Development of a Horizontal Dynamically Mixed Flow Reactor for Laboratory Scale-Up of Photochemical Wohl–Ziegler Bromination

Abstract

Flow reactors with enhanced mixing are of interest to the pharmaceutical industry for a range of photochemical applications. Taylor−Couette (vortex, dynamically mixed) reactors have been reported to have intensified mixing and have been used with heterogeneous systems. Our photochemical workflow has previously been demonstrated for the development of a photochemical Wohl−Ziegler process and scale-up in flow using a plug flow reactor (PFR). In this work, a 20 mL dynamically mixed Autichem, Ltd. prototype photochemical DART reactor (Taylor−Couette reactor) was paired with four custom Kessil PR160L 400 nm lamps. The reactor was evaluated as a 500 g scale-up option for the bromination of ethyl 4-methylbenzoate. Herein we describe our workflow moving from a Pacer International Photochemistry LED Illuminator (HTS system) to the photochemical DART reactor in the scale-up of the synthesis of ethyl 4-(bromomethyl)benzoate via a radical bromination process.

Photochemistry in Pharmaceutical Development: A Survey of Strategies and Approaches to Industry-wide Implementation

“…This last point goes hand in hand with the historical “photochemistry cannot be scaled” misconception, and over the last two decades this has been a stigma when discussing the technology. The literature of the last 100 years discusses the issues with photochemistry and how to overcome them, highlighting merits of both batch and flow reactors. ,− With the advent of the publication of “A Practical Flow Reactor for Continuous Organic Photochemistry” by Booker-Milburn and Berry in 2005 coupled with widely available nearly monochromatic light sources in the 310–800 nm range, i.e., light emitting diodes (LEDs), − this has transformed photochemistry from a seldom-used bond-forming strategy into an innovative technology . Recently, Bonfield et al (2020), Cohen et al (2023), and Callard-Langdon et al (2023) discussed scaling photochemistry in the pharmaceutical industry.…”

Process Intensification of the Continuous Synthesis of Bio-Derived Monomers for Sustainable Coatings Using a Taylor Vortex Flow Reactor

“…There have been several reports of photogeneration of singlet oxygen in flow systems, 37 − 39 and we have recently reported the use of Taylor Vortex reactors for both continuous photochemistry 24 , 25 and electrochemistry. 40 , 41 In addition to our initial publications, further reports using Vortex reactors for photochemistry 42 , 43 have been published during the review process for this paper. The photochemical version of our reactor, the PhotoVortex, ensures highly efficient gas–liquid micromixing, which enables lower equivalents of gaseous O 2 to be used, with very small volumes of gaseous O 2 for generating singlet oxygen.…”

“… a Reactions were typically run for 3 h. This is shorter than the time reported for deposits forming on the reactor walls (fouling) in a different design of The PhotoVortex reactor. 42 However, we normally ran several sequential experiments in our reactor over a period of a week without any intermediate cleaning of the glassware (apart from flushing with clean solvent between experiments), and we did not observe any significant fouling. The choice of rotation speed was ultimately empirical, but formation of the Taylor vortices depends on the surface velocity of the rotor rather than its rate of rotation.…”

Enhancing mass transport to accelerate photoreactions and enable scale-up

“…in a Taylor-Couette reactor, which was recently applied to photochemical processes. 26,27 Since mass transport limitations are the major contributor as the reaction rate limiting step, spinning disk technologies are able to intensify photochemical processes by addressing the surface to volume ratio. 28,29 The advances of microreactors in chemical engineering offered the research field of photochemistry the opportunity to address the challenge of photon transport limitation by using microstructured photoreactors.…”