Safe Continuous Flow Synthesis of the Grignard Reagent and Flusilazole Intermediate via a Dual-Column Microreactor System

With massive production, the agrochemical and specialty chemical industries have seen a sharp increase in the transition from batch to continuous production for highly exothermic processes. This is also true for fine chemicals and pharmaceuticals processes, typically conducted in a batch mode. Highly exothermic reactions can lead to runaway situations, resulting in severe and fatal accidents. Converting batch processes into continuous operation with minimum inventory or holdup in the reactor improves process safety and controllability. A continuous process was developed in this work to produce the key intermediate of silicon-based fungicide flusilazole, which consists of a dual column for Grignard reagent preparation followed by a substitution reaction in a two-stage microreactor system. Herein, we disclose the studies performed to explore a continuous flow process, the reaction parameters of which can be altered as per the process requirements for the completion of the reaction. The improved process explores better heat and mass transfer compared to the batch process, leading to maximum conversion with minimum byproduct formation and high selectivity. The developed process increases production capacity compared to that of the batch process. Handling of moisture-sensitive reagents and high exothermicity were overcome using a two-stage continuous flow reactor. Drastic reduction of reaction time and yield improvement were executed by using a two-stage continuous flow reactor system.