Diisopropylethylamine → (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide

HRID 19020

Reaction equation

HRID 19020 reaction equation
Cl.OC(C)(C)[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[CH:19][C:18]2=[O:32])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1.CN1C=CC(N)=N1.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>[CH3:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:33])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[O:29][CH2:30][CH3:31])=[CH:19][C:18]2=[O:32])[CH2:13][CH:14]([CH3:15])[CH3:16])=[N:6]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 1372541-Methyl-3-aminopyrazoleHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 67505023(S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide hydrochloride

Product 1

HCID 44252016(S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (prepared as in Example 81, 120 mg, 0.36 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (42 mg, 0.43 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (320 mg, 0.72 mmol) and N,N-diisopropylethylamine (100 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, 20% to 70% ethyl acetate/hexanes) to afford (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide as a waxy material. This material was dissolved in diethyl ether (4 mL) and treated with hydrogen chloride in diethyl ether (1 M, 2 mL). Solvents were evaporated and the residue was triturated with diethyl ether. The resulting mixture was filtered to give (S)-2-[4-(2-ethoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride (30 mg, 19%) as a brown solid: HR-ES-MS m/z calculated for C22H28N4O4 [M+Na]+ 435.2003, observed 435.2002; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H) 0.90 (d, J=6.6 Hz, 3H) 1.24 (t, J=6.9 Hz, 3H) 1.30-1.61 (m, 2H) 1.62-1.82 (m, 1H) 3.71 (s, 3H) 3.94-4.13 (m, 3H) 4.48 (d, J=18.1 Hz, 1H) 4.72 (s, 1H) 4.86 (dd, J=10.6, 4.5 Hz, 1H) 6.37 (d, J=1.2 Hz, 1H) 6.97 (t, J=7.4 Hz, 1H) 7.17 (d, J=8.2 Hz, 1H) 7.20-7.32 (m, 2H) 7.52 (s, 1H) 10.68 (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, 20% to 70% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-de91ba3091cd4ab0a288e87520fbf906
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Linked notes

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