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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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).

References

  1. 1

    Gutmann, B., Cantillo, D. & Kappe, C.O. Continuous flow technology—a tool for the safe manufacturing of active pharmaceutical ingredients. Angew. Chem. Int. Ed. Engl. 54, 6688–6728 (2015).

    CAS  Article  Google Scholar 

  2. 2

    Movsisyan, M. et al. Taming hazardous chemistry by continuous flow technology. Chem. Soc. Rev. 45, 4892–4928 (2016).

    CAS  Article  Google Scholar 

  3. 3

    Webb, D. & Jamison, T.F. Continuous flow multi-step organic synthesis. Chem. Sci. 1, 675–680 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Wiles, C. & Watts, P. Continuous flow reactors: a perspective. Green Chem. 14, 38–54 (2012).

    CAS  Article  Google Scholar 

  5. 5

    Hartman, R.L., McMullen, J.P. & Jensen, K.F. Deciding whether to go with the flow: evaluating the merits of flow reactors for synthesis. Angew. Chem. Int. Ed. Engl. 50, 7502–7519 (2011).

    CAS  Article  Google Scholar 

  6. 6

    Ley, S.V., Fitzpatrick, D.E., Ingham, R.J. & Myers, R.M. Organic synthesis: march of the machines. Angew. Chem. Int. Ed. Engl. 54, 3449–3464 (2015).

    CAS  Article  Google Scholar 

  7. 7

    Newman, S.G. & Jensen, K.F. The role of flow in green chemistry and engineering. Green Chem. 15, 1456–1472 (2013).

    CAS  Article  Google Scholar 

  8. 8

    Wiles, C. & Watts, P. Continuous process technology: a tool for sustainable production. Green Chem. 16, 55–62 (2014).

    CAS  Article  Google Scholar 

  9. 9

    Britton, J. & Raston, C.L. Multi-step continuous flow synthesis. Chem. Soc. Rev. 46, 1250–1271 (2017).

    CAS  Article  Google Scholar 

  10. 10

    Jähnisch, K., Hessel, V., Löwe, H. & Baerns, M. Chemistry in microstructured reactors. Angew. Chem. Int. Ed. Engl. 43, 406–446 (2004).

    Article  Google Scholar 

  11. 11

    Sahoo, H.R., Kralj, J.G. & Jensen, K.F. Multistep continuous flow microchemical synthesis involving multiple reactions and separations. Angew. Chem. Int. Ed. Engl. 119, 5806–5810 (2007).

    Article  Google Scholar 

  12. 12

    Wörz, O., Jäckel, K.P., Richter, T. & Wolf, A. Microreactors – a new efficient tool for reactor development. Chem. Eng. Technol. 24, 138–142 (2001).

    Article  Google Scholar 

  13. 13

    Straathof, N.J.W., Su, Y., Hessel, V. & Noel, T. Accelerated gas-liquid visible light photoredox catalysis with continuous flow photochemical microreactors. Nat. Protoc. 11, 10–21 (2016).

    CAS  Article  Google Scholar 

  14. 14

    Su, Y., Straathof, N.J.W., Hessel, V. & Noël, T. Photochemical transformations accelerated in continuous flow reactors: basic concepts and applications. Chem. Eur. J. 20, 10562–10589 (2014).

    CAS  Article  Google Scholar 

  15. 15

    Garlets, Z.J., Nguyen, J.D. & Stephenson, C.R.J. The development of visible-light photoredox catalysis in flow. Isr. J. Chem. 54, 351–360 (2014).

    CAS  Article  Google Scholar 

  16. 16

    Tucker, J.W., Zhang, Y., Jamison, T.F. & Stephenson, C.R.J. Visible-light photoredox catalysis in flow. Angew. Chem. Int. Ed. Engl. 51, 4144–4147 (2012).

    CAS  Article  Google Scholar 

  17. 17

    Porta, R., Benaglia, M. & Puglisi, A. Flow chemistry: recent developments in the synthesis of pharmaceutical products. Org. Process. Res. Dev. 20, 2–25 (2016).

