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Multikilogram per Hour Continuous Photochemical Benzylic Brominations Applying a Smart Dimensioning Scale-up Strategy
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Multikilogram per Hour Continuous Photochemical Benzylic Brominations Applying a Smart Dimensioning Scale-up Strategy
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  • Alexander Steiner
    Alexander Steiner
    Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
  • Philippe M. C. Roth
    Philippe M. C. Roth
    Corning Reactor Technologies, Corning SAS, 7 bis Avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, France
  • Franz J. Strauss
    Franz J. Strauss
    Microinnova Engineering GmbH, Europapark 1, 8412 Allerheiligen bei Wildon, Austria
  • Guillaume Gauron
    Guillaume Gauron
    Corning Reactor Technologies, Corning SAS, 7 bis Avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, France
  • Günter Tekautz
    Günter Tekautz
    Microinnova Engineering GmbH, Europapark 1, 8412 Allerheiligen bei Wildon, Austria
  • Marc Winter
    Marc Winter
    Corning Reactor Technologies, Corning SAS, 7 bis Avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, France
    More by Marc Winter
  • Jason D. Williams*
    Jason D. Williams
    Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
    *E-mail: [email protected]
  • C. Oliver Kappe*
    C. Oliver Kappe
    Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, Austria
    Institute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
    *E-mail: [email protected]
Open PDFSupporting Information (2)

Organic Process Research & Development

Cite this: Org. Process Res. Dev. 2020, 24, 10, 2208–2216
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https://doi.org/10.1021/acs.oprd.0c00239
Published June 15, 2020

Copyright © 2020 American Chemical Society. This publication is licensed under CC-BY.

Abstract

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Although continuous flow technology can facilitate the scale-up of photochemical processes it is not yet routinely implemented on production scale in the fine chemical industries. This can be attributed to additional challenges compared to thermal processes, mostly in the homogeneous irradiation of the flow reactor. Here, we detail the process of bringing a previously developed photochemical benzylic bromination, utilizing in situ bromine generation, from lab to pilot scale. The process setup is discussed in detail, alongside a comprehensive risk assessment and discussion of problems encountered in the investigation of key reaction parameters. Ultimately, an assay yield of 88% was obtained in 22 s irradiated residence time, resulting in a productivity of 4.1 kg h–1 (space-time yield = 82 kg L–1 h–1) representing a 14-fold scale-up versus the lab-scale process.

Copyright © 2020 American Chemical Society

SPECIAL ISSUE

This article is part of the Flow Chemistry Enabling Efficient Synthesis special issue.

Introduction

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Photochemistry has emerged as a powerful tool in chemical synthesis in the past decade. (1) Improvements in LED technology have introduced efficient pseudo monochromatic light sources, which are ideal for performing many photochemical transformations. (2) However, poor light distribution inside a batch reactor leads to prolonged reaction times and possible side product formation by overirradiation. This behavior, described by the Beer–Lambert law, becomes increasingly problematic when scaling up such processes. (3) Continuous flow technology has been demonstrated as a solution to this problem, since narrow reaction channels can ensure homogeneous irradiation, alongside improved heat transfer and mass transfer. (4)
Until now, only a few examples of photochemical steps can be found in fine chemical synthesis on manufacturing scale. (5) The main hurdle is still the relative difficulty of scaling up flow photochemical processes, compared to standard thermal transformations. Numbering up and scaling out can be done relatively easily, (6) but in order to reach production scale these approaches alone are generally insufficient. Smart dimensioning (7) of the photochemical reactor represents the most practical solution. However, a high level of reactor engineering and scale-up expertise is required, since maintaining light flux with increasing reactor size is a complex challenge. (8)
Benzyl bromides represent common photochemically accessible building blocks in the pharmaceutical and other industries, signifying that their scalable synthesis is of importance to multiple fields. (9) Undoubtedly, the direct use of molecular bromine for these bromination reactions is unfavorable, especially on larger scale, due to its high vapor pressure and the associated safety issues. (10) The use of N-bromosuccinimide (NBS) instead is convenient, especially on lab scale, since the associated risks are significantly lower and the crystalline solid is easier to handle. (11) The trade-off when using NBS, however, is poorer reactivity, atom economy, and solubility.
A safe and sustainable solution, which overcomes the drawbacks of both bromine and NBS, is the in situ generation of bromine, (12) especially when combined with flow technology. (13) Bromine generators generally consist of a bromide ion source combined with an oxidant under acidic conditions. Recently, we reported a highly intensified process for photochemical benzylic bromination, using the chemical generator approach for in situ bromine formation (Figure 1a). (14) A commonly used oxidant is H2O2, but there are safety concerns associated with the storage and use of peroxides. Accordingly, we employed NaBrO3, a crystalline solid with a high decomposition temperature of 310 °C, as a safer alternative. (15) By using concentrated hydrobromic acid (one source for both bromide ions and protons), a concentrated sodium bromate solution, and no organic solvent (substrate pumped neat), the bromine generator was considerably intensified. (14)

