Advancing Flow Chemistry Portability: A Simplified Approach to

Communication Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Advancing Flow Chemistry Portability: A Simplified Approach to Scaling Up Flow Chemistry François Lev́ esque,* Nicholas J. Rogus,* Glenn Spencer, Plamen Grigorov, Jonathan P. McMullen, David A. Thaisrivongs, Ian W. Davies,† and John R. Naber Process Research and Development, Merck & Co., Inc., P.O. Box 2000, Rahway, New Jersey 07065, United States

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S Supporting Information *

goal would depend on our capacity to characterize mixers across all scales and define the minimum requirements to ensure sufficient mixing intensity upon scale-up. Understanding the impact of mixing intensity on reaction performance7 has been particularly important in our recent developments around fast continuous flow reactions.8 Part of this laboratory development involves the selection of an appropriate micromixer.9 Choosing a robust mixer and identifying sufficient mixing intensity can be a challenging task, as a variety of options are commonly available for smallscale development of flow chemistry.10 To assist with this decision, several studies have investigated the relationship between lab mixer design, flow rate, pressure drop, and mixing intensity.11,12 It is also possible to estimate the mixing time scale for a given mixer design as a function of the operating conditions.13 This latter approach may be preferable when the kinetics of the reaction of interest has been measured. These quantitative techniques are preferable when one has complete control over the equipment selection, experimental setup, and necessary analytical tools. In manufacturing settings, it is not uncommon to forfeit some of this control in order to operate within existing capital and other production constraints, such as limited instrumentation, fluidic connection size and geometry, and plant safety concerns. This can be especially true when working in the contract manufacturing arena. However, it is still imperative to understand mixing in these environments and apply the information to predict reaction performance. Because of the limited availability of drug substance intermediates and starting materials, it is preferable to characterize the quality of mixing across many scales and in a variety of mixers in a resource-efficient manner through the use of a benchmark reaction. One way to characterize mixing efficiency is to employ a well-documented and highly reliable competitive chemical reaction, such as the fourth Bourne reaction, in which 2,2dimethoxypropane (DMP) and a base (sodium hydroxide) are mixed with an acid (nitric acid).14 The Bourne reaction has been applied to the scale-up of continuous static mixers to show that energy dissipation is a suitable scale-up parameter for reactions controlled by micromixing and that residence time is an appropriate scale-up criterion when mesomixing determines the performance.15 The reaction leads to either the desirable acid−base neutralization or the hydrolysis of DMP (Scheme 1). Complete mixing favors neutralization, while

ABSTRACT: We report mixing characterization of five lab-scale and eight production-scale static mixers using a modified fourth Bourne reaction. An efficient inline method relying on UV−vis spectroscopy was developed to streamline analysis of the product distribution. As a result of these studies, we have designed, 3D-printed, and characterized a stainless steel static mixer. This approach enabled the evaluation of different configurations and ensured efficient scale-up across development and commercial facilities that should allow for enhanced portability of mixing-sensitive processes. KEYWORDS: flow chemistry, static mixer, 3D-printing, inline analysis

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he manufacturers of active pharmaceutical ingredients and their intermediates have recently rediscovered flow chemistry and continuous processing.1 This renewed interest in these technologies2 has arisen from the anticipated benefit in supply chain economics and regulatory pressure in addition to the obvious opportunity for improved control, including heat and mass transfer,3 process safety, access to high-pressure and high-temperature conditions,4 and use of supported catalysts5 and biocatalysts.6 In some parts of the community there has been an assumption of ease and straightforward scalability for flow chemistry. In general, the production capacity of any continuous process can be increased in three ways: “scaling up” by increasing the reactor size, “numbering up” by multiplying the number of reactors performing the transformation in parallel, and “scaling out” by running a reaction for a longer period of time. Two of these approaches are wellsuited for processes where all of the steps are performed in flow (numbering up and scaling out) but are more challenging when a flow step is embedded between two batch operations. In the ideal case, the flow step would be completed within the same amount of time as a typical batch operation, which in our experience is usually 8−24 h. To achieve this requirement, the productivity obtained in a laboratory-scale reactor would need to be increased by several orders of magnitude, precluding the simple scaling-out or numbering-up approaches. However, scaling up by changing the size/geometry of the flow reactor will lead to challenges similar to those generally observed in batch reactions. In the case of reactions that require optimal mixing for selectivity and yield, the need to preserve the same characteristics at production scale is essential. Achieving this © XXXX American Chemical Society

