Chapter 16. Upscaling the Aza-Diels–Alder Reaction for Pharmaceutical Industrial Needs in Flow Chemistry

In this work, the aza-Diels–Alder (aDA) reaction involving cyclopentadiene (CPD) as a dienophile was optimized and scaled up to obtain 1 kg h−1. The Diels–Alder Reaction (DA) involving CPD is scarce in industrial production because of the difficulty of generating CPD in safe and proper conditions. Here, we describe a methodology to continuously generate CPD up to 60 mL min−1 and incorporate an aDA reaction at a low temperature for industrial scale processing. The optimization of the aDA reaction from batch mode in the lab to a continuous flow, multi-kilogram scale is described in detail. Beyond the role of solvent, temperature and acid catalysis in the reaction, different configurations of flow reactors and different reactor sizes were key to the development and construction of the scale-up process to reach the targeted production. The introduction of static mixers into the flow process had a significative impact on the overall productivity of the system. Particular attention was paid to maintaining green chemical principles, reducing solvent use and minimizing impurities in the process. The final setup reached a continuous simple and safe production, taking full advantage of flow chemistry technological benefits in its operation.