Figure 1

Figure 1. (a) Flow schematic for the intensified photochemical benzylic bromination of 2,6-dichlorotoluene 1, including bromine generation in the first FM and quench of excess bromine using sodium thiosulfate in the second FM. (b) General scale-up strategy for Corning Advanced-Flow Reactors, versus the scale-up demonstrated in this study. Scale-up workflow is based on maintaining a consistent residence time, to achieve consistent results (i.e., linear scaling of flow rates with reactor volume). The scale-up comparison demonstrated here represents a direct transfer from a G1 LF FM to a single G3 FM, whereas the standard strategy would suggest 5 × G3 FMs. Fluidic module images copyright 2015 and 2017 Corning Incorporated.

2,6-Dichlorotoluene (DCT, 1) was chosen as a suitable substrate for scale-out for several reasons: (1) the corresponding 2,6-dichlorobenzyl bromide product 2 is a commonly occurring building block in medicinal chemistry, notably in the APIs vilanterol (16) and isoconazole; (17) (2) the steric hindrance of two ortho-chlorine atoms hinders dibromination; (3) the benzyl bromide product 2 is a solid (melting point = 55 °C), facilitating straightforward isolation by filtration. The result was the production of 1.17 kg (97% yield) of 2,6-dichlorobenzyl bromide 2 in less than 4 h of processing time, using a lab scale reactor of 2.8 mL volume. The corresponding productivity of 300 g h–1 (space-time yield = 108.3 kg L–1 h–1) and the outstandingly low process mass intensity (PMI) of 3.08 (including aqueous mass) showcased the industrial potential of this process. (14)
These highly intensified conditions, however, come with significant challenges concerning reactor technology. The biphasic system, consisting of the aqueous HBr and NaBrO3 streams and the organic substrate stream, requires intense mixing throughout the whole reactor. The exothermicity of the occurring reactions (bromine formation, radical substitution, and quench of excess bromine) demand efficient heat transfer. Simultaneously, irradiation at 405 nm is required to facilitate Br–Br bond cleavage. A Corning Advanced-Flow Lab Photo Reactor employed in the development of this process proved to be ideal, meeting these requirements (Figure 1). (14)
However, in order to demonstrate feasibility on pilot scale, a smart dimensioning approach to scale-up was pursued. Hence, in this work, we describe the scale-up of this photochemical benzylic bromination process from a 2.8 mL to a 50 mL photochemical flow reactor. Due to the highly intensified nature of this process, it was envisioned that multikilogram per hour processing could be demonstrated, fulfilling the volume requirements for manufacture of many pharmaceutical intermediates.

Results and Discussion

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Scalability Concept and Experimental Plan

Corning Advanced-Flow Reactors exist in a wide range: from a laboratory scale at a few mL per minute flow rate, up to full industrial production units. (18) To ensure homogeneity of performance across the whole range, the design of fluidic modules (FMs) was specifically carried out to keep the heat- and mass transfer identical. (19) In other words, each FM across the reactor portfolio (i.e., Low Flow, G1, G3, and G4 reactors; cf. Figure 1b) should behave in an identical fashion, but with different throughputs. This philosophy of “Seamless Scale-up” design is the backbone of this technology, so that any process will experience the same physical behavior in each reactor. Therefore, reaction performance can be maintained without the need for thorough reoptimization during scale-up. (20) Importantly for photochemical applications, the increase in irradiated path length for larger reactors is minimized (e.g., 0.4 mm for LF FM vs 1.5 mm for G3 FM) and measures are taken to provide equivalent photon flux.
In the case of the Lab scale Photo Reactor (G1 LF size), though, the FM is designed to maximize light flux in a single FM, making its fluidic properties equivalent to five standard Low Flow (LF) FMs placed in series. Accordingly, scale-up from the Lab scale Photo Reactor requires 5 × G3 FMs for a direct comparison. For the present study, however, only 1 × G3 photochemical FM was available (and 1× G3 standard FM for the reaction quench), meaning that the results cannot be considered as a direct use of the smart dimensioning scale-up strategy in the strictest sense (Figure 1b).
The photochemical benzylic bromination was performed in an Advanced-Flow G3 Photo Reactor (50 mL volume), where the two aqueous streams are combined to form Br2 inside the first FM (Figure 1a). Excitation with 405 nm irradiation initiates the radical substitution reaction on the toluene-derived substrate 1. The output of this first FM is mixed with an aqueous sodium thiosulfate stream in the second FM, (14) to quench any remaining Br2. Aliquots of reactor output can be analyzed by 1H benchtop NMR spectroscopy (Spinsolve Ultra 43 MHz, Magritek), where the different benzylic proton signals, belonging to starting material 1 and product 2, are clearly distinguishable.
As noted in our previous report, performing the reaction with starting material from two different vendors gave dramatically different results. (14) When using DCT 1 purchased from an alternative to the usual vendor, yields dropped (under identical reaction conditions) from >90% to 10–20%. The impurity responsible for this reduced reactivity has not yet been identified. ICP-MS analysis showed no differences in metal content between the two batches, but two minor impurity peaks (total of 1.4% area) could be observed by HPLC analysis of the unreactive batch. Therefore, acquiring 1 from the original supplier and performing a use test of this batch on lab scale were key prerequisites in this scale-up. The tests of this purchased material were in agreement with our previously published results (see Supporting Information (SI) for details), allowing efforts to go ahead.

