1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (S)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide

HRID 18967

Reaction equation

[CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:24][C:23]2=[O:36])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH2:17]C(O)(C)C)[N:13]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.CN1C=CC(N)=N1>ClCCl>[CH:1]1([CH2:7][C@H:8]([N:22]2[CH2:26][C:25]([O:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34][CH3:35])=[CH:24][C:23]2=[O:36])[C:9]([NH:11][C:12]2[CH:16]=[CH:15][N:14]([CH3:17])[N:13]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1

Participants

Conditions

Temperature: 25 °C

Procedure

A solution of (S)-3-cyclohexyl-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (prepared as in Example 28, 200 mg, 0.56 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (87 mg, 0.56 mmol) and 1-hydroxybenzotriazole (80 mg, 0.58 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-methyl-1H-pyrazol-3-amine (60 mg, 0.61 mmol). The reaction mixture was then stirred for 18 h at 25° C., under nitrogen. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium 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)-3-cyclohexyl-N-(1-methyl-1H-pyrazol-3-yl)-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (80 mg, 33%) as a light yellow solid: LR-ES-MS m/z calculated for C24H30N4O4 [M]+ 438, observed [M+H]+ 439; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.78-1.28 (m, 6H) 1.44-1.86 (m, 7H) 3.73 (s, 3H) 3.81 (s, 3H) 4.10 (d, J=18.2 Hz, 1H) 4.49 (d, J=18.2 Hz, 1H) 4.71 (s, 1H) 4.89 (dd, J=10.6, 5.1 Hz, 1H) 6.39 (d, J=2.1 Hz, 1H) 6.95-7.06 (m, 1H) 7.21 (d, J=7.5 Hz, 1H) 7.25-7.36 (m, 2H) 7.54 (d, J=2.1 Hz, 1H) 10.70 (s, 1H).

Workup

stirringThe reaction mixture was then stirred for 18 h at 25° C., under nitrogen
washwashed with 2N aqueous hydrochloric acid, saturated sodium bicarbonate solution
dry with materiala saturated sodium chloride solution and dried over magnesium sulfate
concentrationThe organic layer was concentrated
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-bcc1c1964b8c492286a42481709593c3
Source dataset: uspto-grants-2010_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07741327B2

Linked notes

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