Development of a derivatization method, coupled with reverse phase HPLC, for monitoring the formation of an enolate intermediate

A sensitive liquid chromatographic method has been developed to monitor the formation of an enolate intermediate in a synthetic route to Etoricoxib, a drug candidate for the treatment of arthritis. The method requires the derivatization of the enolate with methyl iodide to form a stable methylketosulfone derivative followed by reverse phase HPLC analysis. Parameters affecting the derivatization, including the nature of derivatizing agent, reaction solvent, amount of dedvatizing agent, reaction time, reaction temperature, and amount of excess base in the reaction were investigated. The derivatization reaction was shown to give selective C-alkylation. The linear range of the chromatographic method for the determination of the starting material, ketosulfone, and the derivative, methylketosulfone, was determined. Finally, the accuracy of the method was established based on recovery experiments.