Ethanol → 2,3-Difluoro-6-(2-methoxyethoxy)aniline

To a suspension of 3,4-difluorophenol (1.43 g) and cesium carbonate (4.89 g) in N,N-dimethylformamide (10 mL) was added 2-methoxyethyl bromide (0.94 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with 1 mol/L aqueous sodium hydroxide solution, water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (39 mL). To the solution was added n-butyllithium (2.64 mol/L n-hexane solution, 3.25 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture was added dryice (10 g), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was acidified by addition of 2 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (1.48 g). The obtained 2,3-difluoro-6-(2-methoxyethoxy)benzoic acid (0.5 g) was dissolved in 1,4-dioxane (10 mL). To the solution were added triethylamine (0.45 mL) and diphenylphosphoryl azide (0.61 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added ethanol (0.99 g), and the mixture was heated for reflux for 5 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. To a suspension of the residue in ethanol (10 mL) was added 5 mol/L aqueous sodium hydroxide solution (4.3 mL), and the mixture was heated for reflux for 2 hours. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with water twice and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1) to give the title compound (75 mg).

1. temperaturethe mixture was heated
2. temperaturefor reflux for 5 hours
3. washthe resulting mixture was washed with 1 mol/L hydrochloric acid, water and brine successively
4. dry with materialdried over anhydrous magnesium sulfate
5. customThe solvent was removed under reduced pressure
6. additionTo a suspension of the residue in ethanol (10 mL)
7. additionwas added 5 mol/L aqueous sodium hydroxide solution (4.3 mL)
8. temperaturethe mixture was heated
9. temperaturefor reflux for 2 hours
10. additionThe reaction mixture was diluted with ethyl acetate
11. washthe resulting mixture was washed with water twice
12. dry with materialbrine, and dried over anhydrous magnesium sulfate
13. customThe solvent was removed under reduced pressure
14. customthe residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=3/1)

ORD record

ord-cd811140fd014e3aacb53c8cc247dab6

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040693B2