1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → 3-t-butoxy-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide

HRID 18974

Reaction equation

[C:1]([O:5][CH2:6][CH:7]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][C:12]1=[O:25])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH2:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([CH3:57])([OH:56])[CH3:55])[N:49]=1>ClCCl>[C:1]([O:5][CH2:6][CH:7]([N:11]1[CH2:15][C:14]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])=[CH:13][C:12]1=[O:25])[C:8]([NH:47][C:48]1[CH:52]=[CH:51][N:50]([CH2:53][C:54]([OH:56])([CH3:55])[CH3:57])[N:49]=1)=[O:10])([CH3:3])([CH3:4])[CH3:2]

Participants

Conditions

Temperature: 25 °C

Procedure

A solution of 3-t-butoxy-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (100 mg, 0.29 mmol) in dichloromethane (10 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (45 mg, 0.29 mmol) and 1-hydroxybenzotriazole (40 mg, 0.30 mmol). The reaction mixture was stirred at 25° C. for 2 h followed by the addition of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 50 mg, 0.32 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 3-t-butoxy-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(2-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (45 mg, 32%) as an off-white solid: LR-ES-MS m/z calculated for C25H34N4O6 [M]+ 486, observed [M+H]+ 487; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 6H) 1.12 (s, 9H) 3.64-3.78 (m, 2H) 3.81 (s, 3H) 3.89 (s, 2H) 4.15 (d, J=18.4 Hz, 1H) 4.45 (d, J=18.4 Hz, 1H) 4.67 (s, 1H) 4.73 (s, 1H) 4.80 (dd, J=7.1, 4.7 Hz, 1H) 6.43 (d, J=2.2 Hz, 1H) 6.94-7.09 (m, 1H) 7.13-7.39 (m, 3H) 7.53 (d, J=2.2 Hz, 1H) 10.64 (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-ec6d24b8ddb04eeead884ea569df34ad
Source dataset: uspto-grants-2010_06
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US07741327B2

Linked notes

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