    CAS  Article  Google Scholar 

  18. 18

    Malet-Sanz, L. & Susanne, F. Continuous flow synthesis. a pharma perspective. J. Med. Chem. 55, 4062–4098 (2012).

    CAS  Article  Google Scholar 

  19. 19

    Schaber, S.D. et al. Economic analysis of integrated continuous and batch pharmaceutical manufacturing: a case study. Ind. Eng. Chem. Res 50, 10083–10092 (2011).

    CAS  Article  Google Scholar 

  20. 20

    Lee, S.L. et al. Modernizing pharmaceutical manufacturing: from batch to continuous production. J. Pharm. Innov. 10, 191–199 (2015).

    Article  Google Scholar 

  21. 21

    Roberge, D.M. et al. Microreactor technology and continuous processes in the fine chemical and pharmaceutical industry: is the revolution underway? Org. Process. Res. Dev. 12, 905–910 (2008).

    CAS  Article  Google Scholar 

  22. 22

    Wegner, J., Ceylan, S. & Kirschning, A. Flow chemistry – a key enabling technology for (multistep) organic synthesis. Adv. Synth. Catal. 354, 17–57 (2012).

    CAS  Article  Google Scholar 

  23. 23

    Zhang, J., Gong, C., Zeng, X. & Xie, J. Continuous flow chemistry: new strategies for preparative inorganic chemistry. Coord. Chem. Rev. 324, 39–53 (2016).

    CAS  Article  Google Scholar 

  24. 24

    Cambié, D., Bottecchia, C., Straathof, N.J.W., Hessel, V. & Noël, T. Applications of continuous flow photochemistry in organic synthesis, material science, and water treatment. Chem. Rev. 116, 10276–10341 (2016).

    Article  Google Scholar 

  25. 25

    Peng, Y. et al. Room temperature batch and continuous flow synthesis of water-stable covalent organic frameworks (COFs). Chem. Mater. 28, 5095–5101 (2016).

    CAS  Article  Google Scholar 

  26. 26

    Liu, Z. et al. Continuous flow synthesis of ZSM-5 zeolite on the order of seconds. Proc. Natl. Acad. Sci. USA 113, 14267–14271 (2016).

    CAS  Article  Google Scholar 

  27. 27

    Hajba, L. & Guttman, A. Continuous flow biochemical reactors: biocatalysis, bioconversion, and bioanalytical applications utilizing immobilized microfluidic enzyme reactors. J. Flow Chem. 6, 8–12 (2016).

    CAS  Article  Google Scholar 

  28. 28

    Planchestainer, M. et al. Continuous flow biocatalysis: production and in-line purification of amines by immobilised transaminase from Halomonas elongata. Green Chem. 19, 372–375 (2017).

    CAS  Article  Google Scholar 

  29. 29

    Tang, X., Allemann, R.K. & Wirth, T. Optimising terpene synthesis with flow biocatalysis. Eur. J. Org. Chem. 2017, 414–418 (2017).

    CAS  Article  Google Scholar 

  30. 30

    Britton, J., Raston, C.L. & Weiss, G.A. Rapid protein immobilization for thin film continuous flow biocatalysis. Chem. Commun. 52, 10159–10162 (2016).

    CAS  Article  Google Scholar 

  31. 31

    Britton, J. & Raston, C.L. Rapid high conversion of high free fatty acid feedstock into biodiesel using continuous flow vortex fluidics. RSC Adv. 5, 2276–2280 (2015).

    CAS  Article  Google Scholar 

  32. 32

    Britton, J. & Raston, C.L. Continuous flow vortex fluidic production of biodiesel. RSC Adv. 4, 49850–49854 (2014).

    CAS  Article  Google Scholar 

  33. 33

    Choedkiatsakul, I., Ngaosuwan, K., Assabumrungrat, S., Mantegna, S. & Cravotto, G. Biodiesel production in a novel continuous flow microwave reactor. Renew. Energ. 83, 25–29 (2015).

    CAS  Article  Google Scholar 

  34. 34

    Asadi, M., Hooper, J.F. & Lupton, D.W. Biodiesel synthesis using integrated acid and base catalysis in continuous flow. Tetrahedron 72, 3729–3733 (2016).

