(422f) Continuous Simultaneous Hydrogenation and Acetylation of 4-Nitrophenol to Paracetamol

Paracetamol (i.e. acetaminophen), the active ingredient of Tylenol®, is one of the largest scale active pharmaceutical ingredients (API) in the world. Current methods to produce paracetamol use non-renewable petrochemical feedstocks, hazardous reagents, have poor Green Chemistry metrics, and operate in batch configuration. New processes to paracetamol should be renewable, safe, environmentally friendly, and operate continuously. Lignin derived phenol and its derivatives are a promising source of the aromatic unit structures needed to synthesize many APIs. To that end, we describe methods to continuously synthesize paracetamol from the hydrogenation and acetylation of 4-nitrophenol.

Traditional hydrogenation methods operate using pressurized stirred tank batch reactors. The high temperature, pressure, and solvent loading of these processes introduce safety issues as well as poor Green Chemistry metrics. Continuous hydrogenation has been shown to mitigate the explosive risks of hydrogenation in industrial processes through reducing required hydrogen headspace and has additional advantages of consistent product quality and superior Green Chemistry metrics.

Careful design of the reaction conditions is required to achieve high selectivity, as the key intermediate of the hydrogenation reaction, 4-aminophenol, is highly reactive and undergoes various side reactions. In previous work, we showed that simultaneous hydrogenation and acetylation of 4-aminophenol in one vessel was highly effective for improving selectivity in a fed-batch mechanochemical reactor. Importantly, careful control of the rate of fed batch acetic anhydride addition was vital for maximizing selectivity.

Here, we implement the reaction engineering strategies learned during our design of our fed-batch mechanochemical synthesis in a flow reactor for continuous, selective paracetamol synthesis with high volumetric productivity. To our knowledge, this is one of the first continuous syntheses of paracetamol from the hydrogenation of 4-nitrophenol with elemental hydrogen.