The Synthesis of Bromomethyltrifluoroborates through Continuous

Article pubs.acs.org/OPRD

The Synthesis of Bromomethyltrifluoroborates through Continuous Flow Chemistry Toby Broom,*,⊥ Mark Hughes,† Bruce G. Szczepankiewicz,‡ Karl Ace,† Ben Hagger,† Gary Lacking,∥ Ranjit Chima,† Graeme Marchbank,† Gareth Alford,† Paul Evans,† Christopher Cunningham,§ John C. Roberts,‡ Robert B. Perni,‡ Malcolm Berry,† Andrew Rutter,† and Simon A. Watson† ⊥

GlaxoSmithKline, Research and Development, 709 Swedeland Road, King of Prussia, Pennsylvania 19406-0939, United States GlaxoSmithKline, Research and Development, Gunnelswood Road, Stevenage SG1 2NY, United Kingdom ‡ Sirtris, a GSK Company, 200 Technology Square, Suite 300, Cambridge, Massachusetts 02139, United States § Glaxo Operations UK, Ltd., Drug Manufacturer, Priory Street, Ware, Hertfordshire SG12 0DJ, U.K. †

S Supporting Information *

ABSTRACT: A continuous flow process was developed for the synthesis of potassium bromomethyltrifluoroborate, a key precursor for Suzuki−Miyaura coupling reagents. The continuous flow process was used to produce potassium bromomethyltrifluoroborate on scales from grams to kilograms, and the successful process utilized a fraction of the resources required for the batch synthesis. In the plant, a team of three people produced approximately 100 kg of potassium bromomethyltrifluoroborate in less than 4 weeks. This process makes it both practical and economical to use potassium bromomethyltrifluoroborate and its derivatives for multikilogram-scale Suzuki−Miyaura couplings.

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INTRODUCTION The Suzuki−Miyaura coupling is a widely used reaction for the preparation of carbon−carbon bonds.1 Since 2006, work by the Molander group and others has demonstrated that this reaction can be used to substitute an aryl halide with methylene groups bearing functionality such as a dialkylamine, an ether, or a thioether.2 This “functionalized methylene” coupling reaction requires a methyl boronate coupling partner 1, which is usually prepared, via bromomethyltrifluoroborate 2, in two steps according to Schemes 1 and 2.3 Compound 2 was an early intermediate in a synthesis that the chemical development team at GSK hoped to use for multikilogram production of a drug candidate. This made it necessary to procure a generous supply of 2, well beyond the amounts that could be purchased from any commercial sources. Therefore, it became critical to prepare 2 on an unprecedented scale. The quality of 2 produced by the published procedure was good, but there are limitations to implementation on a scale greater than 100 g. One limitation is that the exothermic butyllithium addition must be performed while maintaining an internal reaction temperature close to −78 °C. The cryogenic temperature is a requirement for good product quality, but efficient heat removal is more difficult to achieve on a large scale than on a small scale. A second limitation is that the published procedure requires large solvent volumes upon scaleup, leading to low material throughput. In anticipation of the eventual need for hundreds of kilograms of 2, the team required a synthetic strategy that would circumvent the limitations in the existing protocol. The speedy delivery of 50 kg of high-quality 2 was of primary importance to the project. To achieve this goal, the team explored the possibility of running the cryogenic reaction in continuous flow mode. The following factors favored the © XXXX American Chemical Society

development of a continuous process: halogen−metal exchange reactions are generally fast;4 cooling a small tube in a flow kit is much less power intensive than cooling a typical batch reactor; and reactions carried out in flow mode are particularly wellsuited for handling unstable intermediates such as 3. This article describes the chemistry and engineering issues that were encountered and overcome during the development of a continuous flow process for large-scale production of potassium bromomethyltrifluoroborate 2.

