Sevoflurane Synthesis

Sevoflurane (1,1,1,3,3,3-hexafluoroisopropyl fluoromethyl ether) is a recently introduced inhaled anesthetic. It is now one of the most widely used anesthetic because, unlike other fluorinated inhaled anesthetic, it lacks a pungent odor, and thus, can be used for induction of anesthesia. In this paper we reported a new route, which has solved the known problems of other routes commendably. This route mainly consist five parts. Factors influencing the yield of every reaction were discussed, and the results were also discussed on the theories. Firstly, with hexafluoropropene and sulfur for the raw material, hexafluorothioacetone dimmer could be synthsized with the overall yield of 82.5%. The optimum reaction conditions were the temperature of 40℃, KF as the catalyzer and DMF as the solvent. Secondly, hexafluorothioacetone dimmer was oxidized into hexafluoroacetone at the oxidation of KIO₃. Thirdly, transforming hexafluoroacetone into hexafluoroisopropanol via hydrogenation at the catalysis of 5%Pd-C, the optimum conditions were the temperature 90℃, the hydrogen pressure 0.9MPa, reaction time 3 hours. The yield could reache 95%. Finally, sevoflurane was produced from a new synthesis which consisted of a two-stage fluoromethylation of hexafluoroisopropanol. In the first stage, hexafluoroisopropanol was chloromethylated using aluminum trichloride and paraformaldehyde. In the second stage fluorine exchange was carried out at the temperature of 95℃using potassium fluoride for the fluridizer, poly(ethylene glycol) for the solvent, and 2.5 hours, sevoflurane was distilled directly from the reaction vessel, with the overall yield 99.3%.In addition, some systemic researches about the last reaction of the route-the halogen-exchange fluorination were studied, which included the halogen-exchange fluorination with the solvent of ionic liquid as well as the halogen-exchange fluorination in the environment of microwave respectively. It was found when ionic liquid [bpy]BF₄ was chosen for the solvent and CsF for the fluorination reagent, the overall yield 96.6% could be gotten after 3 hours. The fluorination in the environment of microwave also got some satisfying results, which was definitely precious for the relative research.