Development of a Practical and Scalable Manufacturing Process for Ciprofol

Ciprofol is a novel clinical anesthetic and is deemed a better alternative to propofol due to its fewer side effects. Herein, we report an atom-economical and cost-efficient manufacturing process to prepare Ciprofol, which includes regioselective para-halogenation of phenol, followed by esterification and Fries rearrangement in high yields. This strategy adopts para-halogenation to avoid the generation of para-byproducts in the Fries rearrangement. After a benign reduction of bromine and the Wittig reaction, the desired Ciprofol is achieved by ruthenium-catalyzed asymmetric hydrogenation. This new process has been tested on a multigram scale, with an improved overall yield of 60% and enhanced cost efficiency, while offering atom economy advantages. The low yield of the Claisen rearrangement and the use of costly and corrosive reagents in the previously reported synthesis were avoided.