Received: February 28, 2018 Published: June 27, 2018 A

DOI: 10.1021/acs.oprd.8b00063 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

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Scheme 1. Fourth Bourne Reaction Network Where Complete Mixing Favors the k1 Pathway and Poorer Mixing Favors the k2 Pathway

Table 1. Specifications of Mixers Tested in the Laboratory

1)16 using fourth Bourne reaction conditions based on works by Schwolow11a and Baldyga.14 Stock solutions were made using 25 wt% ethanol in deionized water. One solution was prepared with 0.580 M HNO3 and 0.083 M NaCl, and the other solution was prepared with 0.285 M DMP, 0.300 M NaOH, and 0.083 M NaCl. Throughout the laboratory experiments, the ratio of the flow rates of the DMP/NaOH and nitric acid streams remained constant at 2:1, such that the initial inlet concentrations of HNO3, DMP, and NaOH to the micromixer were 0.193, 0.19, and 0.20 M, respectively. This 2:1 flow rate ratio corresponded to the conditions used in one of our flow chemistry applications that we were simultaneously developing. Under these conditions, the DMP conversion was recorded for each mixer as a function of total flow rate between 1−100 mL/min. The five laboratory mixers were identified by “L” and an indexing number. Mixer L1 was a 0.5 mm diameter Y-mixer. Mixer L2 incorporated a static mixer.17 Mixer L3 was

incomplete mixing leads to concentration gradients that promote acetone formation. With a reliable method of measuring mixing efficiency, our approach for scaling mixingsensitive reactions involves (1) optimizing the reaction conditions (e.g., flow rates, temperature, flow ratio, mixer design) at the lab scale, (2) performing the fourth Bourne reaction using the same flow conditions to establish the minimum required mixing efficiency, (3) performing the fourth Bourne reaction at the pilot-plant and production scales to allow the identification of a setup capable of reaching the required mixing efficiency, and (4) performing the reaction on scale under the optimized flow conditions. This systematic approach can be used to scale potentially all mixing-sensitive reactions with rapid kinetics and was applied in a recent publication.8 Our initial goal was to establish the performance of five commercial static mixers that were readily available (Table B



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Scheme 2. Lab-Scale Reactor Setup for Mixer Characterization

Figure 1. Conversion as a function of flow rate.

an arrowhead mixer containing a 10 μm stainless steel frit to improve mixing. Mixers L4 and L5, designed by MiChs,18 were spiral and interdigital mixers, respectively. Initially, analysis of the reaction stream to determine the DMP:acetone ratio was performed by gas chromatography (GC) analysis. Although this method is highly reliable, a realtime analytical tool is preferable. To streamline the analysis process, we developed an inline monitoring19 method using UV−vis spectroscopy (Scheme 2). In this case, instead of following the disappearance of DMP, the formation of acetone was monitored. The UV absorbance was measured at 265 nm, which corresponds to the maximum absorption coefficient of acetone. A calibration curve showed good correlation with the conversion at every concentration without reaching the absorbance maximum at high conversion.20 Testing the method by passing standard solutions through the mixer and UV−vis spectrophotometer revealed the analysis to be effective, and because of the overall small dead volume of the reactor, the monitoring was almost instantaneous. However, when we initially tried to apply the same technique to a reaction stream, large variations of the UV−vis signal were observed. This was attributed to the inherent pulsation observed while using HPLC or peristaltic pumps, which has a detrimental impact on the stoichiometric ratio of the reagents. To address this problem, we switched to the use of piston pumps, which provided feeds with minimal pulsation and covered the flow rate (up to 204 mL/min) and pressure range (up to 3750 psi) required to perform the mixing study. To our great delight, this system modification led to very stable UV−vis absorbance over a specific set of conditions. Working with an inline detector to characterize the lab mixers

