Lithium Hydroxide → 5-Chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acid

HRID 1849805Notes

Reaction equation

HRID 1849805 reaction equation
[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]

Participants

6

Reactant 2

HCID 3939Lithium HydroxideHCID 86703689Methyl 5-chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoate

Product 1

HCID 867036885-Chloro-4-((4,4-difluorocyclohexyl)oxy)-2-fluorobenzoic acidYield 83.2%

Reagents, catalysts & solvents 3

HCID 313Hydrochloric AcidSolventHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

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).

Workup

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 1.5 hours
  3. extractionextracted with ethyl acetate (2×100 mL)
  4. dry with materialThe combined organic layers were dried over anhydrous magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo to dryness
  7. customThe 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%

Sources & evidence

ORD record
ord-93974321de9246a7a3e8d3201a97a75b
Source dataset
uspto-grants-2015_02
Patent number
US08952169B2

Reaction notes

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