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

HRID 19022

Reaction equation

HRID 19022 reaction equation
[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=3[F:24])=[CH:13][C:12]2=[O:25])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH:27][C@@H:28]([CH2:58]O)[CH2:29][N:30]1[CH:34]=[CH:33][C:32]([NH:35]C(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=[N:31]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=C[C:70]=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)(=O)C>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])=[CH:13][C:12]2=[O:25])[C:8]([NH:35][C:32]2[CH:33]=[CH:34][N:30]([CH2:29][C:28]([OH:27])([CH3:58])[CH3:70])[N:31]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 151348Benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphateHCID 66894764(S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acidHCID 66899094HMS5552 HCl

Product 1

HCID 44252021(S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamideYield 34.3%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
25 °C

Procedure

A solution of (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (109 mg, 0.31 mmol) in N,N-dimethylformamide (4 mL) was treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 62 mg, 0.40 mmol), benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (354 mg, 0.8 mmol) and N,N-diisopropylethylamine (103 mg, 0.8 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, 10% to 80% ethyl acetate/hexanes) to afford (S)-3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (52 mg, 34%): HR-ES-MS m/z calculated for C25H30F2N4O4 [M+H]+ 489.2308 observed 489.2308; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H) 1.06 (br. s., 3H) 1.09-1.98 (m, 11H) 3.89 (s, 2H) 4.30 (d, J=18.7 Hz, 1H) 4.61 (d, J=18.7 Hz, 1H) 4.68 (s, 1H) 4.82 (dd, J=10.1, 4.4 Hz, 1H) 5.03 (s, 1H) 6.45 (d, J=2.1 Hz, 1H) 7.26-7.50 (m, 3H) 7.54 (d, J=2.1 Hz, 1H) 10.82 (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, 10% to 80% ethyl acetate/hexanes)

Sources & evidence

ORD record
ord-f35f39abc990400b880373dd7a15fd29
Source dataset
uspto-grants-2010_06
Patent number
US07741327B2

Linked notes

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