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Application of Flow Chemistry
Bram Karsten, Ph.D.
NJ Bio, 675 US Highway 1, Suite B129, North Brunswick, NJ 08902, U.S.A.
In flow chemistry, reactants and reagents are fed into a reactor continuously and the product is removed from the reactor in a continuous stream. This contrasts with batch chemistry where reactants and reagents are fed into a reaction vessel at the beginning of a reaction and products are removed only after the reaction is complete. The most common reactor types are tubular reactors (also called plug flow reactors, or PFRs) and continuous stirred tank reactors (CSTRs). These reactors are schematically pictured in Figure 1. While flow reactors are common in the bulk chemical industry due to their advantages in terms of operating cost, throughput, footprint, and increased control compared with batch reactors, the pharmaceutical industry has only recently started to adopt flow chemistry. For the pharmaceutical industry, important advantages of flow chemistry are increased safety, smaller footprint, higher yields/purities, and the possibility to perform reactions involving very hazardous or unstable reagents or intermediates, electrochemical reactions, and photoreactions.1,2
Heat transfer, mass transfer and increased control
The most touted benefits of flow chemistry compared with batch chemistry are improved heat transfer and mixing, which lead to improved overall control. Due to the much smaller volume of a flow reactor compared with the batch reactor that would be required for the same process, the surface to volume ratio of the flow reactor is much higher. This increased surface to volume ratio leads to greatly improved heat transfer. In addition, highly efficient micromixers can be used in flow chemistry, reducing the mixing time needed for the reactants/reagents. The improved mixing and heat transfer reduce the quantity of byproducts that can form due to concentration and temperature inhomogeneities (hotspots). Examples of efficient micromixers containing triangular structures are shown in Figure 2. The improved heat and mass transfer leads to increased control in flow reactions compared with batch reactions, due to the elimination of irregularities in the composition and temperature of the reaction mixture.3 Furthermore, reaction times can be accurately controlled by changing the flow rate in the reactor.
The efficient mixing and heat transfer in flow reactors allow the use of highly reactive materials, such as organolithium compounds and Grignard reagents, without the need to run these reactions at very low temperatures or adding the reagents very slowly. 4,5 In these cases, the fast temperature rise that would result in a batch reaction is avoided due to efficient heat transfer, while the efficient mixing prevents local excesses of the reagents. Nitration reactions are another example of reactions that can benefit from the improved heat transfer in flow reactors compared with batch reactors.2,4
Improved safety and the ability to safely perform hazardous reactions
Due to the small size of a flow reactor compared with the batch reactor required to produce the same quantity of product, it becomes much easier to handle highly reactive or otherwise hazardous materials. As there will never be an accumulation of large quantities of reactive material inside the reactor at one time, it is possible to perform reactions that would present severe safety issues in a batch process. Reactions involving the use of diazomethane (by in situ generation of diazomethane), of diazonium compounds, of organic azides, as well as halogenation and hydrogenation reactions are examples of improved safety in flow.6,7 Highly exothermic reactions can also be performed safely in a flow process. Due to the more efficient heat transport, it is easier to cool these reactions in flow, and as the feed of the reactants can be stopped immediately if necessary, the risk of a runaway reaction is eliminated.1
The use of diazomethane is a good example of the benefits of flow chemistry when using hazardous materials. While diazomethane is a very useful reagent, the compound is toxic, carcinogenic, volatile, and highly explosive. These properties make the compound very difficult to handle, especially on an industrial scale and many processes go to great lengths to avoid the use of diazomethane, which lengthens development time, increases cost, and reduces the robustness of the process. Generating diazomethane in situ in a continuous flow setup can overcome the safety challenges of using diazomethane on larger scale. Phoenix Chemicals Ltd. has developed a process for the continuous production of diazomethane (50-60 tons/year) from N-methyl-N-nitroso-p-toluene sulfonamide (Diazald®) in the preparation of a key synthetic intermediate of nelfinavir, an HIV protease inhibitor that is also being investigated for the treatment of COVID-19.4 In this process, there is no more than 80 g diazomethane present in the system at any time.8 The abbreviated flow synthesis is depicted in Scheme 1.
