Diisopropylethylamine → (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide

HRID 19010Notes

Reaction equation

HRID 19010 reaction equation
[Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:23]([F:26])=[CH:24][CH:25]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([OH:14])=O)[C:8](=[O:22])[CH:7]=1.[NH2:28][C:29]1[CH:33]=[CH:32][N:31]([CH2:34][C:35]([CH3:38])([OH:37])[CH3:36])[N:30]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([F:27])=[C:4]([C:23]([F:26])=[CH:24][CH:25]=1)[O:5][C:6]1[CH2:10][N:9]([C@@H:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]([NH:28][C:29]2[CH:33]=[CH:32][N:31]([CH2:34][C:35]([OH:37])([CH3:36])[CH3:38])[N:30]=2)=[O:14])[C:8](=[O:22])[CH:7]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-olHCID 66900058(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid

Product 1

HCID 44251878(S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamideYield 34%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (143 mg, 0.36 mmol) in N,N-dimethylformamide (3 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 70 mg, 0.45 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (350 mg, 0.79 mmol) and N,N-diisopropylethylamine (103 mg, 0.80 mmol). The reaction mixture was stirred for 4 h at 25° C., under nitrogen. The reaction mixture was diluted with ethyl acetate, washed with saturated ammonium chloride, water, a saturated sodium chloride solution and dried over sodium sulfate. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes) to afford (S)-2-[4-(3-chloro-2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (65 mg, 34%) as a light yellow solid: HR-ES-MS m/z calculated for C26H31ClF2N4O4 [M+H]+ 537.2075, observed 537.2071; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.79-1.31 (m, 6H) 1.05 (s, 3H) 1.06 (s, 3H) 1.52-1.85 (m, 7H) 3.89 (s, 2H) 4.29 (d, J=18.7 Hz, 1H) 4.64 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.90 (dd, J=10.7, 5.0 Hz, 1H) 5.24 (s, 1H) 6.44 (d, J=2.2 Hz, 1H) 7.45 (td, J=9.6, 2.0 Hz, 1H) 7.54 (d, J=2.2 Hz, 1H) 7.67 (td, J=8.7, 5.3 Hz, 1H) 10.81 (s, 1H).

Workup

  1. washwashed with saturated ammonium chloride, water
  2. dry with materiala saturated sodium chloride solution and dried over sodium sulfate
  3. concentrationThe organic layer was concentrated
  4. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g, 0% to 100% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-6c02a587a87a4f74bfdbc3f3296ef02b
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Reaction notes

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