Water → HCID 68997055, compound

A suspension of 4-fluoro-3-hydroxybenzoic acid (0.19 g), 2,3-difluoro-6-methoxybenzyl bromide (0.6 g) and potassium carbonate (0.5 g) in N,N-dimethylformamide (3 mL) was stirred at room temperature for 8 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (6 mL). To the solution were added methanol (3 mL), water (3 mL) and lithium hydroxide-monohydrate (0.5 g), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1 mol/L hydrochloric acid (15 mL), and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was suspended in a mixed solvent (n-hexane/ethyl acetate=4/1) and collected by filtration, and dried under reduced pressure to give 4-fluoro-3-(2,3-difluoro-6-methoxybenzyloxy)benzoic acid (0.31 g). This material was dissolved in 1,4-dioxane (4 mL). To the solution were added triethylamine (0.41 mL) and diphenylphosphoryl azide (0.21 mL), and the mixture was stirred at room temperature for 1 hour. Then the mixture was heated for reflux for 4 hours. To the reaction mixture was added 1 mol/L aqueous sodium hydroxide solution (4 mL), and the mixture was stirred at room temperature for 1 hour. 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 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=2/1−1/1) to give crude product. To the crude product was added methylene chloride, and the insoluble material was removed by filtration.

1. extractionthe resulting mixture was extracted with diethyl ether
2. washThe extract was washed with water and brine successively
3. dry with materialdried over anhydrous sodium sulfate
4. customThe solvent was removed under reduced pressure
5. dissolutionthe residue was dissolved in tetrahydrofuran (6 mL)
6. additionTo the solution were added methanol (3 mL), water (3 mL) and lithium hydroxide-monohydrate (0.5 g)
7. stirringthe mixture was stirred at room temperature for 1 hour
8. additionTo the reaction mixture was added 1 mol/L hydrochloric acid (15 mL)
9. extractionthe resulting mixture was extracted with ethyl acetate
10. washThe extract was washed with water and brine successively
11. dry with materialdried over anhydrous sodium sulfate
12. customThe solvent was removed under reduced pressure
13. filtrationcollected by filtration
14. customdried under reduced pressure

ORD record

ord-b3e553df0dfa40d291901c67a1da4f68

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040693B2