Paracetamol, the active ingredient in Tylenol®, is one of the most widely produced active pharmaceutical ingredients (API) worldwide. Current production methods rely on non-renewable feedstocks, are unselective, have poor Green Chemistry metrics, and can be hazardous. Lignin-based phenol and its derivatives offer a promising renewable source for aromatic structures. Here, we describe efficient methods for synthesizing paracetamol via hydrogenation and acetylation of 4-nitrophenol.
Continuous hydrogenation can mitigate the explosive hazards associated with hydrogenation by reducing the required hydrogen headspace. However, two key challenges to adapting this reaction in flow are the low solubility of 4-aminophenol, which limits the feasible concentrations at which the reaction can be run, and the instability of 4-aminophenol, which leads to undesired side reactions.
A novel reaction engineering strategy involving the simultaneous hydrogenation and acetylation of 4-nitrophenol in the same vessel rather than in a more traditional telescopic two-step fashion offers a pathway to overcoming both selectivity and solubility limitations.[1] Through removing the unstable and insoluble 4-aminophenol intermediate from the reactive environment and immediately transforming it to the more stable, soluble, and desired paracetamol, side reactions from 4-aminophenol can be mitigated. Furthermore, the reaction is now limited by the solubility of paracetamol.
Here, we describe a multi-stage packed bed reactor implementing simultaneous hydrogenation/acetylation in flow and obtaining paracetamol highly efficiently.[2] The optimized reactor conditions resulted in high selectivity, allowing for the isolation of pure paracetamol crystals in a single crystallization step. The final reactor system produced 98.5% paracetamol with a reaction mass efficiency of 0.54 and a process mass intensity of 7.2. To our knowledge, this represents the most selective and Green continuous synthesis of paracetamol documented to date.
[1] J. Park et al., Green Chemistry, 2024, 26(7), 4079-4091
[2] J. Park et al., ACS Sust. Chem. Eng. 2025, 000 (in press) (doi: 10.1021/acssuschemeng.4c10876)
