Reaktion #325925

Reaktionsgleichung

(R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine

K2CO3

H2O

(2R,3R)-3-amino-4-(benzyloxy)-1,1,1-trifluorobutan-2-ol

prop-1-en-2-yl carbonochloridate

→

1-((2R,3R)-1-(benzyloxy)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea

Ausbeute 59.0%

Lösungsmittel

THF

THF

EtOAc

Reaktionsbedingungen

Aufarbeitung

1. 1
   Waschenwashed with saturated NaCl (25 mL)
2. 2
   Trocknendried over MgSO4
3. 3
   Filtrationfiltered
4. 4
   Einengenconcentrated under reduced pressure
5. 5
   Sonstigeprepared
6. 6
   TemperaturThe reaction mixture was heated at 70° C. for 18 h
7. 7
   EinengenThe reaction solution was concentrated under reduced pressure
8. 8
   Sonstigepurified by ISCO chromatography (12 g column)
9. 9
   Sonstigehexane/EtOAc (0-30% over 20 min)

Vorschrift

To a solution of (R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (20 mg, 0.047 mmol), prepared as described in Procedure 3, 4, 5 and 6, in THF (0.5 mL) was added K2CO3 in H2O (10 mg, 2 M in H2O, 0.071 mmol), followed by the addition of prop-1-en-2-yl carbonochloridate (6 μL, 0.052 mmol). The reaction mixture was stirred at rt for 2 h, diluted with EtOAc (25 mL), washed with saturated NaCl (25 mL), dried over MgSO4, filtered and concentrated under reduced pressure. To the residue was added (2R,3R)-3-amino-4-(benzyloxy)-1,1,1-trifluorobutan-2-ol (23 mg, 0.094 mmol), prepared according to the procedure described in J. Org. Chem., 68(19):7545 (2003), TEA (20 μL, 0.14 mmol) in THF (0.5 mL). The reaction mixture was heated at 70° C. for 18 h. The reaction solution was concentrated under reduced pressure and purified by ISCO chromatography (12 g column) using hexane/EtOAc (0-30% over 20 min) to give 1-((2R,3R)-1-(benzyloxy)-4,4,4-trifluoro-3-hydroxybutan-2-yl)-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)urea (Example 236) as a white solid at a retention time of 17 min (19 mg, 59% yield). LCMS: RT=2.138 min [M+H] 701.29 (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=4.335 min, Purity 94% (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); NMR: 400 MHz 1H (CDCl3) 7.37 ppm, 3H, m; 7.25 ppm, 3H, m; 7.20 ppm, 1H, t, J=7.03 Hz; 7.13 ppm, 4H, m; 6.97 ppm, 2H, t, J=8.35 Hz; 6.89 ppm, 3H, m; 6.69 ppm, 2H, d, J=7.47 Hz; 5.86 ppm, 1H, m; 5.18 ppm, 1H, d, J=8.35 Hz; 5.13 ppm, 1H, s; 4.44 ppm, 2H, m; 4.26 ppm, 1H, d, J=9.67 Hz; 4.14 ppm, 1H, dd, J=8.13, 3.30 Hz; 3.99 ppm, 1H, m; 3.81 ppm, 2H, m; 3.71 ppm, 1H, m; 3.59 ppm, 1H, m.

Quelle