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

HRID 19015

Reaction equation

HRID 19015 reaction equation
Cl.OC(C)(C)[CH2:4][N:5]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:32])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])=[CH:19][C:18]2=[O:31])[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:32])[C@@H:12]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=3[Cl:30])=[CH:19][C:18]2=[O:31])[CH2:13][CH:14]([CH3:16])[CH3:15])=[N:6]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 1372541-Methyl-3-aminopyrazoleHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 66899077(S)-2-[4-(2,3-dichloro-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 57920055(S)-2-[4-(2,3-dichloro-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-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methy-1-pentanoic acid (prepared as in Example 77, 120 mg, 0.34 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-methyl-1H-pyrazol-3-ylamine (50 mg, 0.51 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (303 mg, 0.68 mmol) and N,N-diisopropylethylamine (110 mg, 0.85 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 70% ethyl acetate/hexanes) to afford (S)-2-[4-(2,3-dichloro-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-(2,3-dichloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (1-methyl-1H-pyrazol-3-yl)-amide hydrochloride (58 mg, 36%) as an orange solid: HR-ES-MS m/z calculated for C20H22Cl2N4O3 [M+Na]+ 459.0961, observed 459.0961; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H) 0.92 (d, J=6.6 Hz, 3H) 1.31-1.64 (m, 2H) 1.64-1.82 (m, 1H) 3.71 (s, 3H) 4.21 (d, J=18.4 Hz, 1H) 4.59 (d, J=18.4 Hz, 1H) 4.82-4.89 (m, 1H) 4.90 (s, 1H) 6.38 (d, J=2.1 Hz, 1H) 7.40-7.57 (m, 3H) 7.62 (dd, J=7.8, 1.5 Hz, 1H) 10.73 (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 70% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-0b20bfcd0e37461aa3df531824354dda
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Linked notes

Loading…