[Cl:1][C:2]1[C:3]([O:13][CH:14]2[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].[OH-].[Li+]>O1CCCC1.O.Cl>[Cl:1][C:2]1[C:3]([O:13][CH:14]2[CH2:15][CH2:16][C:17]([F:20])([F:21])[CH2:18][CH2:19]2)=[CH:4][C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]To a solution of methyl 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate (0.314 g, 0.973 mmol) in tetrahydrofuran (15 mL) and water (10 mL) was added lithium hydroxide (0.148 g, 6.18 mmol). The mixture was heated to reflux for 1.5 hours, cooled to ambient temperature. The reaction was diluted with 1 M hydrochloric acid (150 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to dryness. The residue was purified by column chromatography, with a gradient of a solution of 0.2% acetic acid in ethyl acetate and hexanes from 0-50% to afford the title compound as a colorless solid (0.25 g, 83%): 1H NMR (300 MHz, CDCl3) 8.05 (d, J=7.6 Hz, 1H), 6.70 (d, J=12.1 Hz, 1H), 4.63 (br s, 1H), 2.52-1.90 (m, 8H); 19F NMR (282 MHz, CDCl3) δ −92.3 (d, J=238 Hz, 1F), −102.6 (d, J=238 Hz, 1F), −105.3 (s, 1F); MS (ES−) m/z 307.2, 309.2 (M−1).
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