F Jamison.

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Competing interests

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 information

Supplementary Equations

Supplementary Equations. Calculation of required reactor-coil length for a specific residence time and calculation of residence time. (XLSX 10 kb)

Supplementary Video 1. Assembly of a reactor coil. (MP4 17729 kb)

Supplementary Video 2. Assembly of a stainless-steel syringe. (MP4 12523 kb)

Supplementary Video 3. Pressurization of a variable back-pressure regulator. (MP4 3928 kb)

Supplementary Video 4. Assembly of a basic continuous-flow system. (MP4 15832 kb)

Supplementary Video 5. Assembly of a static mixer. (MP4 10616 kb)

Supplementary Video 6. Assembly of a packed-bed reactor (stainless-steel tube cutting and filing). (MP4 9736 kb)

41596_2017_BFnprot2017102_MOESM18_ESM.mp4

Supplementary Video 7. Assembly of a packed-bed reactor (Swagelok fitting and insertion of the metal frit). (MP4 14363 kb)

41596_2017_BFnprot2017102_MOESM19_ESM.mp4

Supplementary Video 8. Assembly of a packed-bed reactor (loading the metal nut and ferrule set onto the PFA tubing and tightening into the Swagelok union). (MP4 3763 kb)

41596_2017_BFnprot2017102_MOESM20_ESM.mp4

Supplementary Video 9. Assembly of a packed-bed reactor (loading of the sand into the packed-bed reactor). (MP4 1557 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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