Calorimetry

The next key step for safe operation was to acquire calorimetric data for the transformations taking place during regular operation, as well as the reactions which could occur in case of equipment failure. According to this analysis, the requirements for reactor temperature control could be established. A THT μRC microcalorimeter was used in titration mode (average of 5 injections) to perform isothermal calorimetry measurements at 25 °C (Table 1). A significant exotherm of −65.1 kJ mol–1 for Br2 formation was observed. This reaction takes place in the first FM, together with the radical substitution reaction (cf. Figure 1a), which contributes a calculated exotherm of about −63 kJ mol–1 (note that this could, in reality, be substantially higher due to the additional light energy input toward bond breakage). For the quenching of Br2 with sodium thiosulfate (occurring in the second FM), a significantly higher exotherm of −115 kJ mol–1 was observed. In case of a failure of either the HBr or bromate pump, a reaction between the remaining reagent and thiosulfate could occur. These reactions are far less exothermic under the tested conditions. Additionally, an expected increase in pressure (caused by presumed SO2 formation) was not observed.
Table 1. Results of Calorimetric Studies to Determine Heat of Reactiona
EntryReactionOccurrenceExperimental ΔHR [kJ mol–1]Calculated ΔHR [kJ mol–1] (21)
1NaBrO3 + 6HBr → 3Br2 + 3H2O1st FM reaction–65.1b–63.5b
2ArCH3 + Br2→ HBr + ArCH2Br1st FM reaction–63b
3
2nd FM quench–115b–174.9b
4
Pump failure–20.0c+31.8c
5BrO3 + S2O32– → ?Pump failure<−0.5d
6BrO3 + ArCH3 → ?Pump failure<−0.5e
a

All measurements were performed isothermally at 25 °C. For entries 1 and 3 dilute aqueous solutions (0.1 M NaBrO3, 0.5 M HBr, 0.09 M Br2, 0.5 M Na2S2O3) were used. For entries 4–6 concentrated solutions (2.64 M Na2S2O3, 2.2 M NaBrO3, 48% HBr) and neat DCT were used. Theoretical exotherms were calculated as the difference of formation enthalpies ΔHf0(products) – ΔHf0(reactants) (entries 1, 3–4), or as a difference of bond energies (entry 2). The required values were taken from ref (21).

b

Calculated per mole of Br2 generated or consumed.

c

Calculated per mole of S2O32– consumed.

d

Calculated per mole of BrO3 consumed.

e

Calculated per mole of DCT consumed.

To estimate the required cooling power of the reactor thermostat, the maximum exotherm was estimated for two cases, both assuming an 18 s residence time (the shortest to be examined, requiring the highest flow rates): first, a reaction reaching 90% conversion (Br2 formation and substitution as the predominant reactions) and, second, reaching only 20% conversion (Br2 formation and quench as the predominant reactions). The heat produced under these conditions was calculated to be 1.0 kW (90% conversion) and 1.2 kW (20% conversion). Therefore, a thermostat with at least 2 kW cooling power was deemed to be necessary, when taking into account the associated uncertainties in these data and calculations.

Reactor Setup

Three HNP microannular gear pumps (2 × mzr-7255 and 1 × mzr-7208) were used to pump the sodium bromate and sodium thiosulfate solutions, as well as DCT 1 (“non-acidic streams”, Figure 2). A metal-free FUJI pump (Super Metering Pump HYM-08) pumped the HBr stream. All connections were made using 1/4” PFA tubing (Bola), with either stainless steel or PFA unions (Swagelok). Before each pump, valves allowed switching between the wash solution (water for all aqueous streams, isopropanol for the substrate stream) and the corresponding process solution. In the three nonacidic streams, inline filters were installed before each pump, along with a check valve and pressure sensor downstream of the pump. In all four streams, overpressure valves set to 10 bar were installed.

