C[O:2][C:3](=[O:22])[CH2:4][O:5][C:6]1[N:11]=[CH:10][C:9]([C:12](=[O:21])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:8][N:7]=1.[OH-].[Na+].CO.ClCCl.C(O)(=O)C.COC>C1COCC1.CO>[F:20][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:12]([C:9]2[CH:10]=[N:11][C:6]([O:5][CH2:4][C:3]([OH:22])=[O:2])=[N:7][CH:8]=2)=[O:21])=[CH:19][CH:18]=1To a solution of [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid methyl ester (prepared above, 82 mg, 0.269 mmol) in THF/methanol (6 mL/0.3 mL) was added 1 N NaOH (0.3 mL, 0.3 mmol). Additional 1 N NaOH aliquots were added after 5 min (0.15 mL), 25 min (0.25 mL), and 2 h (1.0 mL). By thin layer chromatography (15/84/1 methanol/dichloromethane/acetic acid) it appeared that the starting material never disappeared, but LC/MS showed the presence of mostly methyl ether, with some desired acid and no starting material. The reaction mass was extracted with ethyl acetate. The combined organic layers were washed 1× with water, then 2× with 5% NaHCO3. The aqueous layers were combined, acidified to pH 1 with 3% HCl and extracted with dichloromethane. The organic layers were combined, washed with brine, dried and concentrated in vacuo to afford 12.8 mg (16% yield) of the titled carboxylic acid as a white solid. ESI-MS m/z 292 (MH+), 290 (M−H)−.
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