Hydrochloric Acid → 1-(4-Fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine

Temperature

-78 °C

An ether solution (40 mL) of 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (2.0 g, 8.23 mmol) was stirred in an oven-dried round bottom flask at −78° C. under Ar. n-BuLi (2.5 M in hexanes, 3.6 ml, 9.05 mmol, 1.1 eq) was added dropwise. The resulting solution was stirred at −78° C. for 30 min. A solution of 4-fluoro-3-(trifluoromethyl)benzonitrile (1.55 g, 8.23 mmol, 1.0 eq) in Et2O (5 mL) was added dropwise. The resulting reddish mixture was stirred at −78° C. for 2 h. TMSCl (pretreated with Et3N (TMSCl:Et3N=10:1, v:v), 1.14 mL, 1.2 eq) was added dropwise. The dry ice bath was removed, and the resulting slurry was stirred at room temperature for 2 h. The reaction was cooled to −78° C. and a solution of benzyl magnesium chloride in THF (2.0 M, 8.4 mL, 2 eq) was added dropwise. The resulting mixture was slowly warmed up to room temperature and stirred at room temperature overnight. 1N HCl (100 mL) was added. The mixture was stirred at room temperature for 30 min, extracted with Et2O (2×), washed with 1N NaOH, H2O and brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was purified by flash column chromatography (silica gel, hexanes:ethyl acetate) to give 1-(4-fluoro-3-(trifluoromethyl)phenyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine (1.6 g, yield: 44%). LC-MS ESI 3.42 min 429.2 (M−NH3+H); NMR (400 MHz, CHLOROFORM-D) δ ppm 7.66 (dd, J=6.7, 2.3 Hz, 1H), 7.49-7.59 (m, 1H), 7.45 (s, 1H), 7.18-7.30 (m, 6H), 6.74 (d, J=6.9 Hz, 2H), 3.57 (m, 2H).

1. stirringThe resulting reddish mixture was stirred at −78° C. for 2 h
2. customThe dry ice bath was removed
3. stirringthe resulting slurry was stirred at room temperature for 2 h
4. temperatureThe reaction was cooled to −78° C.
5. temperatureThe resulting mixture was slowly warmed up to room temperature
6. stirringstirred at room temperature overnight
7. stirringThe mixture was stirred at room temperature for 30 min
8. extractionextracted with Et2O (2×)
9. washwashed with 1N NaOH, H2O and brine
10. dry with materialdried over Na2SO4
11. filtrationfiltered
12. concentrationconcentrated to dryness
13. customThe residue was purified by flash column chromatography (silica gel, hexanes:ethyl acetate)

ORD record

ord-7ec642a391d54de7af55ca90ee8dc76d

Source dataset

uspto-grants-2010_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07790770B2