(735ak) Renewable Routes to Paracetamol: A Green Chemistry Analysis

Paracetamol is one of the most widely used active pharmaceutical ingredients (APIs) worldwide. Current methods of paracetamol production suffer from the use of petrochemical feedstocks, hazardous reagents, poor selectivity, and batch operation, leading to subpar Green Chemistry metrics. To build new processes to paracetamol, they must be renewable, safe, environmentally friendly, and continuous. Lignin derived phenol is a potentially renewable source of the raw material needed for paracetamol production.

A key difficulty in paracetamol synthesis is accessing the important intermediate 4-aminophenol, which is difficult to obtain selectively due to its instability. We have examined the viability of three routes to 4-aminophanol and paracetamol starting from phenol, a monomer product of lignin depolymerization, as the feedstock. These three routes are the acetamidation of hydroquinone, the imination and reduction of p-benzoquinone, and the hydrogenation of 4-nitrophenol. We examine the performance of each of these routes in regard to Green Chemistry metrics as well as viability for continuous synthesis. In addition, we compare the renewable routes with existing routes from petrochemicals.

Through our analysis, we identified that the 4-nitrophenol route is the most promising in terms of Green Chemistry metrics and continuous viability. Thus, we also examine the Green Chemistry metrics of different reactor configurations for the reaction, including a traditional batch reactor, a novel mechanochemical reactor, and a flow reactor.