Continuous‐Flow Synthesis of Aripiprazole Through the Safe Utilization of In Situ‐Generated THF Hydroperoxide

A novel continuous‐flow synthesis for the antipsychotic aripiprazole has been developed via a two‐step, halogen‐free route. The first step features the underutilized N ‐hydroxybutylation reaction employing in situ‐generated THF hydroperoxide under reductive conditions. The continuous‐flow setup ensures rapid and safe transformation through a telescoped sequence, incorporating on‐demand generation and immediate quenching of the remaining hazardous reagent without isolation. This strategy was also applicable to the synthesis of other pharmaceutically relevant intermediates. The first step was integrated with a continuous‐flow Mitsunobu reaction employing the Tsunoda reagent to give aripiprazole with high productivity. Overall, the developed process offers an environmentally benign alternative to conventional methods, achieving superior atom economy and reaction mass efficiency while eliminating the need for halogenated alkylating agents typically used in high excess.