Figure 2

Figure 2. Piping and instrumentation diagram (PID) showing the process streams in black, heat exchange channels for the reaction and quench FMs in red, and the LED heat exchange channel in blue. PI = pressure sensor; FI = flow meter; TI = temperature sensor.

Flow meters (2 × Bronkhorst Coriflow M14, 1 × Endress and Hauser Promag 53) were installed after the pumps. Due to the nature of the pumps used (gear pumps, in combination with variable pressure and flow rates), flow meters proved to be indispensable in ensuring the desired flow rates. Metal-free parts were used in the whole setup except for the pumps and periphery (filters, valves, mass flow meters) of the nonacidic streams.
The HBr and DCT 1 stream were mixed in a PFA T-piece (1/8” inner diameter) before the inlet of the first FM, while the sodium bromate stream was connected to the other FM inlet. The previous studies exemplified the importance of setting up an organic/aqueous slug flow prior to mixing with the second aqueous stream within the FM. (14) The outlet of the first FM and the thiosulfate stream were connected to the two inlets of the second FM (nonirradiated). The outlet tubing leading to the collection vessel was equipped with an adjustable back pressure regulator (BPR, Bola) and insulated with cotton wool to avoid solidification of product 2 (melting point = 55 °C).
Maintaining a constant LED temperature not only extends the lifetime of the lamps but also, perhaps more importantly in these short trials, ensures that the emission wavelength and photon flux remain constant. Accordingly, a Lauda Proline RP 890 thermostat (1.1 kW cooling power, ethanol as heat exchange fluid) set to 10 °C was used to cool the LEDs, which equilibrated at a temperature <20 °C. Separately, a Lauda Proline RP 4090 CW thermostat (4.0 kW cooling power, water as heat exchange fluid) was used as the reactor thermostat, in combination with a Gather gear pump (2M-J/24/). This booster pump increased the flow rate to 6 L min–1, since a high flow rate is vital to obtaining optimal heat transfer with the FM. To monitor this, the heat exchange channels were equipped with a pressure and several temperature sensors according to Figure 2. The pumps and sensors were controlled and monitored by a central control software (developed by Microinnova Engineering GmbH, within the CODESYS automation framework).
A webcam was also positioned inside the reactor box, combined with a small LED lamp to improve visibility. The live video of the quench FM allows visual monitoring of the reaction, estimation of the bromine concentration entering the quench FM and the efficacy of the quench, thus acting as a semiquantitative visual PAT (process analytical technology) tool. In this case, it is especially useful for adapting the sodium thiosulfate flow rate to ensure effective bromine quenching. Additionally, valuable information can be acquired in the event of failure (e.g., whether all Br2 is being quenched or if no Br2 is formed).
In cases of high conversion (exemplified in Figure 3) only a small quantity of bromine reaches the quench FM. After the first reactor channel turn (∼25% of the FM volume; see Figure 1b for a full view of the reaction channel), most of the bromine is already quenched, and the solution at the outlet is almost colorless. If the stoichiometry is mismatched and the quench occurs under acidic conditions, elemental sulfur is formed from thiosulfate, which can be observed as a yellow color in the quench FM (see Supporting Information). Sulfur formation leads to fouling over time—another important role of visual process monitoring. It should be noted that this fouling only occurred outside of optimal operating conditions and could be effectively cleaned between runs by increasing the reactor temperature to 80 °C while rinsing with toluene.

Figure 3

Figure 3. Snapshot from the live video stream captured by the webcam, showing the quench FM (streams combine and enter in top right corner, flow direction depicted by arrows, see Figure 1b for a full view of the FM). Quenching of the excess Br2 (highlighted by white ellipse) can be observed by a color change as the reaction mixture moves through the channel.

