Oxalyl chloride → (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide

HRID 18951

Reaktionsgleichung

Reaktionsgleichung von HRID 18951
[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[CH:30]=[CH:29][N:28]([CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[N:27]=1.C(N(CC)C(C)C)(C)C>C1C=CC=CC=1.CN(C)C=O.ClCCl>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:8]([NH:25][C:26]2[CH:30]=[CH:29][N:28]([CH2:31][C:32]([OH:34])([CH3:33])[CH3:35])[N:27]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1

Komponenten

8

Edukt 4

HCID 65578Oxalyl chlorideHCID 81531DiisopropylethylamineHCID 593449381-(3-amino-1H-pyrazol-1-yl)-2-methylpropan-2-olHCID 66894643(S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid

Produkt 1

HCID 44252903(S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamideAusbeute 55 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 6228DimethylformamideKatalysatorHCID 241BenzeneLösungsmittelHCID 6344DichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
25 °C

Versuchsvorschrift

A solution of (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid (643 mg, 2.53 mmol) in benzene (8 mL) was treated with oxalyl chloride (342 mg, 2.7 mmol), and N,N-dimethylformamide (1 drop). Effervescence was observed. The reaction mixture was stirred for 3 h at 25° C., under nitrogen. The reaction mixture was concentrated, and dissolved in dichloromethane (8 mL) and treated with 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 442 mg, 2.8 mmol), and N,N-diisopropylethylamine (497 mg, 3.8 mmol). The reaction mixture was stirred at 25° C., under nitrogen for 18 h. The reaction mixture was diluted with dichloromethane, washed with 2N aqueous hydrochloric acid, saturated sodium chloride solution and dried. The organic layer was concentrated, and the crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 80 g; 0% to 10% methanol/dichloromethane) to afford (S)-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionamide (542 mg, 55%) as an off-white powder: LR-ES-MS m/z calculated for C20H30N4O4 [M]+ 390, observed [M+H]+ 391; 1H NMR (DMSO-d6, 300 MHz) δ ppm 1.04 (s, 3 H), 1.06 (s, 3H), 1.08 (m, 1H), 1.26 (m, 1H), 1.44 (m, 2H), 1.50-1.86 (m, 7H), 3.78 (s, 3H), 3.88 (s, 2H), 3.95 (d, Jgem=18.0 Hz, 1H), 4.33 (d, Jgem=18.0 Hz, 1H), 4.66 (s, 1H), 4.78 (dd, J=4.6 Hz, 10.6 Hz, 1H), 5.15 (s 1H), 6.42 (d, J=2.3 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 10.70 (s, 1H).

Aufarbeitung

  1. concentrationThe reaction mixture was concentrated
  2. dissolutiondissolved in dichloromethane (8 mL)
  3. stirringThe reaction mixture was stirred at 25° C., under nitrogen for 18 h
  4. washwashed with 2N aqueous hydrochloric acid, saturated sodium chloride solution
  5. customdried
  6. concentrationThe organic layer was concentrated
  7. customthe crude product was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 80 g; 0% to 10% methanol/dichloromethane)

Quellen und Nachweise

ORD-Eintrag
ord-f02de99b23cb4cfda60091d13d54044f
Quelldatensatz
uspto-grants-2010_06
Patentnummer
US07741327B2

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