反应详情

To a solution of (S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamine (61.2 mg, 0.14 mmol), prepared as described in Procedures 3, 5, 6 and 7, in THF (1 mL), K2CO3 in H2O (28 mg, 2 M in H2O, 0.21 mmol) was added, followed by the addition of isopropenyl chlororoformate (16 μL, 0.15 mmol). The reaction mixture was stirred at room temperature for 2 hr, diluted with EtOAc (25 mL), and the organic portion washed with saturated NaCl (25 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was combined with (2R,3R)-3-amino-4-(benzyloxy)-1,1,1-trifluorobutan-2-ol (22 mg, 0.09 mmol), TEA (38 uL, 0.27 mmol) in THF (1.0 mL) and the reaction mixture was heated at 50° C. for 18 h. The solvent was removed and the residue purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-30% over 30 min) to give 1-((2R,3R)-1-(benzyloxy)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)urea as a clear oil at a retention time of 23-25 min (36.8 mg, 57% yield) LCMS: RT=2.13 min [M+H] 718.32 (LCMS Method 2); HPLC: RT=4.33 min, Purity 92% (HPLC Method 1) NMR: 400 MHz 1H (CDCl3) 8.25 ppm, 1 H, d, J=2.20 Hz; 7.66 ppm, 1 H, dd, J=8.57, 2.42 Hz; 7.35 ppm, 6 H, m; 7.13 ppm, 5 H, m; 7.06 ppm, 2 H, t, J=7.47 Hz; 6.88 ppm, 1 H, d, J=8.79 Hz; 6.58 ppm, 2 H, t, J=7.03 Hz; 5.87 ppm, 1 H, tt, J=52.95, 2.64 Hz; 5.23 ppm, 1 H, d, J=8.35 Hz; 4.52 ppm, 3 H, m; 4.36 ppm, 1 H, d, J=12.74 Hz; 4.24 ppm, 1 H, dd, J=8.13, 3.30 Hz; 4.04 ppm, 1 H, m; 3.93 ppm, 1 H, dd, J=9.89, 3.74 Hz; 3.75 ppm, 1 H, dd, J=10.11, 2.20 Hz; 3.53 ppm, 1 H, d, J=12.74 Hz.

1. additionfollowed by the addition of isopropenyl chlororoformate (16 μL, 0.15 mmol)
2. washthe organic portion washed with saturated NaCl (25 mL)
3. dry with materialdried over MgSO4
4. filtrationfiltered
5. concentrationconcentrated in vacuo
6. temperaturethe reaction mixture was heated at 50° C. for 18 h
7. customThe solvent was removed
8. customthe residue purified by ISCO chromatography (12 g column)
9. customhexanes/EtOAc (0-30% over 30 min)