5-Bromo-2-chlorobenzoic acid → HCID 59235381, compound

Temperature

25 °C

To a solution of 5-bromo-2-chlorobenzoic acid (3.2 g, 13.5 mmol) in dichloromethane (40 mL), oxalyl dichloride (1.7 mL, 27.1 mmol) was added. Then N,N-dimethylformamide (50 mL) was added dropwise. After the vigorous evolution of gas ceased, the mixture was stirred at 25° C. overnight prior to removal of the volatiles under reduced pressure. The residue was dissolved in dichloromethane (20 mL) and cooled to 0° C. Aluminum trichloride (2.7 g, 20.4 mmol) was added in portions, and the mixture was stirred for 10 minutes. Then 1,3-difluoro-2-methoxybenzene (2.0 g, 13.8 mmol) was added, and the mixture was stirred at 0° C. for 2 hours. Then the reaction was allowed to warm to 25° C. overnight. The reaction was quenched with ice-water (30 mL) and extracted with dichloromethane (2×20 mL). The combined organic layers were washed with sodium hydroxide (2 M), water, hydrochloric acid (10%), and brine prior to drying over sodium sulfate. Crude product was obtained after dichloromethane was removed under reduced pressure. The sample was dissolved in tetrahydrofuran/methanol/water (30 mL, v/v/v=2:3:1), and lithium hydroxide monohydrate (700 mg) was added. The mixture was stirred for 1 hour at 25° C. The solvent was removed under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×30 mL), and the extracts were washed with brine, dried over sodium sulfate, and concentrated to a crude product under reduced pressure. The residue was purified by silica column chromatography to give 1.46 g of white solid (30% yield, purity: 95%). 1H-NMR (CDCl3, 400 MHz): δ 7.59-7.62 (m, 1H), 7.49-7.50 (m, 1H), 7.36-7.42 (m, 3H); HPLC-MS method: Method 2, retention time 3.81 min; MS ES+ (m/z): 345 (M−1)−.

1. customto removal of the volatiles under reduced pressure
2. dissolutionThe residue was dissolved in dichloromethane (20 mL)
3. temperaturecooled to 0° C
4. stirringthe mixture was stirred for 10 minutes
5. stirringthe mixture was stirred at 0° C. for 2 hours
6. temperatureto warm to 25° C. overnight
7. customThe reaction was quenched with ice-water (30 mL)
8. extractionextracted with dichloromethane (2×20 mL)
9. washThe combined organic layers were washed with sodium hydroxide (2 M), water, hydrochloric acid (10%), and brine
10. dry with materialto drying over sodium sulfate
11. customCrude product was obtained after dichloromethane
12. customwas removed under reduced pressure
13. dissolutionThe sample was dissolved in tetrahydrofuran/methanol/water (30 mL, v/v/v=2:3:1)
14. additionlithium hydroxide monohydrate (700 mg) was added
15. stirringThe mixture was stirred for 1 hour at 25° C
16. customThe solvent was removed under reduced pressure
17. extractionThe aqueous layer was extracted with ethyl acetate (3×30 mL)
18. washthe extracts were washed with brine
19. dry with materialdried over sodium sulfate
20. concentrationconcentrated to a crude product under reduced pressure
21. customThe residue was purified by silica column chromatography

ORD record

ord-9b10a2aff9224b21a448fee6af505a60

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09061060B2