Paraformaldehyde slurry mediated α-hydroxymethylation reactions in continuous flow

The transition from batch to continuous flow chemistry is driven by increased process safety, reduced production costs, and improved yields. However, a major challenge associated with continuous flow reactors is posed by blockage caused by solid particle accumulation in the micro- and mesochannels. To address these challenges, different methods to handle solids were explored in order to broaden the application of microreactors. Paraformaldehyde (PFA) in solid form was investigated as a safer and more practical alternative to toxic formaldehyde gas and limited-use aqueous formalin solutions. Hydroxymethylation (CH2-OH) reactions, which are relevant within the pharmaceutical industry, were chosen as the focus of this study. Despite numerous reported synthetic methods, long reaction times and moderate yields were frequently encountered. To enhance reaction kinetics for continuous processes, batch optimizations were performed at elevated temperatures, resulting in a significant reduction of reaction time from 3.5 hours to only 8 minutes at 100 °C. The feasibility of the self-assembled oscillatory CØPE reactor was demonstrated with the α-hydroxymethylation of methyl vinyl ketone (MVK) using a paraformaldehyde slurry. Using the optimized conditions and a pressure of 5 bar, the yield was increased from 70% in batch to 80% in continuous flow upon implementation in the CØPE reactor. The major limitation was posed by the lack of an available slurry-compatible high-pressure pump at laboratory scale, which restricted the operating conditions from 300 °C and 100 bar to just 10 bar. Nevertheless, the successful implementation of the PFA slurry in the CØPE reactor is seen as promising for the management of other solid feeds and products, while precipitation and clogging are effectively eliminated.

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