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RESULTS AND DISCUSSION To gain familiarity with the chemistry, the team performed a number of small-scale flow reactions using the conditions reported by Molander.3 A typical reaction utilized a premixed solution of 1.2 M dibromomethane and 1.05 M triisopropylborate in THF at −60 °C as one feed, and a solution of 2.5 M nbutyllithium in hexanes at −60 °C as a separate feed. The flow rates were adjusted to ensure that n-butyllithium was the limiting reagent. Both streams were combined in a plate reactor with a residence time of 45 s at −60 °C, after which the exit stream containing 4 was collected into a stirred reactor (Scheme 3 and Figure 1). With 4 in hand, the next step was to convert the borate ester to a trifluoroborate salt. The published protocol used an aqueous KHF2 slurry to accomplish this transformation. For continuous flow work, an aqueous solution of KHF2 reduced the risk of tubing blockage and also ensured consistent delivery of the fluoride source. However, the limited KHF2 solubility in Special Issue: Continuous Processes Received: April 8, 2013

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dx.doi.org/10.1021/op400090a | Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Scheme 1. Suzuki−Miyaura coupling reagent 1 from key intermediate 2

Scheme 2. Synthesis of potassium bromomethyltrifluoroborate (2)

quickly. Higher flow rates were insufficient to keep lithium fluoride suspended, forcing the team to consider other options. To avoid clogging the reactor, the in-line quench was abandoned, and an off-line quench method was developed instead. The stream containing 4 was collected in a stirred reactor, and at the same time, aqueous HF was added to the reactor, converting 4 to lithium trifluoroborate salt 5 (Scheme 4).6 An excess amount of HF was required to complete the

Scheme 3. Initial conditions in flow

water (3 M at −7 °C) led to large workup volumes and long evaporation times upon scale-up. When a solution of aqueous HF was used instead of aqueous KHF2, concentrations of up to 40 wt % HF in water (20 M) could be used, decreasing solvent volume by more than a factor of 6, and improving throughput immensely. The use of hydrofluoric acid would seem to introduce a new safety hazard into the process, as the contact risk with aqueous HF is well-known.5 In the laboratory, where all of the reagents must be introduced into the reaction manually, solid KHF2 presents a smaller exposure risk than aqueous HF. However, with a continuous flow process, the HF handling would be automated, making operator exposure less of a concern. HF is also less expensive than KHF2, reducing the raw material cost for the process. After deciding that aqueous HF was the preferred reagent for the borate to trifluoroborate conversion, the next step was to determine the optimal conditions for HF addition to the solution containing 4. The team investigated an in-line quench scenario where 30% aqueous HF was introduced after 4 had formed.5 At this concentration, the freezing point of aqueous HF is approximately −70 °C, which ensured that ice would not form when the HF solution contacted the cold reaction mixtures during the quench. While ice did not form, small quantities of highly insoluble lithium fluoride did form. This precipitated from the mixture and blocked the tube reactors

Scheme 4. Quench of the triisopropylborate 4 with HF

borate to trifluoroborate reaction, because some HF was consumed by unreacted triisopropyl borate remaining from the first step (Scheme 3). Also, LiF can react with HF to make LiHF2, which could divert more HF from the desired transformation. The trifluoroborate yield was approximately 60−76% (solution yield of lithium salt) which was similar to the yields obtained using the published protocol. Although the product yield was satisfactory, the product purity needed improvement. During the early runs, a particularly troublesome impurity, butyltrifluoroborate 7, was identified in the product. The introduction of 7 was an undesirable consequence of incomplete halogen−metal ex-

Figure 1. Laboratory-scale continuous flow process diagram. B



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Scheme 5. Side reaction of n-BuLi with triisopropylborate and subsequent reaction with HF

change. If n-butyllithium was not consumed immediately by halogen−metal exchange with dibromomethane, it reacted directly with triisopropyborate, producing lithium butyltriisopropoxyborate 6 (Scheme 5). This species is very similar to the desired intermediate 4, and consequently 6 would undergo conversion to a trifluoroborate when treated with HF, producing lithium n-butyltrifluoroborate 7; analysis of this material was concordant with that reported.7 When 5 was contaminated with 7, it proved to be very difficult to remove the n-butyl impurity. The team optimized the stoichiometry for the flow setup by increasing the excess of dibromomethane to 1.3 equiv and lowering the amount of triisopropylborate to 1 equiv to ensure that all the nbutyllithium was consumed by halogen−metal exchange, thereby suppressing the formation of 7. These conditions were successfully employed to produce tens of grams of 5 that met purity specifications. To prepare kilograms of 5, the team embarked on the first pilot plant campaign. However, a number of unforeseen challenges were encountered in the plant. The adiabatic temperature rise for the addition reaction (Scheme 3) was 200 °C for 1 M reaction as measured by reaction calorimetry using Mettler Toledo RC1. In the laboratory, where the more efficient and more expensive “plate” reactors were used, heat dissipation was sufficient to maintain the temperature below −45 °C, and product formation occurred smoothly. In the pilot plant, the use of the less efficient, but more economical, “shell and tube” reactors8 led to the rapid rise in temperature from −80 °C to greater than −40 °C during the addition reaction (Scheme 3). The temperature spike resulted in the formation of a precipitate that clogged the reactor and stopped the flow. The precipitate formed as reaction intermediates decomposed to generate less soluble products. Prior to the addition of fluoride, lithium triisopropylborate salt 4 is the immediate product of (bromomethyl)lithium addition to triisopropyl borate. Lithium triisopropoxyborate salt 4 is thermally unstable above −40 °C. When the temperature exceeded −40 °C, 4 yielded diisopropylboronate 8 and lithium isopropoxide (Scheme 6).