dramatically reduced the amount of time dedicated to analysis. Furthermore, it allowed us to verify that a steady state was achieved before recording the final absorbance value and advancing to the next set of experimental conditions. Overall, mixers L3, L4, and L5 gave the best mixing efficiency, reaching less than 20% conversion to acetone at combined flow rates of 30 mL/min (Figure 1). This trend was aligned with expectations, as these mixers have a small mixing length scale either through geometry or fluid pathway design. It is also interesting to point out the limited influence of the static mixer in L2 relative to the Y-mixer (L1), where improved mixing was observed only at a low flow rate. In every case, a sharp drop in conversion was observed over a relatively small change in flow rate. For example, in the case of mixer L5, at 22 mL/min a conversion of 44% was obtained, whereas at 28 mL/ min the conversion was limited to only 10%. Interestingly, the conversion data for several mixers exhibit a degree of curvature where the acetone conversion increases slightly before decreasing at higher flow rates. While unexpected, this trend has been reported in previous investigations.11a This behavior is observed at higher conversion levels (greater than 50%) and is an indicator of particularly poor mixing. The fourth Bourne reaction is a mixing-sensitive reaction and is more commonly used to understand the mixing intensity under conditions where the DMP conversion is low. Rather than establishing firm conclusions about the mixing for conditions where the DMP conversion was elevated, we qualitatively deemed these conditions inappropriate for mixing-sensitive reactions and focused on understanding the flow rates that afforded modest to low DMP conversion. C



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Scheme 3. Pilot-Plant Equipment Setup for Fourth Bourne Reaction Testing.a

For nitric acid solution flow rates greater than 90 kg/h, an alternate setup was used in which the nitric acid was fed using flow meter A and DMP/ NaOH was fed using a manually controlled flow meter capable of flow rates up to 2180 kg/h. a

controllers to adjust the flow rates. For equipment that is common in the manufacturing environment, pressure-driven flow has been shown to be more stable and less oscillatory than pump-driven flow. Similar to the lab investigations, the total flow rate was varied while keeping the ratio of the DMP/base solution and acid solution mass flow rates constant at 2:1. During the pilot-plant experiments, the pressure drop was measured across the flow reactor, and a slip stream of the reaction mixture was sampled for conversion prior to collection in waste drums. The volume downstream of the mixer and sample port was approximately 60 mL. Given the anticipated fast kinetics of the fourth Bourne reaction and the flow rates investigated in the pilot plant, we did not anticipate this nominal volume to impact the conversion results. Multiple GC injections of the offline samples showed reasonable stability over a 6 day period. Eight mixers were studied in the plant setting: three Ymixers, three T-mixers, and two mixers with coaxial feed. In scaling up from the lab to the pilot plant, with line of sight to the factory, we tested larger mixers with inner diameters of 4.9 mm up to 12.5 mm over total flow rates ranging from 1.0 to 16.4 L/min. This maximum total flow rate was determined by the capacity of the mass flow controller. Details about the eight mixers can be found in Table 2. When scaling up mixing-sensitive reactions with flow reactors containing static mixers, three key pieces of information are needed: (1) the minimum mixing intensity required for the reaction of interest, (2) the flow rate needed to achieve the target productivity (and its associated pressure drop), and (3) the residence time required in the reactor. We were able to determine which flow reactors met the mixing intensity and throughput criteria by comparing DMP conversions as functions of the flow rate. Results from our pilot-plant mixing investigation are given in Figure 2. Where possible, the mixing sensitivity was explored up to a total flow rate of 16.4 L/min; however, this flow rate could not be achieved in every reactor, as the associated pressure drop surpassed the pilot-plant equipment limitations. On the basis

Overall, higher flow rates led to better mixing conditions. The increased flow rates also resulted in a higher pressure drop across the mixer, consistent with typical behavior in such systems. Pressure drop refers to the loss of pressure that occurs when a fluid flows between two points through a fluid network, and it is influenced by the velocity of the fluid, the viscosity of the mixture, and the tubing diameter and length. The pressure drops for the data reported in Figure 1 were also recorded and are reported in the Supporting Information. The pressure drop followed normal trends for static mixers and was correlated with the mixing effectiveness. However, a universal curve describing mixing effectiveness as a function of pressure drop could not be obtained, likely because other mixer features (e.g., mixing volume prior to static elements) played an impactful role in a subset of the experiments.21 Subsequent to the lab study, we evaluated similar mixers at the plant and production scales. Transitioning from the lab to the plant proved to be challenging: the goal was to maximize the mixing efficiency without exceeding the pressure drop limits. On a lab scale, the pressure drop can be overcome through the use of high-pressure pumps, but in a plant it is difficult to achieve high-pressure flow without using specialized pumps, particularly when pulsation cannot be tolerated. For this production-scale study, the pressure drop was restricted to 70 psi, which was considered a reasonable upper limit for a plant setup that uses pressurized tanks to feed the mixers. We consider these flow conditions to be broadly available at production sites and preferable to many manufacturers over purchasing specialized capital equipment to pump at higher pressures. Consequently, continuous flow reactions designed with this criterion in mind for scale-up would be transferable to a wider network of external vendors. The reactor setup shown in Scheme 3 was assembled in the pilot plant for the fourth Bourne reaction. Feed solutions were prepared at 25 °C at the same concentrations as the stock solutions used in the lab investigations. These solutions were transferred through the pilot-plant static mixer by pressurizing the vessels to 70 psig with nitrogen and using mass flow D



