The efficient synthesis of Pregabalin with impurity control using a continuous flow system

This article developed a microreactor system for the continuous synthesis of Pregabalin. Due to the exceptional heat transfer and mixing capabilities exhibited by the system at the microscale, the Hofmann rearrangement reaction, traditionally requiring multiple sequential steps in batch reactors, can now be efficiently achieved in a consolidated single-step microreactor process. The reaction was executed at a comparatively elevated temperature range of 40–50 °C, and took 5–6 min to achieve the yield of over 90 %, which was a significant improvement compared to the conventional batch reactor method, requiring 7–8 h with a yield of 83 %. The microreactor system utilized its excellent mass and heat transfer performance to reduce the level of the key impurity to below 0.15 % at higher reaction temperatures, meeting the quality requirements for pharmaceutical production. Through experimental research, we determined the effects of reaction conditions like concentration, temperature, and residence time on the reaction rate, as well as key trace impurities.