    CAS  Article  Google Scholar 

  35. 35

    Roberge, D.M., Ducry, L., Bieler, N., Cretton, P. & Zimmermann, B. Microreactor technology: a revolution for the fine chemical and pharmaceutical industries? Chem. Eng. Technol. 28, 318–323 (2005).

    CAS  Article  Google Scholar 

  36. 36

    Snead, D.R. & Jamison, T.F. A three-minute synthesis and purification of ibuprofen: pushing the limits of continuous flow processing. Angew. Chem. Int. Ed. Engl. 54, 983–987 (2015).

    CAS  Article  Google Scholar 

  37. 37

    Adamo, A. et al. On-demand continuous flow production of pharmaceuticals in a compact, reconfigurable system. Science 352, 61–67 (2016).

    CAS  Article  Google Scholar 

  38. 38

    Snead, D.R. & Jamison, T.F. End-to-end continuous flow synthesis and purification of diphenhydramine hydrochloride featuring atom economy, in-line separation, and flow of molten ammonium salts. Chem. Sci. 4, 2822–2827 (2013).

    CAS  Article  Google Scholar 

  39. 39

    Dai, C., Snead, D.R., Zhang, P. & Jamison, T.F. Continuous flow synthesis and purification of atropine with sequential in-line separations of structurally similar impurities. J. Flow Chem. 5, 133–138 (2015).

    CAS  Article  Google Scholar 

  40. 40

    Zhang, P., Russell, M.G. & Jamison, T.F. Continuous flow total synthesis of rufinamide. Org. Process. Res. Dev. 18, 1567–1570 (2014).

    CAS  Article  Google Scholar 

  41. 41

    Mascia, S. et al. End-to-end continuous manufacturing of pharmaceuticals: integrated synthesis, purification, and final dosage formation. Angew. Chem. Int. Ed. Engl. 52, 12359–12363 (2013).

    CAS  Article  Google Scholar 

  42. 42

    Heider, P.L. et al. Development of a multi-step synthesis and workup sequence for an integrated, continuous manufacturing process of a pharmaceutical. Org. Process. Res. Dev. 18, 402–409 (2014).

    CAS  Article  Google Scholar 

  43. 43

    Britton, J. & Jamison, T.F. A unified continuous flow assembly-line synthesis of highly substituted pyrazoles and pyrazolines. Angew. Chem. Int. Ed. Engl. 56, 8823–8827 (2017).

    CAS  Article  Google Scholar 

  44. 44

    McTeague, T.A. & Jamison, T.F. Photoredox activation of SF6 for fluorination. Angew. Chem. Int. Ed. Engl. 55, 15072–15075 (2016).

    CAS  Article  Google Scholar 

  45. 45

    Andrade, L.H., Kroutil, W. & Jamison, T.F. Continuous flow synthesis of chiral amines in organic solvents: immobilization of E. coli cells containing both ù-transaminase and PLP. Org. Lett. 16, 6092–6095 (2014).

    CAS  Article  Google Scholar 

  46. 46

    Barnes, J.C. et al. Iterative exponential growth of stereo- and sequence-controlled polymers. Nat. Chem. 7, 810–815 (2015).

    CAS  Article  Google Scholar 

  47. 47

    Wu, J. et al. Continuous flow synthesis of ketones from carbon dioxide and organolithium or Grignard reagents. Angew. Chem. Int. Ed. Engl. 53, 8416–8420 (2014).

    CAS  Article  Google Scholar 

  48. 48

    Wu, J., Kozak, J.A., Simeon, F., Hatton, T.A. & Jamison, T.F. Mechanism-guided design of flow systems for multicomponent reactions: conversion of CO2 and olefins to cyclic carbonates. Chem. Sci. 5, 1227–1231 (2014).

    CAS  Article  Google Scholar 

  49. 49

    Zhang, Y., Blackman, M.L., Leduc, A.B. & Jamison, T.F. Peptide fragment coupling using a continuous flow photochemical rearrangement of nitrones. Angew. Chem. Int. Ed. Engl. 52, 4251–4255 (2013).

