反应详情

To a solution of 3-(4-bromophenyl)-2,2-bis(3-(trifluoromethoxy)phenyl)propanoic acid (260 mg, 0.47 mmol) in toluene (10 mL) was added diphenylphosphoryl azide (0.409 mL, 1.9 mmol) followed by triethylamine (0.264 mL, 1.9 mmol). The reaction mixture was heated at reflux for 1 h, then trifluoroethylamine was added and the reaction mixture was heated at reflux for another 1 h. The reaction mixture was allowed to cool to rt and diluted with EtOAc (30 mL) and washed successively with sat. NH4Cl (10 mL), sat. NaHCO3 (10 mL) and sat. NaCl (20 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified on a ISCO silica gel column (12 g) with elution at 0 to 20% EtOAc/hexane over 20 min, then further purified by preparative HPLC YMC ODS S5 30×100 mm column 40-100% MeOH/H2O (90% in water, 0.1% TFA) gradient over 10 min with flow rate 40 mL/min and UV detection at 220 nm to yield 1-(2-(4-bromophenyl)-1,1-bis(3-(trifluoromethoxy)phenyl)ethyl)-3-(2,2,2-trifluoroethyl)urea (Example 278) as a white solid (200 mg, yield 65%). LCMS: RT=2.24 min [M+H] 645.0 (2 min Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); HPLC: RT=4.476 min, Purity 100% (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.2% PPA; 4 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 3.68-3.77 (m, 2H), 3.81 (s, 2H), 4.80 (t, J=6.15 Hz, 1H), 5.15 (s, 1H), 6.52 (d, J=7.91 Hz, 2H), 6.97 (s, 2H), 7.09-7.17 (m, 4H), 7.23-7.27 (m, 3H), 7.34 (t, J=7.91 Hz, 2H).

1. temperatureThe reaction mixture was heated
2. temperatureat reflux for 1 h
3. temperaturethe reaction mixture was heated
4. temperatureat reflux for another 1 h
5. washwashed successively with sat. NH4Cl (10 mL), sat. NaHCO3 (10 mL) and sat. NaCl (20 mL)
6. dry with materialThe organic layer was dried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe crude product was purified on a ISCO silica gel column (12 g) with elution at 0 to 20% EtOAc/hexane over 20 min
10. customfurther purified by preparative HPLC YMC ODS