(359c) Routes to Renewable Production of Paracetamol: A Green Chemistry Analysis of Industrial Viability

The active pharmaceutical ingredient (API) paracetamol, an important ingredient in many over-the-counter (OTC) drugs such as Tylenol®, is one of the most widely produced pharmaceuticals worldwide. Supply chain shortages of paracetamol due to recent world events such as COVID-19 have increased interest in developing new methods to synthesize paracetamol that are green enough to facilitate permitting the establishment of new production plants.

Current methods to produce paracetamol are characterized by chemistry involving petrochemical feedstocks as well as dated and environmentally harmful reaction conditions, including batch processing and harsh reactants. To introduce new paracetamol supply chains, a new process is necessary that is based on renewables, environmentally friendly, and economically viable on a large scale. Lignocellulosic material is a promising alternative source of aromatic unit structures owing to its regional abundance and renewability, and may be the starting point for developing viable new routes to paracetamol.

A key bottleneck in the synthesis of paracetamol is access to the important intermediate 4-aminophenol, which is unstable and difficult to obtain selectively. Traditional syntheses obtain 4-aminophenol through the nitration of petrochemically derived benzene. We have examined the viability of three novel, alternate routes to 4-aminophenol and paracetamol, all 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 have examined the performance of each of these routes with the goal of determining their industrial viability. High reaction rate (indicating viability for continuous synthesis) and high Green Chemistry metrics (such as yield, RME, and E-factor) were considered.

Through our analysis, we identified that the 4-nitrophenol route is the most promising in terms of Green Chemistry metrics and continuous viability. Important problems holding back other reaction routes include slow reaction speed, low selectivity/yield from side reactions, and poor Green Chemistry metrics stemming from too many required reactants or reaction steps.