Carbon Dioxide → 2-Amino-5-(trifluoromethyl)benzoic acid

Temperature

-78 °C

4-(trifluoromethyl)aniline (25 g, 0.15 mol) was dissolved in THF (275 mL), then treated with Boc anhydride (41 g, 0.19 mol), ET3N (19 g, 0.19 mol), and 4-(dimethylamino)pyridine (0.1 g, 0.8 mmol). The mixture was refluxed for 3 hours, the solvents removed in vacuo, and the organic residue dissolved in EtOAc, washed with 1 M NaOH, then 1 M HCl, then dried and concentrated. The resulting product was recrystallized from heptane yielding 39 g final product as a white solid. The solid (0.15 mol) was dissolved in THF (350 mL) and cooled to −78° C. under nitrogen, then treated dropwise with BuLi (1.6 M in hexane, 282 mL, 0.45 mol). After 1 h, the solution was warmed to 0° C. and held for 1.5 h. The mixture was poured onto excess solid CO2 and stirred overnight at RT. After partitioning against 1 M HCl, the THF layer was evaporated and the residue dissolved in EtOAc, washed with 1 M HCl, then dried and concentrated. The solid product was triturated with hexan to yield the final product as a white solid (15.8 g). LC/MS retention time 2.70 min, m/z (obs, M−H)=304.1. Finally the Boc anthranilate (11.3 g) was dissolved in CH2CL2 (26 mL) and treated with TFA (21 mL). After stirring at RT for 2 h, the solution was dried in vacuo, the resulting residue dissolved in toluene (100 mL), concentrated to dryness, and the dissolution/drying process repeated twice more, yielding the desired product as a white solid (10.8 g), LC/MS retention time 1.2 min, m/z (obs, M−H)=204.0.

1. temperatureThe mixture was refluxed for 3 hours
2. customthe solvents removed in vacuo
3. dissolutionthe organic residue dissolved in EtOAc
4. washwashed with 1 M NaOH
5. dry with material1 M HCl, then dried
6. concentrationconcentrated
7. customThe resulting product was recrystallized from heptane yielding 39 g final product as a white solid
8. temperaturethe solution was warmed to 0° C.
9. waitheld for 1.5 h
10. customAfter partitioning against 1 M HCl
11. customthe THF layer was evaporated
12. dissolutionthe residue dissolved in EtOAc
13. washwashed with 1 M HCl
14. customdried
15. concentrationconcentrated
16. customThe solid product was triturated with hexan

ORD record

ord-fd383968755b45f8867dcf73b86d7f20

Source dataset

uspto-grants-2010_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07678802B2