Safety Assessment

A critical aspect of running such highly intensified chemistry on a large scale was to ensure safe operation. Accordingly, a detailed risk assessment was formulated (see Supporting Information), studied, and signed by all scientists present in the laboratory during the experiments. It includes the possible risks/failures, how the failure would be observed during the run, its consequences, and the required actions. Importantly, it was calculated that no more than 10 mL (30 g) of liquid bromine could ever be present in the 50 mL photoreactor at any one time, even in the event of complete pump and reactor failure.
Two major threats to safe operation were identified. The first is the formation of excess bromine which does not react in the first FM, and therefore cannot be effectively quenched in the second FM, thus leaving the reactor and building up in the collection vessel. The second is cooling of the reacted mixture in the outlet tubing or BPR below the melting point of the benzyl bromide 2 (55 °C), leading to its precipitation and clogging of the reactor.
A startup and shutdown procedure for this process was developed, which addresses these two main concerns. During the startup procedure, turning on the LEDs and filling the reactor with substrate before switching on the Br2 generator is crucial. The first threat of forming excess bromine during the startup is thereby mitigated. Similar applies to the shutdown procedure: by first switching the Br2 generator streams to water, bromine formation stops before the DCT stream is switched or the LEDs are turned off. Furthermore, it is important to avoid turning off pumps wherever possible, which would lead to an increased chance of precipitation of the product in the outlet tubing by cooling below the melting point. By stopping bromine formation first, product formation is also stopped, which prevents clogging. Preparation of and familiarization with this document allowed safe operation of the reactor and timely reaction to any faults, preventing equipment damage or danger to the operators.
During one run, for example, it was observed that a significant quantity of gas was formed in the collection vessel (attributed to boiling water, caused by a temperature rise, since no pressure increase was observed during calorimetric experiments). Also, no bromine was visible via the webcam in the quench FM. According to the risk assessment, it was concluded that the absence of bromine could only be associated with pump failure on the HBr or sodium bromate stream. The measure taken was to switch both HBr and bromate streams to water. This avoided further buildup of either HBr or bromate in the collection vessel. The usual shutdown procedure was then applied. The problem was found to be a broken coupling between the motor and pump head of the HBr pump. Since the motor was still turning as normal, this fault was not detected by the automation software.

Reaction Parameter Optimization

The starting point for these experiments was the set of conditions from the lab scale long run (Table 2 entry 1). To analyze the reaction, samples were extracted with DCM and excess acid neutralized, and then the ratio of 1 to 2 was determined by 1H benchtop NMR, based on the benzylic proton signals. Since no side products are observed in this reaction, the conversion of 1 (equal to the assay yield of 2) can be calculated from this ratio. Due to the highly concentrated reaction conditions, it was anticipated that the reaction mixture would absorb all incident light, despite the short irradiated path length (1.5 mm). Consequently, the maximum available LED power was utilized in all experiments, to ensure the highest possible photon flux. Owing to the high throughput of this process, material consumption was limited by operating for around 2 min (at least 5 reactor volumes) for each experimental run.
Table 2. Results of Reaction Parameter Optimization
EntryTemp [°C]aResidence time [s]bEquiv of Br2bConversion [%]
1c6018.11.1010
2c6020.11.1031
36022.11.1176
4d6022.01.0977
56023.91.1181
     
6d6518.01.1168
7d6519.61.0460
8d6522.01.1179
96522.01.1088
10d6524.01.1368
     
116022.01.1877
126521.91.1963
13d6522.01.1984
a

Thermostat set temperature.

b

Calculated from flow rates observed at the respective mass flow meters.

c

Average of two separate runs.

d

4 bar back pressure applied; optimum conditions are highlighted in bold.

Under the initial conditions, only 10% of the brominated product 2 was observed. Increasing residence time, temperature, or the equivalents of bromine have been demonstrated, on small scale, to be beneficial for the extent of conversion. Therefore, the influence of those three parameters was investigated. Increasing residence time to 24 s (by lowering flow rates) increased the conversion to 81% (entries 2–5). This significant increase in conversion by increasing residence time by only a few seconds can be ascribed to an initiation period, which is observed in this type of radical transformation. (11a) Using a longer residence time, however, significantly decreases the reaction productivity and should be minimized where possible.
The temperature was increased to 65 °C (entries 6–10). The optimum residence time at this increased temperature was found to be within the screened range at about 22 s. At shorter residence times the system does not have sufficient time to react, while at longer residence times the biphasic mixing gets worse, thus slowing the reaction. These trends are visualized in Figure 4. Interestingly, pressure did not seem to significantly influence the reaction (entry 3 vs 4 or entry 8 vs 9). This was not clear from the beginning, considering that reactions at 65 °C are already above the boiling point of Br2 (58.8 °C).

Figure 4

Figure 4. Overview of selected results from Table 2 (entries 1–10), highlighting the rough trends (dotted lines) of conversion vs residence time. Note: these trends are added only as a visual aid, and are not intended to be extrapolated or to represent a model of the reaction performance. Conversion of 1 was determined by 1H benchtop NMR.

