Experimental and theoretical analysis of Friedel–Crafts acylation of thioanisole to 4-(methylthio)acetophenone using solid acids

Abstract

4-(Methylthio)acetophenone is an important drug intermediate used for the synthesis of Vioxx (Rofecoxib), an NSAID, which has selective COX-2 inhibition. It is typically produced on industrial scale by Friedel–Crafts acylation using homogeneous corrosive and polluting acid catalysts such as aluminium chloride in more than stoichiometric amounts with acetyl chloride as the acylating agent. This process creates pollution problems related to the disposal of catalyst and treatment of acidic effluent and needs to be replaced by a green process. In the current work, a simple process was developed based on the use of heterogeneous catalysts. The activities of 20% w/w Cs_2.5H_0.5PW₁₂O₄₀/K-10 clay, Amberlyst-15, Indion-190 and Indion-130 were studied in the acylation of thioanisole with acetic anhydride to prepare 4-(methylthio)acetophenone. Amberlyst-15, a cation exchange resin, was found to be the best catalyst. The effects of various parameters were studied using this catalyst. Dynamic adsorption studies were performed independently to get adsorption equilibrium constants for the reactants and products. A theoretical model was developed to account for kinetics and mechanism and the various constants were evaluated from the experimental data. Simulations were performed to validate the model against experimental data and there was a excellent agreement between theory and experiment.