Water → HCID 68517453, compound

Temperature

130 °C

A mixture of 2-chloro-3-nitropyridine (0.12 g), 2-chloro-5-(2,3-difluoro-6-methoxy-benzyloxy)-4-methoxyaniline (0.26 g) and N,N-diisopropylethylamine (0.14 mL) in acetonitrile (3 mL) was stirred at 130° C. in a reaction vessel equipped with a reflux condenser overnight. The reaction mixture was poured into water, 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 (4 mL)-methanol (4 mL). To the solution were added nickel(II) bromide (9 mg) and sodium borohydride (89 mg) under ice-cooling, and the mixture was stirred under ice-cooling 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 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=67/33−35/65) to give 3-amino-2-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]pyridine (62 mg). This material was dissolved in tetrahydrofuran (2 mL). To the solution were added sodium hydride (55%, 20 mg) and thiophosgene (0.012 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added N,N-dimethylformamide (1 mL), and the mixture was stirred at room temperature for 1 hour. 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 purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1−1/2) to give the title compound (28 mg).

1. customequipped with a reflux condenser overnight
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 (4 mL)-methanol (4 mL)
7. additionTo the solution were added nickel(II) bromide (9 mg) and sodium borohydride (89 mg) under ice-
8. temperaturecooling
9. stirringthe mixture was stirred under ice-
10. temperaturecooling 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 brine
15. dry with materialdried over anhydrous magnesium 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=67/33−35/65)

ORD record

ord-22cb92e1b3154b04b6e7f6170c93effd

Source dataset

uspto-grants-2012_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08217069B2