Preparation
1.9,11-Epoxy Reaction
Add 10g of 6-methyl-17-hydroxy-1,4,9-trien-pregn-3,20-dione and 120ml of acetone to a reaction flask, stir, cool to 0℃, add 9g of NBS over 30 minutes, maintain the reaction at 5-10℃ for 2 hours, add 10% sodium carbonate aqueous solution to neutralize to pH=6.5, raise the temperature to 20±2℃, add 15ml of 10% sodium hydroxide aqueous solution over 1 hour, maintain the temperature at 20-25℃ for 2 hours, neutralize to pH=7 with acetic acid, concentrate under reduced pressure until there is no acetone odor, dilute to ice water, filter, dry to obtain 11.2g of 9,11-epoxide.
2.9,11-Ring-opening reaction
Add 11.2g of 9,11-epoxide obtained from the reaction of 9,11-epoxide and 60ml of DMF to a reverse flask, stir, cool to -5℃, introduce hydrogen fluoride gas, maintain the reaction at -5～0℃ for 1 hour, dilute in ice water, adjust the pH to 7 with ammonia, filter, dry, and obtain 9.5g of fluorometholone. Recrystallize in acetone to obtain 8.5g of fluorometholone, MP: 290-300℃.
Refining:
Add 100g of crude fluorometholone (97%) to 400mL of N,N-dimethylformamide, stir and heat to 80-90℃, maintain for 0.5h, until completely dissolved, then slowly add 1L of anhydrous methanol, maintaining the temperature within the range of 60-70℃ throughout the addition process. After addition, maintain for 0.5h, then cool to 0-5℃ and maintain at 0-5℃ for crystallization for 12h. Filter to obtain off-white crystalline fluorometholone concentrate, dry to obtain 30g of fluorometholone concentrate (purity 99.55%, known single impurities 0.14%, total impurities 0.09%).
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