Process-Intensified Continuous Flow Synthesis of Propofol

Abstract This work presents a significantly improved and scaled continuous flow process for the synthesis of propofol (2,6-diisopropylphenol), a WHO-essential anesthetic agent. Building upon previous research, the two-step synthesis featuring a Friedel–Crafts bisalkylation of 4-hydroxybenzoic acid followed by base-mediated decarboxylation was reoptimized, taking into consideration critical industrial constraints such as solvent toxicity, reagent cost, productivity, and process robustness, leading to substantially reduced residence time and enhanced productivity through strategic modifications including neat isopropanol injection, adoption of a greener glycerol-based solvent system with potassium hydroxide, and implementation of kilolab-/pilot-scale equipment. The scaled-up process demonstrates remarkable space-time yield exceeding 2 kg·h–1·L–1 for the bisalkylation step and overall productivities surpassing previously reported methods. This advancement makes a step forward to a realistic pathway for more sustainable and decentralized manufacturing of this critical pharmaceutical compound.