Direct synthesis of acetaminophen from p-aminophenol hydrochloride and sodium acetate for pharmaceutical applications

Abstract

The common strategy for the synthesis of acetaminophen typically requires two steps: firstly, p-aminophenol hydrochloride is converted into its free amine form as p-aminophenol; subsequently, it is reacted with acetic anhydride under basic or acidic conditions at high temperature to afford the final product. In this study, we report a one-step method for the direct synthesis of acetaminophen from p-aminophenol hydrochloride and sodium acetate, without the need to isolate the free amine. Several coupling reagents were evaluated for effectiveness in promoting the reaction. The results showed that the coupling agents 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU) and N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC. HCl) in H2O/ACN solvent system, were identified as the most effective, affording acetaminophen in yields of 87-89%. This transformation represents a new synthetic approach that has not been previously reported. Furthermore, the scalability of the reaction was demonstrated with up to 500 g of starting material, achieving an overall yield of 84-90%. This method holds high potential for application in the Vietnamese pharmaceutical industry.