Continuous-Flow Phase-Transfer-Catalyzed N -Alkylation for Trazodone Synthesis: Development and Optimization

This study explores the feasibility of synthesizing trazodone in continuous mode using a tubular reactor and investigates the impact of ultrasound on phase-transfer-catalyzed (PTC) N-alkylation. A continuous flow apparatus was designed in which the 2-(3-chloropropyl)-1,2,4-triazolo4,3-apyridin-3-(2H)-one (TAP), the trazodone precursor, was prepared. While attempts to directly convert the solid–liquid (S–L) batch synthesis from a reference study into continuous mode were unsuccessful, a novel liquid–liquid (L–L) approach was developed. The L–L reaction system comprised an aqueous phase containing TAP, potassium carbonate, and tetrabutylammonium bromide, while the organic phase included 1-bromo-3-chloropropane in ethyl acetate. The key reaction parameters, such as temperature, residence time, and concentration of different reaction components, were examined for their influence on TAP conversion, product yield, and selectivity. These reaction parameters were optimized under continuous flow conditions to achieve a high product yield. The activation energy and the apparent kinetic constant, assuming pseudo-first-order reaction kinetics, were estimated from the experimental data. Ultrasound irradiation positively impacted the reaction, improving substantially the yield of the continuous flow synthesis. The elementary reaction mechanisms for both S–L and L–L phase transfer-catalyzed processes were proposed.