[F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([O-:14])=[O:13])[C:9]([O-:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:15])([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1To a stirred solution of 7.58 g (22.0 mmol) of diethyl 2-(2-fluoro-4-biphenylyl)-2-methylmalonate VI in 50 ml of absolute ethanol, maintained under nitrogen gas at ~15° C. (ice bath) is added 8.72 g (109.0 mmol, 5.0 mol-equiv.) of 50% aqueous sodium hydroxide. The temperature is maintained at <25° C. for 6 hours. The resulting suspension is diluted with 150 ml water and the pH is adjusted to ~8.0 with dilute hydrochloric acid. The solution is transferred to a separatory funnel and is extracted with 3×60 ml of methylene chloride. The aqueous layer is acidified to pH <1 with concentrated hydrochloric acid and is then extracted with 200 ml of ethyl acetate in three portions. The combined extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to give 5.9 g 2-(2-fluoro-4-biphenylyl)-2-methyl malonic acid. This material is dissolved in 15 ml of glacial acetic acid and the solution is heated to reflux for ~17 hours. Water (15 ml) is added and the solution is allowed to cool slowly with stirring and seeding. After 1 hour stirring at room temperature, the mixture is cooled with stirring to 0°-5° C., then let stand for ~15 hours. The product is isolated and washed with a few ml of cold 50% aqueous acetic acid then dried to give 4.67 g flurbiprofen Ib of melting point 113°-115° C.
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