Water → 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

HRID 1365541Notes

Reaction equation

HRID 1365541 reaction equation
[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]([C:17]2[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=2)([NH2:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[C:31]([O-:34])([O-])=O.[K+].[K+].O.[NH2:38][C@H:39]([CH2:46][O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C@@H:40]([OH:45])[C:41]([F:44])([F:43])[F:42]>C1COCC1.CCOC(C)=O>[CH2:48]([O:47][CH2:46][C@@H:39]([NH:38][C:31]([NH:16][C@:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([C:17]1[CH:22]=[C:21]([O:23][C:24]([F:29])([F:28])[CH:25]([F:27])[F:26])[CH:20]=[C:19]([F:30])[CH:18]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:34])[C@@H:40]([OH:45])[C:41]([F:44])([F:43])[F:42])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1

Participants

7

Reactant 4

HCID 962WaterHCID 11430Potassium CarbonateHCID 59134703(S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethanamineHCID 59459201(2r,3r)-3-Amino-4-(benzyloxy)-1,1,1-trifluorobutan-2-ol

Product 1

HCID 589200751-((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)ureaYield 57%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

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.

Workup

  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)

Sources & evidence

ORD record
ord-4049795de5e1455aae119871f41766d6
Source dataset
uspto-grants-2011_02
Patent number
US07888376B2

Reaction notes

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