Various glass and stainless steel microreactors are available. Glass is more chemically resistant and therefore ideal for multipurpose work but stainless steel is more robust and has better heat transfer properties, which makes it a better choice in a production environment, if the reaction is compatible.
A microreactor reaction takes place in a narrow channel, typically 200µm in diameter, so only tiny quantities of reagents are ever in the reactor at the same time. The heat transfer properties are much better than batch reactors, so potentially dangerous hotspots where reagents first meet in a large vessel are not created. It is important that all of the ingredients remain in solution at all times within the reactor, as solids will cause blockages. This isn’t a safety issue – the pump will sense a build-up in pressure that results from a blockage – but it does stop production. If the starting materials are liquids, this has another bonus because it is often possible to carry out reactions without solvents, resulting in a cleaner reaction that results in cost savings and higher output rates, as well as environmental benefits.
Because the reaction remains constant throughout the scale-up process, making larger quantities is simply a case of running the reactor for longer rather than making larger batches. Process development is much faster since, although the reaction conditions, such as temperature and flow rate, may vary in the course of process development, the actual reaction cell conditions remain constant for any campaign size. All that has to be done is optimise the concentration to maximise the yield and flow rate so the reaction remains in the microchannel long enough to go to completion, but not so long that by-products start to form.
The speed of process development makes it straightforward to create libraries of similar compounds in kilo quantities very quickly, using the same reaction protocol with different starting materials. Some examples from a library of mono- Boc-protected diamines are shown in Figure 1. These were all made by reacting diamines with Boc2O under conditions that discouraged diprotection. This set of compounds was synthesised in one working day to multi 100g amounts without having to transfer the project to a kilo lab. Kilogram-quantities could also be tailored to the customer’s precise needs.
Continuous microreactors permit the use of reagents that are otherwise too dangerous in largescale production. Chemicals such as diazomethane isolating intermediate products. This saves time and money, important when scaling up the complex multi-step syntheses that are often required for pharma ingredients.
Unstable intermediates can also be easier to handle in a microreactor than a batch vessel. n-Butyllithium is commonly used in the lab to form anions, but the lithiated intermediates need to be kept cold. This adds expense and complexity to batch reactions, as cryogenic jackets are required to keep the reaction at –70°C. However, because the channels in a microreactor are so narrow and the high surface to volume ratio enables good heat transfer, the reaction mixture keeps flowing at a constant rate and in many cases it only needs to be cooled to 0°C. There are cases, however, where –20°C or lower are essential, even in the microsystem.
An example of a reaction we carried out for a customer is shown in Figure 3. The product is a key intermediate for an active pharmaceutical ingredient (API), and we had experienced problems with the process in a batch reactor as the yields were extremely variable from batch to batch.
The starting material, a substituted orthobromo heterocycle, was mixed with n-BuLi in a microreactor. The unstable lithiated intermediate was then mixed with a substituted 1-pyrroline in a second microreactor. The stability or instability of this new intermediate was not known, so before it could be isolated, a protecting group was added in a third microreactor, making incorporating the next synthesis step straightforward. A solution containing the now-stable protected intermediate could then be collected, and purified once enough product had been made during the four or five day production campaign.
Although the lithiated intermediate is unstable above –30°C, in practice it could be handled safely in a microreactor at temperatures up to +30°C because of efficient heat transfer control and its submission to the interception step within seconds that prevents it from degradation. The development time for this whole process was just three months, and more than 3kg could be made in 24hr. It also had a better purity profile than the product made batch-wise due to improved control of the reaction, and formation of side products was suppressed. Typical side products for this type of reaction include Wurtz coupling, competing nucleophilic addition of BuBr and substance-specific side reactions.
This ability to alter impurity profiles can also allow reactions that create inseparable mixtures in a batch reactor to be used successfully. A good example is the synthesis of methylene cyclopentene by the cyclisation of 1,5-hexadiene (Figure 4). The correct product, the kinetic one (A), forms first. However, the thermodynamic product, 1-methylcyclopent-1-ene(B), where the double bond is inside the ring, is more stable and forms in a batch reactor as the product remains in contact with the catalyst. This does not just reduce the yield of the correct product – the boiling points of the two are almost the same (75-77oC vs. 75-76°C), making separation extremely difficult. The solution was to stop the reaction as soon as methylene cyclopentane has formed by adding a continuous quench. For this, a continuously operating microreactor was ideal. The key is to establish the optimal residence time within the reactor – too short will result in low conversion rates and too long and the rearrangement will take place.
Microreactors also have pragmatic advantages over traditional batch vessels. They take up less space on the factory floor and yet can still be used to make large quantities of product. 2-Benzoyl pyridine is an important building block, with an annual demand of about 15 tonnes. It is made using the Grignard reaction shown in Figure 5, and in a microreactor this takes just 15 seconds. The product in our hands also had better quality than the product that comes out of a batch reactor, as the reaction was better controlled, making a distillation step unnecessary. The product was made in a stainless steel Alfa Laval reactor, which takes up just 30cm by 50cm of space on the bench, and should be able to produce between 200 and 300kg/day of the product because of the fast reaction and rapid flow rate.
Microreactors have great potential to expand the range of reactions available for the manufacture of fine chemicals. They will never completely replace batch reactors, but in many processes they can save time and make the production of volatile products at scale possible. Regulatory agencies such as the US Food and Drug Administration have noted that continuous processing should be able to improve efficiency and manage variability. But using microreactors to their full potential will require chemists to think differently. Chemists are trained to think in terms of batch processing whether at lab scale in a glass flask, or in large reactors in production. Today, microreactor processes are often designed to compete with successful batch processes. If continuous processing is considered from the outset, then microreactors are sure to become more widely used to make fine chemicals.
Acknowledgements: Thanks to SAFC Pharma colleagues Gregor Wille, Patrick Kaiser, and Fabian Wahl for their help with the preparation of this article.
Andreas Weiler is global business director at SAFC Pharma based in Buch, Switzerland.
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