In entry 7, the flow rates of the bromine generator were erroneously set too low, resulting in a bromine loading of only 1.04 equiv. The reduced conversion of 60% shows the effect of having too little bromine in the reaction. However, when increasing the bromine equivalents to 1.2, no increase in conversion was observed.
Entries 4 and 11 both provide 77% of the brominated product 2, demonstrating that under these conditions applying pressure has no influence (a similar relationship is seen between entries 9 and 13—88% and 84% respectively). At the higher temperature of 65 °C and higher bromine loading, the pressure did have an influence on the reaction outcome. Without additional back pressure (entry 12) only 63% conversion was observed, while adding 4 bar increased it to 84% (entry 13). It is noted that applied back pressure only influences the conversion when more bromine (1.2 equiv) is present in reactions at higher temperature (65 °C). This is proposed to be caused by Br2 vaporizing in the absence of pressure, thus shortening the residence time. Consequently, the additional back pressure of 4 bar can counteract this effect.
Additional reaction information can be gleaned from the relationship between the temperature differences observed in the heat exchange medium (see placing of temperature sensors in Figure 5a). The heat generated in the reaction FM rises with increasing conversion, while the opposite occurs in the quench FM (Figure 5b). The overall lower ΔT in the reaction FM compared to the quench FM can be explained by two phenomena: the exotherm of the quench is higher than that of the combined Br2 formation and substitution reactions (Table 1). Additionally, the incoming solutions in the first FM must be heated from room temperature to the corresponding reaction temperature, thus decreasing the observed ΔT in the reaction FM.

Figure 5

Figure 5. (a) Illustrated positions of the temperature sensors in the reactor heat exchange channel. (b) Temperature increase in the heat exchange channel after passing through the reaction or quench FM, plotted against the performance of the reaction (conversion of 1).

In Table 3, the results from this study are compared with those obtained previously, using the lab scale reactor. A maximum productivity of 4.1 kg h–1 was reached, using a 22 s residence time, providing an 88% NMR yield of the brominated product 2. This is a 14-fold increase versus the lab scale productivity of 0.3 kg h–1. The two results can be compared by converting the productivities into space-time yields, revealing that the space-time yield of 108 kg L–1 h–1 in the Lab reactor is higher than the 82 kg L–1 h–1 of the G3 reactor. It should also be noted that caution must be applied in extrapolating to productivity per hour, since such a long run was not possible in this setup, due to restraints in the quantity of available starting materials.
Table 3. Direct Comparison between the Performances of the Lab Reactor vs G3 Reactor
 Lab reactoraG3 reactor
Reactor volumeb [mL]2.850
Optimal conditions18 s, 60 °C, 1.1 equiv of Br222 s, 65 °C, 1.1 equiv of Br2
Yield [%]97c88c
Productivity [kg h–1]0.34.1
Space-time yield [kg L–1 h–1]10882
a

Values based on the previously published scale-out experiment. (14)

b

Volume of the photochemical reaction FM only (G3 quench FM omitted).

c

Assay yield, determined by ratio of starting material to product by 1H NMR.

However, one must consider the scale-up strategy discussed previously (Figure 1b): the Lab reactor, consisting of one FM, translates to a G1 or G3 reactor consisting of five FMs. As a result of the five times higher flow rate, the mixing with five FMs would be substantially improved. As only one G3 FM was available, the flow rate had to be significantly decreased to below the G3 minimum flow rate specifications (minimum recommended flow rate for a biphasic system is 400 mL min–1). Therefore, the scale-up did not follow the system’s specific guidance (from Lab reactor to G3) and led to suboptimal heat- and mass transfer. (20a) Consequently, the achieved conversion of 88% and only marginal decrease in space-time yield is quite remarkable, considering the presence of only a single G3 photochemical reaction FM and the longer irradiated path length (0.4 mm in LF FM vs 1.5 mm in G3 FM).

Further Studies

It remains to be demonstrated that the G3 reactor containing five FMs placed in series will provide better results. Investigating this question would therefore be of interest in proof-of-concept scalability studies. The G1 reactor has an intermediate size between the Lab and G3 reactor. A G1 reactor, consisting of 5 FMs (each equipped with 405 nm LEDs), is more readily available than the corresponding G3 reactor system and has a smaller footprint, more suited to a research laboratory. Due to its smaller size, it would also consume less starting material, which is desirable for parameter optimization studies.
A G1 reactor with five FMs (5 × 9 mL = 45 mL irradiated volume) would consume about 2.8 kg h–1 of DCT 1 using the current flow rates, while the throughput in a G3 reactor with five FMs (5 × 50 mL = 250 mL irradiated volume) would be 15.7 kg h–1 (likely higher, due to anticipated improved reaction performance at higher flow rates, allowing a shorter residence time). An initial G1 experiment, using only one FM, would verify the transferability of the present G3 results. Then, using all five FMs, the improved performance of the Lab reactor could be replicated. These results should then also be transferrable to a G3 reactor with five FMs.

