Green, Renewable, and Continuous Manufacturing of the Active Pharmaceutical Ingredient Paracetamol
Author(s)
Park, Jimin
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Abstract
Paracetamol, 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, are unselective, have poor Green Chemistry metrics, and include potentially hazardous reaction conditions. New processes to paracetamol should be renewable, Green, selective, and safe. Lignin derived phenol and its derivatives are a promising source of the aromatic unit structures needed to synthesize many APIs. To that end, we explore chemical routes to synthesize paracetamol from three phenol derivatives: hydroquinone, p-benzoquinone, and 4-nitrophenol. We show that routes from 4-nitrophenol have the greatest potential for industrial viability and scale-up through a detailed analysis of the Green Chemistry metrics of routes starting from each feedstock.
Careful design of the reaction conditions is required to achieve high selectivity, as the key intermediate of the synthesis, 4-aminophenol, is highly reactive and undergoes various side reactions. We showed that simultaneous hydrogenation and acetylation of 4-nitrophenol in one vessel was highly effective for improving selectivity in a batch reactor through removing the unstable intermediate from the reactive environment. Importantly, careful control of the rate of acetic anhydride addition is vital for maximizing selectivity.
Traditional hydrogenation methods operate using pressurized batch stirred tank 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.
Here, we implement the simultaneous hydrogenation/acetylation strategy to two novel reactor systems: a mechanochemical semi-batch reactor and a multi-stage packed bed reactor. The key principle behind both reactors is to feed hydrogen in continuous mode, thus reducing explosive headspace and improving safety metrics. With the addition of process intensification strategies such as solvent-free mechanochemical synthesis as well as bypassing solubility limitations, near quantitative yields of paracetamol are achieved with extremely low process mass intensities (6 – 8).
Our final reactor system yields 98.5% paracetamol with a reaction mass efficiency and process mass intensity of 0.54 and 7.2, respectively. Paracetamol meeting United States Pharmacopeia specifications was isolated from the reaction effluent. To our knowledge, this is the most selective and Green synthesis of paracetamol in the literature to date.
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Date
2025-04-22
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Dissertation