Synthetic Research On Flumethasone And Fluticasone Propionate

This thesis is focusing on the synthesis of glucocorticoid drug Flumethasone and Fluticasone propionate.Low-cost8-DM acetate was employed as the starting material to synthesize Flumethasone. After acid-catalyzed esterification with isopropenyl acetate,3-enol esters was formed. Fluorination with Selectfluor was carried out to synthesize6-fluorinated intermediate3-3without separation. Followed by epoxy ring-opening with anhydrous hydrogen fluoride,6a,9a-difluoro intermediates was formed. At last, Flumethasone was synthesized after alkaline hydrolysis of21-ester. The total yield was47%. Reactions were carried out at room temperature, and easy to operate and control.Flumethasone was the raw material to synthesize Fluticasone propionate. After oxidation by periodate acid and esterification by propionyl chloride,17a-propionate ester-17β-carboxylic acid was synthesized. Then, intermediate17β-thio-anhydride was formed after acylation rearrangement with N,N-dimethylthiocarbamoyl chloride and sodium iodide. Fluticasone propionate was synthesized by steps of nucleophilic substitution with bromochloromethane under alkaline conditions to synthesize chloromethyl thiocarboxylate,21-iodo exchange and fluorination by silver fluoride with42%overall yield. Crude purity was96.9%. After acetone recrystallization, refined purity was98.6%. Reaction was monitored by TLC. The structure of the products was analyze by NMR, mass, IR, etc. to confirm.