Conclusion

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The previously developed photochemical benzylic bromination, using a Br2 generator under highly intensified conditions, has been successfully transferred from lab to pilot scale (>4 kg h–1 productivity). Preliminary studies concerning heat formation and starting material quality, combined with the optimization data from the lab scale, laid the foundations for a successful scale-up demonstration. A detailed risk assessment, startup and shutdown procedures, and additional safety measures proved indispensable in ensuring safe operation.
The influence of reaction parameters, such as residence time, temperature, equivalents of Br2, and pressure, were studied. Optimum conditions of a 22 s residence time at 65 °C, using 1.1 equiv of Br2, resulted in an 88% assay yield of the brominated product 2. This corresponds to a productivity of 4.1 kg h–1 of 2,6-dichlorobenzyl bromide 2, with a space-time yield of 82 kg L–1 h–1. This work represents a rare example of the significant scale-up of a flow photochemical process, which demonstrates progress toward the widespread implementation of large scale flow photochemistry in the fine chemical industries.

Experimental Section

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Reactor Setup

The reactions were conducted in a commercial continuous-flow photoreactor: Corning G3 Photo Reactor. (22) The reactor used in this work consisted of two fluidic modules (310 mm × 250 mm, 1.5 mm channel depth, 50 mL internal volume per FM), encased within a high capacity heat exchange channel. LED panels equipped with an array of 405 nm LEDs were mounted on both sides of the first fluidic module. A Lauda Proline RP 890 thermostat (1.1 kW cooling power, ethanol as heat exchange fluid, Tset = 10 °C) was used to cool the LEDs. A temperature sensor was positioned in the heat exchange channel at the outlet of the LED panels. For controlling the temperature in the fluidic modules, a Lauda Proline RP 4090 CW thermostat (4.0 kW cooling power, water as heat exchange fluid) was used in combination with a Gather gear pump (2M-J/24/) as a booster pump to increase the flow rate to 6 L min–1. A pressure sensor and three temperature sensors were added to the heat exchange channels as indicated in Figures S11 and S15.

Pumps

Sodium thiosulfate: HNP mzr-7208-hs-f S +SW. 2,6-Dichlorotoluene: HNP mzr-7255-hs-f S +W. Sodium bromate: HNP mzr-7255-cs-f S. HBr: Fuji Super Metering Pump HYM P0-B2-NS-PL-08

Inline Filters

Sodium bromate and 2,6-dichlorotoluene: HNP F-MI3-T. Sodium thiosulfate: Swagelok filter 40 μm.

Pressure Relief Valves

HBr: Fuji Safety Valve AZ02505, others: Swagelok proportional relief valves. All were set to 10 bar.

Startup Procedure

(1) Prime all pumps—both washing fluid and process fluid should be fully primed to the corresponding three-way valve. (2) Fill reactor with water. (3) Turn on the process channel thermostat and allow it to reach a stable temperature (Tset = 60 °C, Toutlet > 55 °C). (4) Turn on LED thermostat and booster pump and allow it to reach a stable temperature (Tset = 10 °C, Toutlet ≈ 19 °C). (5) Turn on LEDs and wait for the corresponding heat exchange channel temperature to equilibrate. (6) Turn on pumps, with their corresponding wash solutions. Allow lagged outlet tube to be preheated with warmed water/isopropanol. (7) Once all temperatures have equilibrated, switch solution input valves in the following order: (1) Na2S2O3, (2) DCT, (3) HBr, (4) NaBrO3.

General Procedure for Optimization Runs

The reactor was started according to the startup procedure. Then, the desired flow rates for the first experiment were set. The pump speeds [%] were adjusted until the flow meters read the desired flow rates. After letting the system equilibrate for about five residence times (∼2 min), a sample of ∼40 mL was collected. By adjusting the flow rates or by changing pressure or temperature, the next conditions were set. After the last sample had been taken, the reactor was turned off following the shutdown procedure.

Shutdown Procedure

(1) Switch HBr and NaBrO3 pumps to water, while still pumping DCT and retaining all pumps at the same pump speed (to avoid precipitation of the product in the tubing of the reactor outlet). (2) Wait until no more Br2/product is formed (flush ∼3–5 reactor volumes). (3) Switch DCT and NaS2O3 pumps to isopropanol and water, respectively. (4) Turn off LEDs. (5) Turn off thermostats and booster pump. (6) Turn off pumps (order is not important since all are pumping only water/isopropanol).

Sample Workup

The organics were extracted using DCM (40–50 mL). Any acidic residue is neutralized by washing with saturated sodium bicarbonate solution. To determine the conversion, a 1H spectrum of the DCM phase was measured on a benchtop NMR (Spinsolve Ultra 43 MHz, Magritek). Given the incomplete conversion, in contrast to the lab scale results, (14) no attempts were made to isolate pure product 2.

Supporting Information

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The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.0c00239.

