Using sodium dithionite as a reducing agent in the synthesis of propacetamol hydrochroride from phenol

Abstract

Propacetamol, a prodrug form of paracetamol, is used in injections for fast and effective pain relief. Propacetamol is water soluble and is used in postoperative care as well as intravenous administration in case the patients cannot take oral or rectal paracetamol. Studies on propacetamol synthesis at laboratory scale as well as industrial scale with safe, simple and economic procedures are crucial. In this study, we synthesized propacetamol from phenol as the starting material. In the first step, phenol was converted to p-nitrosophenol through a nitrosation process. This nitrosation reaction yielded the optimal result as the reaction selectively occured, the product was not plasticized. Next, p-nitrosophenol was reduced to p-aminophenol in the presence of sodium dithionite as the reducing agent. The reaction produced p-aminophenol at a yield of 89,6% with high selectivity and less impurity. After that, paracetamol was obtained through acetylation of p-aminophenol. Ochloroacetylation of paracetamol was performed by using the amount of diethylamine reduced by 2,5 times compared to previous studies to form 4-acetamidophenyl-2-chloroacetate in 85,5% yield. This intermediate was then alkylated to form propacetamol base, followed by treatment with HCl solution in acetone at low temperature to obtain propacetamol hydrochloride in 32,5% yield. The study has shown that propacetamol hydrochloride was successfully achieved with high efficiency and safety from phenol as the starting compound.