Continuous Flow Synthesis of the Nerve Agent Antidote Pralidoxime (2‐PAM) Iodide

Abstract Pralidoxime salts are important medical countermeasures towards different organophosphorus compounds, either nerve agents or pesticides, as they act as acetylcholinesterase reactivators, avoiding health issues and even death that can result from intoxication with such chemicals. In this work, we present an expeditious study focuses on the optimization of a two‐step continuous‐flow synthesis of 2‐PAM. Initial attempts to replace the solvent composition in the oxime formation reaction with acetonitrile resulted in lower yields, highlighting the significance of a polar protic solvent. Subsequent optimization under continuous‐flow conditions revealed the successful execution of oxime formation at room temperature with a residence time of 20 minutes, achieving an impressive 96 % conversion, surpassing literature‐reported conditions. The methylation step required a high residence time of 60 minutes at 120 °C for a substantial conversion of 78 %. The two‐step continuous‐flow process demonstrated robustness, yielding 75 %, with space‐time yields of 0.32 g/h and 0.18 g/h. Further concentration adjustments increased space‐time yields to 3.2 g/h and 2.2 g/h. Despite solvent incompatibility, a strategic alteration of the reaction sequence allowed for a successful cascade process, integrating the methylation step in acetonitrile and the oxime formation in water. The continuous‐flow system, incorporating a heat exchanger, exhibited stability, maintaining full conversion and a space‐time yield of 0.3 g/h over extended periods. This systematic optimization not only enhances the efficiency of 2‐PAM synthesis but also provides insights into a scalable and practical continuous‐flow cascade process.