These problems in the plant prompted a return to small-scale work using similar “shell and tube” heat exchangers to better mimic plant conditions. The team found that a series of three modifications provided a process that could operate without clogging in the plant. First, a more dilute solution of triisopropylborate (0.3 M instead of 1.0 M) served to slow the rate of the exothermic addition reaction and blunt the temperature spike (the adiabatic temperature rise was now only 60 °C). Second, a higher flow rate dissipated the evolved heat more efficiently upon butyllithium addition. Third, the reactors PAU8A and PAU8B were set up in series, and 0.5 equiv of butyllithium was introduced to each reactor, further reducing the reaction rate in order to better maintain the internal temperature below −45 °C. Together, these modifications provided the temperature control necessary to prevent unwanted side reactions (Scheme 6). Using the revised conditions, the second plant campaign went very well (Figure 2). Unlike the first pilot-plant campaign, there were no blockages. The second campaign ran for 240 consecutive hours, and 10 kg of 5 were produced each day for a total of 100 kg. This was double the amount necessary to fulfill the original request for 50 kg of 2. After 3850 L of solution of 5 was collected, this solution was divided into five batches; each batch was concentrated from 770 to 334 L by distillation. This solution was used for the final cation exchange from lithium salt10 5 to potassium salt 2 (Scheme 7). After the addition of aqueous KF, the pH was adjusted to 6.5−7 so that decomposition of 2 did not occur during the subsequent solvent-swap to acetonitrile. Lithium fluoride, potassium bifluoride, and potassium fluoride precipitated from the mixture and were subsequently removed by filtration, while potassium bromomethyltrifluoroborate 2 remained in solution. Addition of toluene to the solution afforded 2 as a crystalline solid. After filtration and drying, a total of 109 kg of 2 was isolated from the campaign. While the production of 5 was efficient and completed in 10 days via continuous processing, it took an additional 14 days to convert all of 5 to 2. Further development might afford a continuous flow method for the cation-exchange step, but due to time constraints, the team chose to use a traditional largescale batch distillation and isolation for the final transformation. The use of a “continuous-hybrid” approach where the most appropriate processing technology for a given step is selected proved to be very successful in delivering the project objectives.

Scheme 6. Poorly controlled exotherm leads to side reactions from 4

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SUMMARY At the outset of this work, the synthesis of potassium bromomethyltrifluoroborate (2) was limited to maximum batch sizes of about 100 g. A continuous flow strategy provided the temperature control needed to prepare much larger amounts of 2. After adjusting the reaction conditions so that no solids were present during the flow portion of the synthetic sequence, the process ran for 10 consecutive days in the pilot plant. This resulted in the preparation of over 100 kg of 2 in less than one month. The continuous flow reaction facilitated a halogen−metal exchange, followed by an addition, while the subsequent transformation of a borate ester to a trifluoroborate

Lithium isopropoxide and any unreacted triisopropylborate can combine to generate lithium tetraisopropoxyborate, which is very insoluble9 at −40 °C, and led to complete blockage of the flow apparatus (Scheme 6). Moreover, lithium isopropoxide can subsequently react with 4 to generate significant amounts of ether 9, which introduced an impurity into the product. C



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Figure 2. Diagram of second pilot-plant campaign setup.

