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

반응식

HRID 18951 반응식
[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

참가 물질

8

반응물 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

생성물 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)-propionamide수율 55%

시약·촉매·용매 3

HCID 6228Dimethylformamide촉매HCID 241Benzene용매HCID 6344Dichloromethane용매

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온도
25 °C

실험 절차

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).

후처리

  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)

출처 및 근거

ORD 기록
ord-f02de99b23cb4cfda60091d13d54044f
출처 데이터셋
uspto-grants-2010_06
특허 번호
US07741327B2

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