  • Further details of reaction setup, risk assessment, experimental results and NMR data (PDF)

  • Video of quench FM during experimental runs (MP4)

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Author Information

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  • Corresponding Authors
    • Jason D. Williams - Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, AustriaOrcidhttp://orcid.org/0000-0001-5449-5094 Email: [email protected]
    • C. Oliver Kappe - Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, AustriaOrcidhttp://orcid.org/0000-0003-2983-6007 Email: [email protected]
  • Authors
    • Alexander Steiner - Center for Continuous Flow Synthesis and Processing (CC FLOW), Research Center Pharmaceutical Engineering GmbH (RCPE), Inffeldgasse 13, 8010 Graz, AustriaInstitute of Chemistry, University of Graz, NAWI Graz, Heinrichstrasse 28, 8010 Graz, Austria
    • Philippe M. C. Roth - Corning Reactor Technologies, Corning SAS, 7 bis Avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, France
    • Franz J. Strauss - Microinnova Engineering GmbH, Europapark 1, 8412 Allerheiligen bei Wildon, Austria
    • Guillaume Gauron - Corning Reactor Technologies, Corning SAS, 7 bis Avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, France
    • Günter Tekautz - Microinnova Engineering GmbH, Europapark 1, 8412 Allerheiligen bei Wildon, Austria
    • Marc Winter - Corning Reactor Technologies, Corning SAS, 7 bis Avenue de Valvins, CS 70156 Samois sur Seine, 77215 Avon Cedex, France
  • Funding

    The CC FLOW Project (Austrian Research Promotion Agency FFG No. 862766) is funded through the Austrian COMET Program by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry for Digital and Economic Affairs (BMDW), and by the State of Styria (Styrian Funding Agency SFG).

  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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The authors gratefully acknowledge Patheon Austria GmbH & Co KG (Linz, Austria) for the generous loan of the Lauda Proline RP4090 CW used in this study, and would like to thank Prof. W. Goessler (University of Graz) for performing ICP analysis.

Abbreviations

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API

active pharmaceutical ingredient

BPR

back pressure regulator

DCM

dichloromethane

DCT

2,6-dichlorotoluene

FM

fluidic module

LED

light emitting diode

NBS

N-bromosuccinimide

PFA

perfluoroalkoxy alkane

PMI

process mass intensity

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Organic Process Research & Development

Cite this: Org. Process Res. Dev. 2020, 24, 10, 2208–2216
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https://doi.org/10.1021/acs.oprd.0c00239
Published June 15, 2020

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  • Abstract

    Figure 1

    Figure 1. (a) Flow schematic for the intensified photochemical benzylic bromination of 2,6-dichlorotoluene 1, including bromine generation in the first FM and quench of excess bromine using sodium thiosulfate in the second FM. (b) General scale-up strategy for Corning Advanced-Flow Reactors, versus the scale-up demonstrated in this study. Scale-up workflow is based on maintaining a consistent residence time, to achieve consistent results (i.e., linear scaling of flow rates with reactor volume). The scale-up comparison demonstrated here represents a direct transfer from a G1 LF FM to a single G3 FM, whereas the standard strategy would suggest 5 × G3 FMs. Fluidic module images copyright 2015 and 2017 Corning Incorporated.

    Figure 2

    Figure 2. Piping and instrumentation diagram (PID) showing the process streams in black, heat exchange channels for the reaction and quench FMs in red, and the LED heat exchange channel in blue. PI = pressure sensor; FI = flow meter; TI = temperature sensor.

    Figure 3

    Figure 3. Snapshot from the live video stream captured by the webcam, showing the quench FM (streams combine and enter in top right corner, flow direction depicted by arrows, see Figure 1b for a full view of the FM). Quenching of the excess Br2 (highlighted by white ellipse) can be observed by a color change as the reaction mixture moves through the channel.

    Figure 4

    Figure 4. Overview of selected results from Table 2 (entries 1–10), highlighting the rough trends (dotted lines) of conversion vs residence time. Note: these trends are added only as a visual aid, and are not intended to be extrapolated or to represent a model of the reaction performance. Conversion of 1 was determined by 1H benchtop NMR.

    Figure 5

    Figure 5. (a) Illustrated positions of the temperature sensors in the reactor heat exchange channel. (b) Temperature increase in the heat exchange channel after passing through the reaction or quench FM, plotted against the performance of the reaction (conversion of 1).

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      (d) Ni, S.; El Remaily, M. A. E. A. A. A.; Franzén, J. Carbocation Catalyzed Bromination of Alkyl Arenes, a Chemoselective Sp3 vs. Sp2 C-H Functionalization. Adv. Synth. Catal. 2018, 360, 41974204,  DOI: 10.1002/adsc.201800788
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    22. 22
      For details on the G3 reactor used in this study, see: https://www.corning.com/worldwide/en/innovation/corning-emerging-innovations/advanced-flow-reactors.html.
  • Supporting Information

    Supporting Information


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    • Further details of reaction setup, risk assessment, experimental results and NMR data (PDF)

    • Video of quench FM during experimental runs (MP4)


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