Besides enabling the use of hazardous materials, flow reactors also offer safety benefits for reactions requiring high pressures and temperatures.3 As flow reactors are generally narrow tubes, it is possible to safely increase the pressure inside these reactors by using a back-pressure regulator as well as a pump that can create high pressures (e.g., an HPLC pump). Due to the high pressure that can be generated in a flow reactor, it is possible to use solvents at temperatures far exceeding their normal boiling points, enabling faster reactions and reactions that would not happen under normal reflux conditions. The use of high-pressure gases (e.g., for hydrogenation reactions) is also easier and safer in flow than in batch, where high-pressure autoclaves would be needed.3
Electrochemical reactions in flow
Synthetic electrochemistry has recently seen a revival in research laboratories as an environmentally friendly synthesis method that can eliminate the use of stoichiometric oxidants and reductants and enable reactions which are difficult to perform using more conventional techniques.9 A limitation of electrochemical reactions, however, is the scale-up of the process. In a batch reactor, a simple scale-up would mean the use of very large electrodes as well as increased separation between the electrodes. As the resistance of an electrochemical cell increases with the distance between electrodes, large-scale batch electrochemical reactions would require relatively high voltages to achieve the desired current (reaction rate). The high electrode potentials would lead to side reactions, degradation of the solvent, overoxidation/over-reduction, etc.
Flow chemistry has the potential to solve many of the issues related to scaling up electrochemical reactions.10,11 Since flow reactors are much smaller than batch reactors, and further scaling up can be achieved by a “numbering up” approach using many smaller reactors in parallel12, the distance between electrodes can be kept small, meaning that in many cases a supporting electrolyte (an added salt used to reduce the resistance of the electrochemical cell) is not necessary. Additionally, in flow reactors mass transport around the electrodes is better, further enhancing the efficiency of the electrochemical process.
An example of a flow-electrochemistry enabled drug molecule synthesis was reported by Waldvogel et al13. The synthesis is displayed in Scheme 2. Here, 2,6-dichlorobenzaldoxime is oxidized on a graphite electrode to the nitrile oxide. This compound then undergoes a 1,3-dipolar cycloaddition with methyl acetoacetate to give an isoxazole that serves as a building block for dicloxacillin, an important antibiotic.
Photoreactions in flow
Like electrochemistry, photochemistry is often seen as an environmentally friendly synthesis method because light is used in place of hazardous reagents. As in electrochemistry, however, the technology finds limited use in industrial batch processes due to problems with the use of photochemistry on larger scales. The main limitations of photochemistry in batch reactors are the low penetration of light into reaction mixtures (often only a few millimeter), as well as issues with non-uniform irradiation of the reaction mixture. The low light penetration necessitates long exposure times in batch photoreactors, leading to possible degradation of the product and the formation of byproducts.7
In flow chemistry, reactions are performed in narrow tubes that can be made of transparent material. This greatly reduces the path length compared to batch photoreactors, and effectively solves the problem of low light intensities and non-uniform irradiation. Flow photoreactors can be either home-built or obtained commercially and in both cases a variety of light sources can be used, e.g., LEDs, UV tube lights, mercury lamps, lasers, etc.7
An example of flow photochemistry in the synthesis of a useful product is the synthesis of the antimalarial drug Artemisin from dihydroartemisinic acid, reported by Lévesque and Seeberger.14 The synthesis is depicted in Scheme 3. In this method, ultraviolet light is used to generate singlet oxygen, which is used for the oxidation of dihydroartemisinic acid to an allylic hydroperoxide. The hydroperoxide is then further converted into Artemisinin. The flow setup consists of two reactors and is capable of producing 200 g of Artemisinin per day.
Multistep synthesis in flow
So far, we have mostly discussed individual reactions that can be performed in continuous flow. However, flow chemistry is a very powerful tool in the multistep synthesis of organic compounds. By feeding the outlet of one reactor directly into the next, sometimes with continuous flow purification of intermediates, a fully continuous flow synthesis can often be achieved. Some examples of drug molecules that have been synthesized through fully continuous processes are imatinib (three steps), 15,16 tamoxifen (five steps)17, ibuprofen (three steps)18, and atropine (2 steps).19 A flow synthesis of imatinib (Gleevec) is depicted in Scheme 4.
Multistep synthesis can be performed in highly automated systems, leading to fully automatic production systems for APIs. These systems can make full use of the benefits of flow chemistry and offer compact systems with high throughput and short reaction times. A good example of this is the refrigerator-sized system designed by groups at MIT.20 Their compact system is a reconfigurable flow system that was used to produce hundreds to thousands of doses per day of diphenhydramine HCl, lidocaine HCl, diazepam, and fluoxetine HCl, including purification and formulation.
