DOI: 10.1021/op5002512

A continuous flow system complete with inline analytics is described. Sampling from a high pressure reactor and automated delivery mechanisms are detailed. The ability of the system to maintain critical process parameters (CPP) throughout a reaction process is demonstrated. Setup performance was evaluated using the Claisen rearrangement of allyl phenyl ether (1).

Flow synthesis has garnered industrial interest from the promise of reducing wasteful and inefficient batch-manufacturing process development(1) by replacing the conventional “scale up” approach with “scale out” continuous production.(2) The development of synthetic protocols to supply material for early phase discovery (medicinal chemistry), formulation, and clinical trials consumes significant time and resources and carries a high cost.(3) Further, the effort put into developing a robust and compliant batch scale-up methodology goes for naught if the active pharmaceutical ingredient (API) ultimately fails later stage trials. By developing a flow process early on, any amount of product required may be obtained by running the flow system with the same conditions for the appropriate length of time. The promise of flow technology is that, once optimized, a process remains viable through the entire drug development process. Furthermore, quality by design (QbD) can be facilitated by flow synthesis because of the ability to closely monitor and control CPPs (those parameters “whose variability has an impact on a critical quality attribute (CQA) and therefore should be monitored or controlled to ensure the process produces the desired quality,” e.g., temperature, flow rate, stoichiometry; “where a CQA is a physical, chemical, biological, or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality,”(4) e.g., yield, impurity) during a run.(5) Ultimately, flow-reactor technology will be employed for full-scale commercial API production.(6)

• 1.

  Wu, H., Dong, Z., Haitao, L., and Khan, M. Org. Process Res. Dev. 2014, 18, 10.1021/op500056a.
• 2.

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  (b) Wiles, C.; Watts, P. Green Chem. 2014, 16, 55– 62

  (c) Moseley, J. D.; Woodman, E. K. Org. Process Res. Dev. 2008, 12, 967– 981
• 3.

  Ullah, F.; Samarakoon, T.; Rolfe, A.; Kurtz, R. D.; Hanson, P. R.; Organ, M. G. Chem.—Eur. J. 2010, 16, 10959– 10962

  and references cited therein
• 4.

  Guidance for Industry, Q8(R2) Pharmaceutical Development; U. S. Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research: Silver Springs, MD, 2009; p 18.
• 5.

  Calibrese, G. S.; Pissavini, S. AIChE J. 2011, 54, 828– 834
• 6.

  (a) Alsten, J. G.; Reeder, L. M.; Stanchina, C. L.; Knoechel, D. J. Org. Process Res. Dev. 2008, 12, 989– 994

  (b) Roberge, D. M.; Zimmermann, B.; Rainonee, F.; Gottsponer, M.; Eyholzer, M.; Kockmann, N. Org. Process Res. Dev. 2008, 12, 905– 910