Hydrochloric Acid → Methyl 4-bromo-3-(trifluoromethoxy)benzoate

To a solution of 4-amino-3-(trifluoromethoxy)benzoic acid (2.00 g, 9.10 mmol) in MeOH (25.0 mL), was slowly added HCl (1.0 mL, 1.0 M in ether) at room temperature. The resulting reaction mixture was stirred at room temperature overnight. Benzene (20 mL) was added, and the reaction was heated at reflux with a Dean-Stark trap to remove the half volume of the solvent. The rest of the solvent was then evaporated to give the product. MS (ESI) m/e=235.9 [M+1]+, Calc'd for C8H6F3NO3, 235.1. The crude product was used in the next step without further purification. To an ice-cooled suspension of methyl 4-amino-3-(trifluoromethoxy)benzoate hydrogen chloride salt (8.60 g, 31.70 mmol) in 17.1 mL of water and concentrated HBr (48%, 17.1 mL), was slowly added a prepared 2.5 M solution of sodium nitrite (2.20 g in 12.7 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes. Meanwhile, a solution of CuSO4 (6.68 g) in 35 mL of water was heated and sodium bromide (6.52 g) was added. The solution became a green color, and a solution of Na2SO3 (2.80 g) in water (10 mL) was then added to it. The solution was cooled at 0° C. and washed with water (25×3 mL). The water was then decanted off. Concentrated HBr (16.7 mL) was added, and the solution became a purple color. The solution of CuBr was slowly added to the diazonium salt (prepared above) at 0° C. After addition, the ice-bath was removed, and an oil-bath was placed under the reaction vessel. The reaction mixture was then heated to 60° C. for 15 minutes, at 80° C. for 15 minutes, and then at 100° C. for 20 minutes. The reaction mixture was next cooled to room temperature and made basic with Na2CO3 to a pH 8. The aqueous solution was extracted with EtOAc (100×2 mL). The organic layer was washed with brine (25 mL) and dried with MgSO4. The solvent was removed to give the crude product 28.2. 1H NMR (CDCl3) δ 3.96 (s, 3H), 7.75 (d, J=8.4 Hz, 1 H), 7.86 (d, J=8.4 Hz, 1 H), 7.98 (s, 1H).

1. customat room temperature
2. customThe resulting reaction mixture
3. temperaturethe reaction was heated
4. temperatureat reflux with a Dean-Stark trap
5. customto remove the half volume of the solvent
6. customThe rest of the solvent was then evaporated
7. customto give the product
8. customThe crude product was used in the next step without further purification
9. temperatureTo an ice-cooled
10. stirringThe reaction mixture was stirred at 0° C. for 10 minutes
11. temperatureThe solution was cooled at 0° C.
12. washwashed with water (25×3 mL)
13. customThe water was then decanted off
14. additionConcentrated HBr (16.7 mL) was added
15. additionThe solution of CuBr was slowly added to the diazonium salt (prepared above) at 0° C
16. additionAfter addition
17. customthe ice-bath was removed
18. customan oil-bath was placed under the reaction vessel
19. temperatureThe reaction mixture was then heated to 60° C. for 15 minutes, at 80° C. for 15 minutes
20. waitat 100° C. for 20 minutes
21. temperatureThe reaction mixture was next cooled to room temperature
22. extractionThe aqueous solution was extracted with EtOAc (100×2 mL)
23. washThe organic layer was washed with brine (25 mL)
24. dry with materialdried with MgSO4
25. customThe solvent was removed

ORD record

ord-5e8f817e6a3c44b585ad1198269cf8dd

Source dataset

uspto-grants-2011_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08003648B2