Synthesis of Prilocaine Hydrochloride in Continuous Flow Systems

Herein, we showcase how continuous flow technology enables the development of time-efficient, high-yielding synthetic routes for the anesthetic drug prilocaine. Starting from toluene nitration, prilocaine was synthesized in 74% (high-performance liquid chromatography (HPLC)) overall yield with a total residence time of just 13.6 min. Continuous flow technology markedly enhanced the nitration step's selectivity, increasing it from 59% in batch to 79%. The toluidine alkylation step benefited significantly from superheating at 150 °C and enhanced mixing in the flow system, reducing the reaction time from 48 h in batch to merely 4.4 min, affording 98% yield. Additionally, we present streamlined continuous flow reaction, telescoping, and inline workup strategies.