    CAS  Article  Google Scholar 

  50. 50

    Kleinke, A.S. & Jamison, T.F. Hydrogen-free alkene reduction in continuous flow. Org. Lett. 15, 710–713 (2013).

    CAS  Article  Google Scholar 

  51. 51

    Shen, B. & Jamison, T.F. Rapid continuous synthesis of 5-deoxyribonucleosides in flow via Brønsted acid catalyzed glycosylation. Org. Lett. 14, 3348–3351 (2012).

    CAS  Article  Google Scholar 

  52. 52

    Shen, B., Bedore, M.W., Sniady, A. & Jamison, T.F. Continuous flow photocatalysis enhanced using an aluminum mirror: rapid and selective synthesis of 2-deoxy and 2,3-dideoxynucleosides. Chem. Commun. 48, 7444–7446 (2012).

    CAS  Article  Google Scholar 

  53. 53

    Webb, D. & Jamison, T.F. Diisobutylaluminum hydride reductions revitalized: a fast, robust, and selective continuous flow system for aldehyde synthesis. Org. Lett. 14, 568–571 (2012).

    CAS  Article  Google Scholar 

  54. 54

    Leduc, A.B. & Jamison, T.F. Continuous flow oxidation of alcohols and aldehydes utilizing bleach and catalytic tetrabutylammonium bromide. Org. Process. Res. Dev. 16, 1082–1089 (2012).

    CAS  Article  Google Scholar 

  55. 55

    Palde, P.B. & Jamison, T.F. Safe and efficient tetrazole synthesis in a continuous flow microreactor. Angew. Chem. Int. Ed. Engl. 50, 3525–3528 (2011).

    CAS  Article  Google Scholar 

  56. 56

    Sniady, A., Bedore, M.W. & Jamison, T.F. One-flow, multistep synthesis of nucleosides by Brønsted acid-catalyzed glycosylation. Angew. Chem. Int. Ed. Engl. 50, 2155–2158 (2011).

    CAS  Article  Google Scholar 

  57. 57

    Zhang, Y., Jamison, T.F., Patel, S. & Mainolfi, N. Continuous flow coupling and decarboxylation reactions promoted by copper tubing. Org. Lett. 13, 280–283 (2011).

    CAS  Article  Google Scholar 

  58. 58

    Yoshida, J.-i., Nagaki, A. & Yamada, T. Flash chemistry: fast chemical synthesis by using microreactors. Chemistry 14, 7450–7459 (2008).

    CAS  Article  Google Scholar 

  59. 59

    Yoshida, J.-i., Takahashi, Y. & Nagaki, A. Flash chemistry: flow chemistry that cannot be done in batch. Chem. Commun. 49, 9896–9904 (2013).

    CAS  Article  Google Scholar 

  60. 60

    Browne, D.L. et al. Continuous flow reaction monitoring using an on-line miniature mass spectrometer. Rapid Commun. 26, 1999–2010 (2012).

    CAS  Article  Google Scholar 

  61. 61

    Hall, A.M.R. et al. Practical aspects of real-time reaction monitoring using multi-nuclear high resolution FlowNMR spectroscopy. Catal. Sci. Technol. 6, 8406–8417 (2016).

    CAS  Article  Google Scholar 

  62. 62

    Brodmann, T., Koos, P., Metzger, A., Knochel, P. & Ley, S.V. Continuous preparation of arylmagnesium reagents in flow with inline IR monitoring. Org. Process. Res. Dev. 16, 1102–1113 (2012).

    CAS  Article  Google Scholar 

Download references

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

Affiliations

Authors

Contributions

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

Corresponding author

Correspondence to Timothy F Jamison.

Ethics declarations

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)

41596_2017_BFnprot2017102_MOESM12_ESM.mp4

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

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

41596_2017_BFnprot2017102_MOESM13_ESM.mp4

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

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

41596_2017_BFnprot2017102_MOESM14_ESM.mp4

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

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

41596_2017_BFnprot2017102_MOESM15_ESM.mp4

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

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

41596_2017_BFnprot2017102_MOESM16_ESM.mp4

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

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

41596_2017_BFnprot2017102_MOESM17_ESM.mp4

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

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)

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)

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

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.