countercurrent mode. Initial mixing of streams was done via a T-piece. Preparation of 5 in BHR Marbond13 Plate Reactor (2 mL internal volume). A mixture of dibromomethane (5 g, 28.8 mmol) and triisopropyl borate (4.73 g, 25.2 mmol) in tetrahydrofuran (19 mL) was prepared. This was enough solution to run for 15 min; the first 6 mL of solution was discarded while the reaction achieved steady state, and another 2.4 mL was left to avoid pumping the system dry. This solution was pumped at 1.8 g/min and mixed in flow with 2.5 M n-butyllithium in hexanes (1 equiv) pumped at 0.5 mL/min. These flow rates ensured that the mixture was held at −60 °C for 45 s. The reaction mixture was collected in a batch reactor and quenched at room temperature with 30% (w/w) hydrofluoric acid (4.5 mL, 75 mmol) to give a solution of compound 5 (2.15 g, 68%). 1H NMR assay14 was used to determine the yield of 5 in solution. Preparation of 5 in Shell and Tube Reactor8,15 (35 mL internal volume). A mixture of dibromomethane (633.9 g, 3.65 mol) and triisopropyl borate (527.6 g, 2.81 mol) in tetrahydrofuran (8.19 kg) was prepared. This was enough solution to run for 320 min; the first 53 mL of solution was discarded during startup. This solution was pumped at 14.8 g/min and mixed in flow with 2.5 M n-butyllithium in hexanes (1 equiv) pumped at 1.8 mL/min. The flow mixture was held at −60 °C for 1.97 min. The reaction mixture was collected in a batch reactor with NaCl/ice cooling, and quenched with 30% (w/w) hydrofluoric acid (4 equiv) pumped at 1.2 g/min to give a solution of compound 5 (349 g, 74%). Preparation of 5 in Pilot Plant (shell and tube reactor, 86 mL internal volume). Plant Equipment. All custom lines were composed of perfluoroalkoxy (PFA) polymer tubing, fixed lines were Hastelloy C22, and all joints were made using Hastalloy Swagelok parts. Pumps manufactured by HNP Mikrosysteme GmbH, model MZR-7255, were used for all reagents and solvents (the hydrofluoric acid pump was fitted with silicon carbide gears and the others with zirconium oxide). PAU8A,B and precooler were identical, the tube reactor was 10

Scheme 7. Salt exchange from lithium to potassium

salt was accomplished continuously, but in the flow collecting tank rather than in-line. The most time-consuming part of the entire process was the cation exchange of the initially generated lithium salt for the final potassium salt. It would be worthwhile to determine whether lithium salt 5, while unstable to isolation,10,11 could be used directly in Suzuki−Miyaura coupling reactions, eliminating the need for a lengthy isolation process of potassium salt 2. As with many continuous flow processes, the amount of material generated was directly proportional to the amount of time the process was allowed to run. The upper limit for material that could be generated by the process in its current form is in the range of several tons per year. The continuous flow strategy makes the synthesis of 2 far more economical than the routes used by current commercial suppliers. It also makes it practical to use 2, and perhaps 5, in multikilogram synthetic campaigns.

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EXPERIMENTAL SECTION Aqueous hydrofluoric acid was diluted to 30% (w/w) in the laboratory reactions from 40% (w/w) commercially available material. n-Butyllithium (2.5 M) in hexanes was purchased and used as obtained. All other materials were used as obtained from commercial sources. Laboratory Equipment. All lines were composed of perfluoroalkoxy (PFA) polymer. A Jasco HPLC pump was used to pump n-butyllithium solutions.12 Pumps manufactured by HNP Mikrosysteme GmbH, models MZR-7255 for the THF solution and MZR-4605 for hydrofluoric acid were used. Chillers were supplied by Huber. The tube reactor was 8 mm by 1500 mm and was fitted with Sulzer SMX static mixers; the shell was 50 mm outside diameter with the coolant run in a D



