Development of a Kilogram-Scale Route for Clinical Sample Production of the Intravenous Anesthetic Cipepofol

Propofol has been widely used as a clinical anesthetic for a few decades. Its derivative with a three-membered ring, Cipepofol, was found to be equally effective and with less side effects. Here, we report a process for the scale-up total synthesis of Cipepofol. It could be obtained in five steps from the commercially available 2-isopropylphenol. The key reactions involved Claisen rearrangement, Simmons–Smith cyclopropanation, and chiral resolution through carbamate formation/crystallization, followed by hydrolysis and wiped-film distillation. The reaction conditions were mild, and the involved reagents were easily accessible. With this process, the final product was synthesized in a 14% overall yield, without column chromatographic purification. The synthetic route offered a shorter, robust, and economical production of Cipepofol (chemical purity > 99.5%, 99.5% ee) in kg scale.