Scaled up and telescoped synthesis of propofol under continuous-flow conditions

Herein we report a machine-assisted and scaled-up synthesis of propofol, a short-acting drug used in procedural sedation, which is extensively in demand during this COVID-19 pandemic. The continuous-flow protocol proved to be efficient, with great potential for industrial translation, reaching a production up to 71.6 g per day with process intensification (24 h-continuous experiments). We have successfully telescoped a continuous flow approach obtaining 5.74 g of propofol with productivity of 23.0 g/day (6 h-continuous experiment), proving the robustness of the method in both separated and telescoped modes. Substantial progress was also achieved for the in-line workup, which provides greater safety and less waste, also relevant for industrial application. Overall, the synthetic strategy is based on the Friedel-Crafts di-isopropylation of low-cost p-hydroxybenzoic acid, followed by a decarboxylation reaction, giving propofol in up to 84% overall yield and very low by-product formation. The continuous flow synthesis of propofol 3 is presented as a two-step protocol. The isopropylated intermediate 2 was obtained from 4-hydroxybenzoic acid (1) in up 43.8 g, 85% yield and 30 min residence time. Propofol 3 was then obtained in 71.6 g, 87% yield, and 16 min residence time. A safe and cost-competitive machine-assisted protocol is described with a process intensification demonstration (24 h experiments) and a telescoped process intensification (6 h).