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Table 2. Specifications of the Flow Reactors Tested in the Pilot Plant

a

Literature value. bCalculated on the basis of the measured outer diameter and wall thickness.

of these results, we considered flow reactors P2, P3, P5, P7, and P8 the most suitable for mixing-sensitive reactions with rapid kinetics. Of these flow reactors, we considered P2, P3, and P8 to be the most robust for the manufacturing environment, as they enabled us to explore the impact of the mixing intensity on the reaction over a wider range of flow rates.

Some of the known general trends related to mixing efficiency can be observed by comparing the results for P1, P2, and P3. Both P1 and P2 involved a Y-mixer design made from 1/4 in. pipe; however, a static mixer was integrated at the point of mixing in P2. Inclusion of this mixing element resulted in approximately 25% lower DMP conversion in P2 than in P1 across the range of flow rates investigated. The impact of increasing the mixer diameter can be assessed by comparing E



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Figure 2. DMP conversion as a function of total flow rate in flow reactor.

with internal diameters of 8 and 10 mm, respectively. These more densely packed mixing elements resulted in the lowest DMP conversions for this investigation. Over the flow range investigated, the DMP conversion decreased from 18% at 2 L/ min to 4% at 7 L/min in P7 and dropped from 25% at 2 L/min to 10% at 11.5 L/min in P8. While these mixer designs afforded the greatest mixing efficiency, they also resulted in the largest pressure drop across the flow rates investigated and could be difficult to implement in processes where throughput is an important design factor.

the results for P2 and P3. Increasing the diameter decreases the superficial velocity of the fluid, and the overall pressure drop decreases. These features tend to result in poorer mixing efficiency and could explain why P2 outperforms P3 in the flow rate range of 4−10 L/min. At a large enough flow rate, a sufficient amount of fluid energy is transferred to mixing, and the difference in DMP conversion between P2 and P3 becomes slight. The incorporation of a static mixer in a tube alone does not inherently lead to improved mixing. Mixers P4 and P6 were 1/ 4 in. and 3/8 in. T-mixers, respectively, equipped with a static mixer. However, these mixers exhibited the highest levels of DMP conversion in this investigation. We suspect that this is related to poor initial mixing in the dwell volume of the tee prior to the static mixing zone (see the corresponding mixer schematic in Table 2). When the mixing elements protrude into the dwell volume, as they did in P5, the mixing efficiency improves and the DMP conversion drops quickly, though it should be noted that also a different static mixer design was used in P5 than in P4 and P6. Mixers P4 and P6 were constructed using screwed pipe sections with preinstalled static mixing elements, which limited the fabrication options to ensure that initial contact of the inlet streams occurred near the mixer elements. Mixer P5 was also constructed with preinstalled static mixing elements but in tubing that could better be positioned near the stream inlets. This uncertainty between mixer design and mixer fabrication highlights the need for a benchmark test, such as the fourth Bourne reaction, to quantify mixing devices holistically in the manufacturing setting rather than by the geometry and static mixer elements alone. The ability to incorporate 3D-printing technology in static mixer design and fabrication removes some of this uncertainty. Furthermore, this capability is extremely valuable as it enables production-sized mixers and reactors to be tailored to the needs of the specific chemical transformation. Additionally, mixers can be designed and manufactured relatively quickly to rapidly evaluate the mixing intensity and reaction performance. Mixers P7 and P8 were 3D-printed mixers with a static mixer