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mm by 2000 mm and was fitted with Sulzer SMX static mixers and constructed from Hastalloy C22, the shell was a baffled tube of 70 mm outside diameter with coolant run in a counter current fashion. PAU15 CR1 was a 30-L batch reactor constructed from Hastelloy C22. Chillers were supplied by Huber and heat exchangers by Exergy. For a schematic diagram of the plant apparatus, refer to Figure 2. Initial mixing of streams was done via a T-piece. A glass-lined, steel 150-L batch reactor was charged with tetrahydrofuran (122.4 kg), dibromomethane (9.48 kg, 54.5 mol), and triisopropylborate (7.9 kg, 42 mol); the lines were rinsed with tetrahydrofuran (2 × 2 kg). This was enough solution to run for 16 h at steady state. Fresh batches of starting solution were prepared throughout the 10-day run as needed. The butyllithium and hydrofluoric acid reservoirs were refilled as needed. For startup/shutdown procedure see reference 15. At Steady State.16 The (i-PrO)3B/CH2Br2 solution was pumped at 150 g/min from PAU2 through a heat exchanger (Tj = −80 °C). The 2.5 M n-butyllithium in hexanes solution was pumped at 12.47 g/min from TGB though PAU8 precooler (Tj = −80 °C) after which the feed was split in a ∼1:1 ratio before being mixed with the other solution in reactors PAU8A and PAU8B. The reactors were placed in series, allowing 1/2 of the reaction to occur in each reactor. The total reaction time in both reactors was 1.95 min with an internal reactor temperature of −45 °C in PAU8A and −65 °C in PAU8B, both with jacket temperatures of −80 °C. The outlet of PAU8B was fed to PAU15 CR1 (Tj = −12 °C), where it was quenched with 30% w/w hydrofluoric acid pumped at 12 g/min from additive tank PAU8 (Tj = 22 ± 5 °C). PAU15 CR1 took 70 min to fill (20 L) before being discharged to the Hastelloy C22 400-L batch reator;17 during this time the contents warmed to −7 °C. PAU15 CR1 was sampled periodically and analyzed off-line by NMR to verify content quality (average solution yield of 5 was 66%). Preparation of 2. A total volume of 3850 L of solution containing 100 kg of 5 was produced. This was divided into 200 L drums for transportation. The solution was processed in five equal batches, and each batch was processed using this procedure. A Hastelloy C22 400-L batch reactor was filled with 400 L of solution, then the volume was reduced to 200 L. A further 200 L was added, and then the volume was reduced to 200 L. After another charge of 170 L, the volume was reduced to 334 L containing solution of 5 (20 kg in 334 L). To this was added 46.5% w/w potassium fluoride solution in water (25.1 kg, 1.82 equiv) and 45% w/w potassium hydroxide solution in water (8.4 kg, 0.57 equiv). Constant volume distillation was performed with acetonitrile (800 L, temperature 70 to 81 °C). The slurry was cooled to 60 °C. The inorganic salts were filtered from the mixture, and then the cake washed with acetonitrile (40 L). The combined filtrate and washings solution was concentrated to ∼9 vols (180 L). Toluene (200 L) was added to the mixture at 60 °C over 1.5 h, and then the mixture was cooled to ambient temperature over 30 min. The slurry was filtered to collect the product; then the cake was washed with TBME (76 L). The wet cake was dried under vacuum at 20 °C for 18 h to remove residual solvents, giving compound 2 (21.8 kg, 91%) as a colorless solid. The overall isolated yield of 2 from triisopropylborate was 60%.

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ASSOCIATED CONTENT

S Supporting Information *

1 H NMR, 19F NMR, and IC data for potassium bromomethyltrifluoroborate (2). This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Present Address

∥ Jaguar Land Rover UK, Halewood, Liverpool, Merseyside L24 9BJ, U.K.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Special thanks to Nick Yarwood, Spence Calvert, Matthew Till, Lionel Kirbyshire, Michael Wilkins, Mick Wood, Adam Pratt, and Wayne Tunnah for the operation of the flow and batch equipment.

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ABBREVIATIONS MRT mobile reactor trolley PAU preassembled unit TGB toxic glovebox RV reaction vessel CR1 crystallizer 1 PTWS pressure test with solvent Tj jacket temperature