Another example is a recently published cyanation process by Gilead, used to make an intermediate in the synthesis of remdesivir, an antiviral medication used in the treatment of COVID-19.22 Important shortcomings of the previously reported process, which was used for preclinical and early-stage clinical demands, included the need to perform the reaction at -78°C, the decomposition of the starting material and loss of diastereoselectivity when reagent addition times were increased (which was needed to maintain the low temperature), and the inherent hazards of the use of cyanide in an acidic reaction mixture. Using flow chemistry, the team was able to scale up the process to produce about 50 kg/day (18 tons/year) of cyanated product. The reaction takes place at -30°C and is performed in two reaction loops with a total volume of 2.5 L and a residence time of 2.5 min. After workup by crystallization, the product is obtained in 75% yield with a purity of 99.8%. The flow chemistry route is depicted in Scheme 6.
Although these examples at first do not seem impressive in terms of production quantities (28 kg/day and 50 kg/day), it is important to note that the annual production capacity of each reactor exceeds 10 tons/year. In both cases, this result is achieved using reactor volumes of less than 10 L and total reaction times of less than 1h. In comparison, the nitration reaction took 2 h in batch, after dropwise addition of the nitric acid. An 8 L reactor would only be able to produce around 1 kg of material per batch, compared to 1.2 kg/hour for the 8 L flow reactor.21 As noted, the cyanation reaction posed significant problems in batch and scale-up proved much easier in flow. Nevertheless, when performed in batch, the reaction took 2 h to complete, after addition of all reagents at -78°C, compared to 2.5 min in flow, and a 2.5 L reactor would be able to produce about 1.5 kg of material per batch, compared to 2 kg/h for the similarly-sized flow reactor.
These examples illustrate some of the benefits of using flow chemistry on production scale: short reaction times, small reactors compared to batch, improved safety, and the ability to perform reactions that are problematic in batch. Further scale up can easily be achieved by running multiple flow reactors in parallel, an approach that is often described as “numbering up.”12 An example of a production-scale flow reactor is depicted in Figure 3.
So far, we have mostly focused on the benefits of flow chemistry when compared to batch. Of course, there are also challenges to the use of flow chemistry. First, scientists and engineers are often familiar with batch processes, and batch reactors are often immediately available at the scale required, which makes batch reactions seem more attractive than they actually are. Second, batch reactors are more versatile than flow reactors; a single batch reactor can be used for many different reactions, while flow reactors typically need to be designed and sized for a specific process. Besides additional capital expenses, this means that using flow chemistry requires a larger engineering effort early in the process development, while the benefits will only appear later. The benefits of a flow process do not always outweigh these extra expenses. Third, reactions involving solids and slurries, either as starting materials or as products, tend to cause clogging of flow reactors. Fourth, flow chemistry works best for reactions that are relatively fast. Reactions that take a long time to complete are often better suited for batch, as long residence times translate to large reactor volumes in flow reactors. Finally, many compounds are currently made in batch, meaning that suitable processes already exist. Translating these processes to flow requires additional investments in capital, as well as additional process development expenses. These extra expenses may not always be outweighed by the benefits of an improved process.
Flow chemistry has received a lot of attention during the past decade. While performing reactions in flow rather than in batch does not alter the fundamental chemistry, flow chemistry can create new opportunities for more efficient, safer, and greener syntheses. Due to the increased surface to volume ratio of flow reactors, heat transfer and mixing are much more efficient in flow reactors than in batch, which offers increased control and often higher reaction selectivity. Due to the small volume of flow reactors, safety issues with many batch procedures are avoided. Flow chemistry also opens up new possibilities for the use of photochemistry and electrochemistry. Both these techniques are promising and environmentally friendly, but their use has been limited due to their inherent scalability problems in batch processes. In flow reactors, many of these limitations can be circumvented due to the small size of the reactor channels. Continuous flow reactions are also very well suited for performing multistep synthetic routes in highly automated systems. Flow reactors offer high throughput with a small footprint and have shown their utility in the production-scale synthesis of APIs and intermediates.
As a final remark, it is important to note, that while flow chemistry often makes use of complex equipment, many reactions can be performed – at least on small scale – using simple tubing and basic syringe pumps. For many reactions, the potential of performing the reaction in flow can be explored using this relatively simple and inexpensive equipment, taking away an important barrier to adoption.
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