Ionic liquid-assisted vs. green solvent-free synthesis of azaperone: a comparative optimization study

Abstract In this study, an efficient and environmentally benign synthetic route for the veterinary sedative azaperone was developed and systematically optimized. The reaction was investigated using various phase-transfer catalysts (PTCs), including the anion-exchange resin Amberlite, triethylammonium chloride, and selected synthesized ionic liquids (ILs), to elucidate the influence of catalyst structure on product yield and selectivity. The effects of solvent polarity, temperature, reaction time, and reactant molar ratios were systematically screened to establish optimal reaction parameters. Structural characterization and confirmation of azaperone were achieved using FT-IR, GC–MS, 1 H-NMR, and 13 C-NMR spectroscopy. Under optimized conditions, the solvent-free pathway afforded azaperone with a 90% isolated yield (85% purity), whereas the organic solvent-based approach (1,4-dioxane) yielded 83% product with 88% purity. Three synthesized n-butyl-containing ionic liquids—1-butylpyridinium bromide, 1-butyl-3-methylimidazolium bromide, and diethyldibutyl ammonium bromide—were evaluated as dual reaction media and catalysts. Although these ILs exhibited high thermal stability and excellent recyclability over multiple runs (up to three cycles with > 93% recovery), they afforded lower isolated yields (up to 73%) due to elevated inherent viscosity and mass-transfer limitations as supported by time-dependent kinetic studies. Quantitative green chemistry metrics including E-factor (0.28 for solvent-free vs. 6.84 for 1,4-dioxane), Process Mass Intensity (PMI), and Atom Economy are reported to substantiate sustainability claims. Statistical analysis (ANOVA with Tukey’s test, p < 0.05) confirmed the significance of the observed differences. This comparative study highlights the tradeoffs between operational simplicity, reaction kinetics, and environmental metrics, providing a scalable foundation for green pharmaceutical synthesis as confirmed by gram-scale experiments (30 mmol scale, 87% yield).