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REFERENCES

(1) (a) Suzuki, A. Cross-coupling Reactions of Organoboron Compounds with Organic Halides. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.; Wiley-VCH Verlag GmbH: Weinheim, Germany, 1998; pp 49−97. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457−2484. (c) Suzuki, A. J. Organomet. Chem. 1999, 576, 147−168. (2) (a) Molander, G. A.; Febo-Ayala, W.; Ortega-Guerra, M. J. Org. Chem. 2008, 73, 6000−6002. (b) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2767−2770. (c) Molander, G. A.; Sandrock, D. L. Org. Lett. 2007, 9, 1597−1600. (d) Molander, G. A.; Canturk, B. Org. Lett. 2008, 10, 2135−2138. (e) Fleury-Bregeot, N.; Raushel, J.; Sandrock, D. L.; Molander, G. A.; Dreher, S. D. Chem.Eur. J. 2012, 18, 9564−9570. (f) Molander, G. A.; Gormisky, P. E.; Sandrock, D. L. J. Org. Chem. 2008, 73, 2052−2057. (g) Astrazeneca AB; Astrazeneca UK Ltd. WO/2009/136191 A1, 2009. (viii) Ortho-McNeil-Janssen Pharmaceuticals, Inc.; WO/2009/62676 A2, 2009. (h) Addex Pharma S.A. WO/2009/62676 A2, 2009. (3) Molander, G.; Ham, J. Org. Lett. 2006, 8, 2031−2034. (4) Rogers, H. R.; Houk, J. J. Am. Chem. Soc. 1982, 104, 522−525. (5) Safety notes: Aqueous solutions of HF up to 40% w/w (or 48% w/v) do not fume. Beyond this concentration, HF will fume and pose serious risks to personal safety. For freezing point information of aqueous HF solutions at various concentrations, see www.hfacid.com. (6) (a) Translation of Zh. Neorg. Khim. Salyn’, Ya. V.; Nefedov, V. I.; Maiorova, A. G.; Kuznetsova, G. N.; Sukakova, T. N.; Krasnoshchekov, V. V. Russ. J. Inorg. Chem. 1978, 23, 829−831. (b) Ryss, I. G.; Sluckaja, M. M.; Palevskaja, S. D. Zh. Fiz. Khim. 1948, 22, 1322−1330. (7) Frohn, H.-J.; Franke, H.; Fritzen, P.; Bardin, V. V. J. Organomet. Chem. 2000, 127−135. (8) Perry, R. H.; Green, D. W. Perry’s Chemical Engineers’ Handbook, 6th ed.; McGraw-Hill: New York, 1984; Chapter 11. (9) (a) Brown, H. C.; Nazer, B.; Sikorski, J. A. Organometallics 1983, 2, 634−637. (b) Brown, H. C.; Mead, E. J. J. Am. Chem. Soc. 1956, 78, 3614−3616. E



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(10) In our hands, attempts to isolate the lithium salt were unsuccessful; only gummy residues were isolated. (11) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R. J. Org. Chem. 1995, 60, 3020. (12) The HPLC pump could be used safely if thoroughly primed with inert solvents (THF, heptane) in both front and rear portions. The rear portion was flushed on a periodic basis to ensure there was no buildup of materials. (13) (a) Phillips, C. H.; Lauschke, G.; Peerhossaini, H. Appl. Therm. Eng. 1997, 17, 809−824. (b) Reay, D. A. Int. J. Refrig. 2002, 4, 460− 470. (c) (Chart Marston Ltd.). WO/1998/55812, 1998. (14) Typical concentration is ∼3 wt %/wt. To 13.8 g of a solution containing 4 is added 178 mg of DMF; 50 μL of the mixture is taken and diluted with 800 μL of d6-acetone. (15) The reagents were precooled by wrapping the feed tubing around the shell under the insulation. (16) A PTWS was performed on the plant before use to ensure no leaks were present; isohexane was used in place of butyllithium, THF in the presence of the solution of reagents, and water in the presence of hydrofluoric acid. The plant was primed with solvents from PTWS, and the TGB recirculation was started. The chillers were cooled to their −80 °C set point. PAU2 and 8 were started, followed by the TGB, all material was sent to waste for 10 min (∼1.6 kg of solution). The reaction mixture was then fed into PAU15 CR1, and the first 20 L was discarded. The reaction was declared to be at steady state when NMR samples met specifications, solution assay greater than 2.5% w/ w. The shutdown procedure was the reverse of the startup exchanging the PTWS solvents for reagents. (17) The transfer is done using a vacuum on RV1104. As it was not possible to add material to PAU15 CR1 while under vacuum, the reaction mixture from PAU8B was sent to waste, and hydrofluoric acid charging was suspended for ∼15 min (∼2.4 kg of solution).

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The Synthesis of Bromomethyltrifluoroborates through Continuous

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