Preparation method of high-purity flurbiprofen known impurities

[0036] Example 1

[0037] Add magnesium powder (2.55g, 0.105mol) to the reaction flask, under nitrogen protection and stirring, add dropwise 4-bromo-2-fluorobiphenyl (25.1g, 0.1mol) in anhydrous tetrahydrofuran (125ml) solution, control the temperature to 20 ~35°C, the dropwise addition is complete, the reaction is heated to reflux (65°C) for 2h, and the reaction is monitored by TLC; the temperature is reduced to room temperature under nitrogen protection, and sodium 2-bromo-2,3-dimethylsuccinate (26.9g, 0.1mol), after the addition, react at 65°C for 2h.; After the reaction is completed, the solvent is evaporated under reduced pressure, toluene (125ml) and dilute hydrochloric acid (125ml) are added, stirred and heated to dissolve, then stand still, separate the organic phase and use the water phase Extract once with toluene (50ml), combine the organic phases, wash with purified water until neutral, concentrate the organic phase under reduced pressure until solids precipitate out, stop concentration, cool down and crystallize, filter to obtain an off-white solid, and dry under reduced pressure at 50°C to obtain 2 -(2-Fluoro-4-biphenyl)-2,3-dimethylsuccinic acid crude product, 25.3g, molar yield 80.0%.

[0038] Example 2

[0039] Combine 10g of crude 2-(2-fluoro-4-biphenyl)-2,3-dimethylsuccinic acid, 70ml of methanol and water (1:1, v/v), heat to dissolve under stirring, and add activated carbon 0.2g, reflux and decolorize for 0.5h, hot filter, stir the filtrate and lower the temperature to 0-10℃, crystallize for 1h, filter, and dry the filter cake under reduced pressure and vacuum at 45℃ to obtain 2-(2-fluoro-4-biphenyl)- The refined product of 2,3-dimethylsuccinic acid is 7.72g, the HPLC purity is 99.1%, and the yield is 77.2%.

[0040] Example 3

[0041] Combine 10g of crude 2-(2-fluoro-4-biphenyl)-2,3-dimethylsuccinic acid, 50ml of ethanol and water (2:1, v/v), heat to dissolve under stirring, and add activated carbon 0.5g, reflux and decolorize for 0.5h, heat filter, stir the filtrate and lower the temperature to 0~10℃, crystallize for 1h, filter, and dry the filter cake under reduced pressure and vacuum at 45℃ to obtain 2-(2-fluoro-4-biphenyl)- 2,3-Dimethylsuccinic acid refined product 7.55g, HPLC purity 99.4%, yield 75.5%.