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CONCLUSION We have used simple competitive chemical reactions, hydrolysis of DMP versus acid−base neutralization, to characterize the mixing efficiency at the lab scale through the pilot-plant scale. With this information in hand, it is possible to transfer a mixing-sensitive flow process from the lab to production facilities. It is possible to determine the Bourne conversion that corresponds to the optimized conditions for the desired reaction at the lab scale, translate that Bourne conversion to the plant scale, and confidently choose a mixer and flow rate combination to match the results at the plant scale. By running this test reaction, we have a tool that allows us to semiempirically characterize flow reactors with a high level of confidence. We anticipate that this approach could be quickly employed to streamline the scale-up of a broad class of mixing-dependent reactions. In addition to quantifying the mixer performance scale in one’s own piloting facility, this approach can be used to mitigate technology transfer risks. Moving from one plant to another presents numerous challenges since not every production facility has the same type of equipment (reactor/ pumps/mixer) or production requirements. We found the fourth Bourne experiment to be a great tool to evaluate our internal capabilities and potential external suppliers, and we have demonstrated this in North America, Europe, and Asia. Applying our approach in the manufacturing setting illustrated that (1) mixing intensity was significantly higher in flow reactors that contained a static mixer, (2) the 3D-printed mixer F



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(7) (a) Bourne, J. R. Mixing and the Selectivity of Chemical Reactions. Org. Process Res. Dev. 2003, 7, 471−508. (b) Bourne, J. R.; Lenzner, J.; Petrozzi, S. Micromixing in static mixers: an experimental study. Ind. Eng. Chem. Res. 1992, 31, 1216−1222. (8) Thaisrivongs, D. A.; Naber, J. R.; McMullen, J. P. Using Flow To Outpace Fast Proton Transfer in an Organometallic Reaction for the Manufacture of Verubecestat (MK-8931). Org. Process Res. Dev. 2016, 20, 1997−2004. Gauthier, D. R.; Sherry, B. D.; Cao, Y.; Journet, M.; Humphrey, G.; Itoh, T.; Mangion, I.; Tschaen, D. Highly Efficient Synthesis of HIV NNRTI Doravirine. Org. Lett. 2015, 17, 1353− 1356. Thaisrivongs, D. A.; Naber, J. R.; Rogus, N. J.; Spencer, G. Development of an organometallic flow chemistry reaction at pilot plant scale for the manufacture of verubecestat. Org. Process Res. Dev. 2018, 22, 403. (9) Myers, K. J.; Bakker, A.; Ryan, D. Avoid Agitation by Selecting Static Mixers. Chem. Eng. Prog. 1997, 93, 28−38. (10) (10) Hessel, V.; Löwe, H.; Schönfeld, F. Micromixersa review on passive and active mixing principles. Chem. Eng. Sci. 2005, 60, 2479−2501. (11) (a) Schwolow, S.; Hollmann, J.; Schenkel, B.; Röder, T. Application-Oriented Analysis of Mixing Performance in Microreactors. Org. Process Res. Dev. 2012, 16 (9), 1513−1522. (b) Gobert, S. R. L.; Kuhn, S.; Braeken, L.; Thomassen, L. C. J. Characterization of Milli- and Microflow Reactors: Mixing Efficiency and Residence Time Distribution. Org. Process Res. Dev. 2017, 21, 531−542. (c) Reckamp, J. M.; Bindels, A.; Duffield, S.; Liu, Y. C.; Bradford, E.; Ricci, E.; Susanne, F.; Rutter, A. Mixing Performance Evaluation for Commercially Available Micromixers Using Villermaux−Dushman Reaction Scheme with the Interaction by Exchange with the Mean Model. Org. Process Res. Dev. 2017, 21, 816−820. (12) For historical work on the topic, see: Hartridge, H.; Roughton, F. J. W. A method of measuring the velocity of very rapid chemical reactions. Proc. R. Soc. London, Ser. A 1923, 104, 376−394. (13) (a) Falk, L.; Commenge, J.-M. Performance comparison of micromixers. Chem. Eng. Sci. 2010, 65, 405−411. (b) Johnson, B. K.; Prud’homme, R. K. Chemical processing and micromixing in confined impinging jets. AIChE J. 2003, 49, 2264−2282. (14) Baldyga, J.; Bourne, J. R.; Walker, B. Non-isothermal micromixing in turbulent liquids: Theory and experiment. Can. J. Chem. Eng. 1998, 76, 641−649. It should be noted that this original work used HCl instead of HNO3 because of material compatabiltiy. The work in ref 7a showed that the reaction kinetics was not impacted by this substitution. (15) Taylor, R. A.; Penney, W. R.; Vo, H. X. Scale-up Methods for Fast Competitive Chemical Reactions in Pipeline Mixers. Ind. Eng. Chem. Res. 2005, 44, 6095−6102. (16) For a study on a dynamic mixer, see: Dolman, S. J.; Nyrop, J. L.; Kuethe, J. T. Magnetically Driven Agitation in a Tube Mixer Affords Clog-Resistant Fast Mixing Independent of Linear Velocity. J. Org. Chem. 2011, 76, 993−996. (17) For more information about the Koflo mixer, see: http://www. koflo.com/. (18) For more details about mixers 4 and 5, see: http://www.michs. jp/index_en.html. (19) For a recent discussion of process analytical technology, see: Chanda, A.; Daly, A. M.; Foley, D. A.; LaPack, M. A.; Mukherjee, S.; Orr, J. D.; Reid, G. L., III; Thompson, D. R.; Ward, H. W., II Industry Perspectives on Process Analytical Technology: Tools and Applications in API Development. Org. Process Res. Dev. 2015, 19, 63−83. (20) See the Supporting Information. (21) For pressure drop values across each mixer at various flow rates, see the Supporting Information. (22) For more information about the 3D-printed mixer, see: https:// www.innosyn.com/. (23) For more details about the SMX static mixer, see: http://www. sulzer.com/en/Products-and-Services/Mixpac-CartridgesApplications-Static-Mixers/Static-Mixers/General-Purpose-Mixers.

