Hydrochloric Acid → 2-Chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxymethyloxyaniline

To a solution of 5-chloro-2-(2,3-difluoro-6-methoxybenzyloxy)-4-nitrophenol (0.52 g) and N,N-diisopropylethylamine (0.52 mL) in methylene chloride (5 mL) was added (chloromethyl)methyl ether (0.17 mL) under ice-cooling, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (7.5 mL). To the solution were added methanol (7.5 mL) and nickel(II) bromide (17 mg). To the mixture was added sodium borohydride (0.17 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−1/1) to give the title compound (0.4 g).

1. temperaturecooling
2. extractionthe resulting mixture was extracted with ethyl acetate
3. washThe extract was washed with water and brine
4. dry with materialdried over anhydrous sodium sulfate
5. customThe solvent was removed under reduced pressure
6. dissolutionthe residue was dissolved in tetrahydrofuran (7.5 mL)
7. additionTo the solution were added methanol (7.5 mL) and nickel(II) bromide (17 mg)
8. additionTo the mixture was added sodium borohydride (0.17 g) under ice-
9. temperaturecooling
10. stirringthe mixture was stirred at the same temperature for 30 minutes
11. stirringstirred at room temperature for 30 minutes
12. additionThe reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution
13. extractionthe resulting mixture was extracted with ethyl acetate
14. washThe extract was washed with water and brine
15. dry with materialdried over anhydrous sodium sulfate
16. customThe solvent was removed under reduced pressure
17. customthe residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−1/1)

ORD record

ord-77d52a1cba2044a581b582c4d076f26a

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08217069B2