Abstract: OBJECTIVE To improve the key step of ring-opening fluorination in the preparation of betamethasone, to resolve the shortcomings of the traditional fluorination agent, which will produce large amount of waste liquid. METHODS Screening different fluorination agents, and the optimal conditions for ring-opening fluorination were achieved by investigating reaction solvent, temperature, concentration of HF, and so on. RESULTS The HF-BmimOTf complex was chosen as favorable fluorination agents, the optimal ring-opening fluorination of betamethasone epoxide was obtained. The solvent toluene and ionic liquidBmimOTf could be recycled in this process, which dramatically reduced the production cost and the amount of polluted fluorine-containing waste water. CONCLUSION The process has the potential for the industrial production of betamethasone.