Controlling explosive and highly energetic reactions: scaling up the liquid-phase aerobic oxidation of alcohols and aldehydes in flow

Abstract

Multiphasic continuous-flow reactors can improve the sustainability of the synthesis of active pharmaceutical ingredients (APIs). Although this technology has been proven at the laboratory scale, its implementation at the pilot scale remains limited, especially for oxidation reactions using oxygen, a cost-effective and readily available green oxidizing agent. This limitation largely stems from the hazardous nature of these reactions and the challenges related to scaling up the gas–liquid process. Here, we present two examples of the successful, seamless scale-up of the aerobic oxidation of primary alcohols and aliphatic aldehydes in a compact heat exchanger reactor, while preserving the segmented flow characteristics and intensified conditions observed at the laboratory scale. Using a Kobelco SMCR® with a total reactive volume of 43 mL, a productivity of 20 g h⁻¹ and 692 g h⁻¹ could be achieved for the aerobic oxidation of benzyl alcohol into benzaldehyde and 2-ethylhexanal into 2-ethylhexanoic acid, respectively. The results crucially demonstrate the potential for implementing milli-structured reactors in pharmaceutical process chemistry.