4-Bromo-2-chloroaniline → 4-(4-Bromo-2-chlorophenylamino)-6-chloronicotinic acid

To a solution of 2-chloro-4-bromoaniline (6.776 g, 33.1 mmol) in 50 ml anhydrous THF was added LHMDS (50 ml, 50 mmol, 1M/THF) over a period of 15 min at −78° C. It was stirred for an additional 30 min., then a solution of 4,6-dichloronicotinic acid (3 g, 15.7 mmol) in 50 ml THF was added dropwise. After complete addition the mixture was gradually allowed to warm to room temperature and the reaction mixture was stirred for an additional 12 hours. The mixture was quenched with H2O and 1N HCl was added (pH 0-1) followed by brine. It was extracted using THF and dried with Na2SO4. The solvent was removed and the solid crude product was suspended in 200 ml EtOAc. The suspension was heated with stirring at the reflux temperature for 5 min. It was cooled to room temperature and the precipitate was filtered and washed with EtOAc and dried at 50° C. for 5 h in oil pump vacuo to obtain the title compound as an off-white solid (4.05 g, 72%). Rf (CHCl3/MeOH 10:1)=0.3. 1H-NMR (500 MHz, DMSO-D6): δ=10.12 (s, 1H), 8.65 (s, 1H), 7.88 (s, 1H), 7.62-7.57 (dd, 1H), 7.55-7.48 (dd, 1H), 6.67 (s, 1H).

1. additionAfter complete addition the mixture
2. stirringthe reaction mixture was stirred for an additional 12 hours
3. customThe mixture was quenched with H2O and 1N HCl
4. additionwas added (pH 0-1)
5. extractionIt was extracted
6. dry with materialdried with Na2SO4
7. customThe solvent was removed
8. temperatureThe suspension was heated
9. stirringwith stirring at the reflux temperature for 5 min
10. temperatureIt was cooled to room temperature
11. filtrationthe precipitate was filtered
12. washwashed with EtOAc
13. customdried at 50° C. for 5 h in oil pump vacuo

ORD record

ord-7efc225b45804fc68e8654b7bc90308c

Source dataset

uspto-grants-2011_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08063049B2