Controlling the Exothermicity of O‑Arylation by Evaporative Cooling during the Process Development of Fluoxetine Hydrochloride

This study illustrates the optimization of the O-arylation step of fluoxetine hydrochloride (1) synthesis. In the entire process, this is the most critical step that dictates the yield and quality of the product. The highlight of the process is the concept of evaporative cooling that was employed in manipulating the above highly exothermic reaction by introducing toluene as the cosolvent. The evaporative cooling not only aided in getting an efficient procedure but also increased the yield of 1 and simplified the work-up procedure. This was a protective approach adopted for process safety, considering the worst-case scenario in the plant.