Multistep Continuous Flow Synthesis of 14C-Labeled cis/trans-Chrysanthemic Acid.

Natural pyrethrins and their analogues, synthetic pyrethroids, are widely used insecticides due to rapid action and broad efficacy. For tracer studies to comprehensively assess their safety, carbon-14 (14C)-labeled compounds are required. However, the conventional batch synthesis of 14C-labeled chrysanthemic acid-a key precursor for labeled pyrethroids-poses several challenges, including the handling of explosive and volatile intermediates, the management of safety concerns, and radioactive contamination risk. To address these issues, we have developed the first multistep continuous flow synthesis of 14C-labeled cis/trans-chrysanthemic acid. Our approach utilizes a series of sealed devices to perform diazotization, rhodium (Rh)-catalyzed cyclopropanation, hydrolysis, and continuous extractive workup without isolating hazardous intermediates. This setup enables safe, efficient, and scalable production, as the continuous flow system allows direct transfer between reaction steps and the rapid adjustment of scale by modulating feed rates. The newly developed flow synthesis of 14C-labeled cis/trans-chrysanthemic acid demonstrated significantly reduced safety concerns and the risk of radioactive contamination and improved operational efficiency compared with the conventional batch method.