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

HRID 19006

Reaction equation

HRID 19006 reaction equation
[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11](O)=[O:12])[C:7](=[O:21])[CH:6]=1.[CH3:27][N:28]1[CH:32]=[CH:31][C:30]([NH2:33])=[N:29]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[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:11]([NH:33][C:30]2[CH:31]=[CH:32][N:28]([CH3:27])[N:29]=2)=[O:12])[C:7](=[O:21])[CH:6]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 1372541-Methyl-3-aminopyrazoleHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 66893500(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid

Product 1

HCID 57920065(S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-propionamideYield 45%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-propionic acid (prepared as in Example 67, 125 mg, 0.33 mmol) in N,N-dimethylformamide (3 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (40 mg, 0.40 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (300 mg, 0.67 mmol) and N,N-diisopropylethylamine (85 mg, 0.65 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-(2-chloro-6-fluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-propionamide (68 mg, 45%): 1H NMR (300 MHz, DMSO-d6) δ ppm 0.60-1.36 (m, 6H) 1.42-1.91 (m, 7H) 3.73 (s, 3H) 4.25 (d, J=18.7 Hz, 1H) 4.62 (d, J=18.7 Hz, 1H) 4.90 (dd, J=10.3, 5.4 Hz, 1H) 4.96 (s, 1H) 6.40 (d, J=2.1 Hz, 1H) 7.38-7.54 (m, 3H) 7.55 (d, J=2.1 Hz, 1H) 10.74 (s, 1H). HR-ES-MS m/z calculated for C23H26ClFN4O3 [M+Na]+ 483.1569, observed 483.1568.

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-96ce387522614b439ff2904fafa62192
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Linked notes

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