with a static mixer provided the highest intensity of mixing but had throughput limitations due to pressure drop, and (3) not all of the pressure drop across the flow reactor contributed to effective mixing.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00063.

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Remaining experimental procedures and a discussion of the equipment used (PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

François Lévesque: 0000-0001-9529-4993 David A. Thaisrivongs: 0000-0002-0387-8885 Present Address †

I.W.D.: Princeton Catalysis Initiative, 226 Frick Chemistry Lab, Princeton, NJ 08544. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge André de Vries and Raf Reintjens from InnoSyn for the fabrication of the 3D-printed mixers P7 and P8 and Robert Hartman for insightful discussions on the use of inline analytical tools. We also acknowledge Guillermo Germes, the Rahway Satellite Lab, and the production staff of our Small Scale Organics pilot plant in Rahway, NJ, for their role in performing fourth Bourne testing.

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ABBREVIATIONS DMP, 2,2-dimethoxypropane; GC, gas chromatography; UV− vis, ultraviolet−visible REFERENCES

(1) Cole, K. P.; McClary Groh, J.; Johnson, M. D.; Burcham, C. L.; Campbell, B. M.; Diseroad, W. D.; Heller, M. R.; Howell, J. R.; Kallman, N. J.; Koenig, T. M.; May, S. A.; Miller, R. D.; Mitchell, D.; Myers, D. P.; Myers, S. S.; Phillips, J. L.; Polster, C. S.; White, T. D.; Cashman, J.; Hurley, D.; Moylan, R.; Sheehan, P.; Spencer, R. D.; Desmond, K.; Desmond, P.; Gowran, O. Kilogram-scale prexasertib monolactate monohydrate synthesis under continuous-flow CGMP conditions. Science 2017, 356, 1144−1150. (2) Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. The Hitchhiker’s Guide to Flow Chemistry,. Chem. Rev. 2017, 117, 11796−11893. (3) Yoshida, J.-I.; Takahashi, Y.; Nagaki, A. Flash chemistry: flow chemistry that cannot be done in batch. Chem. Commun. 2013, 49, 9896−9904. (4) Gutmann, B.; Cantillo, D.; Kappe, C. O. Continuous-flow technologya tool for the safe manufacturing of active pharmaceutical ingredients. Angew. Chem., Int. Ed. 2015, 54, 6688−6728. (5) Kirschning, A.; Solodenko, W.; Mennecke, K. Combining Enabling Techniques in Organic Synthesis: Continuous Flow Processes with Heterogenized Catalysts. Chem. - Eur. J. 2006, 12, 5972−5990. (6) Sheldon, R. A.; Woodley, J. M. Role of Biocatalysis in Sustainable Chemistry. Chem. Rev. 2018, 118, 801−838. G


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