2,6-Lutidine → (5)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide

HRID 2365710노트

반응식

HRID 2365710 반응식
[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:23])([F:22])[F:21])[C:12]2=[O:24])[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[CH3:31][N:32]1[CH:36]=[CH:35][C:34]([NH2:37])=[N:33]1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([N:11]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[C:20]([F:22])([F:21])[F:23])[C:12]2=[O:24])[C:8]([NH:37][C:34]2[CH:35]=[CH:36][N:32]([CH3:31])[N:33]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1

참가 물질

7

반응물 4

HCID 79372,6-LutidineHCID 65578Oxalyl chlorideHCID 1372541-Methyl-3-aminopyrazoleHCID 70945341(S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid

생성물 1

HCID 70674334(5)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide수율 77.1%

시약·촉매·용매 2

HCID 6228Dimethylformamide촉매HCID 6344Dichloromethane용매3회

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온도
0 °C

실험 절차

A solution of (S)-3-cyclopentyl-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionic acid (100 mg, 0.29 mmol) in methylene chloride (2.9 mL) at 0° C. was treated with oxalyl chloride (0.03 mL, 0.34 mmol) followed by N,N-dimethylformamide (5 drops). The resulting solution was stirred at 0° C. for 30 min. At this time, the solution was warmed to room temperature and stirred for 30 min. The reaction was then concentrated in vacuo. The residue was re-suspended in methylene chloride (2×5 mL) and then concentrated in vacuo. The residue was then dissolved in methylene chloride (1 mL) and was added to a pre-cooled solution of 1-methyl-1H-pyrazol-3-ylamine (Matrix, 30 mg, 1.05 mmol) and 2,6-lutidine (0.05 mL, 0.47 mmol) in methylene chloride (3 mL) at 0° C. The reaction was allowed to gradually warm to room temperature and was stirred at room temperature overnight. After this time, the reaction was diluted with methylene chloride (50 mL) and was washed with a 1N aqueous hydrochloric acid solution (2×100 mL), a saturated aqueous sodium bicarbonate solution (2×100 mL) and water (1×100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (50-75% ethyl acetate/hexanes) afforded (S)-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)-2-(1-oxo-4-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-propionamide (94 mg, 77%) as a white solid; ES+-HRMS m/e calcd for C21H23N4O2F3 (M+H)+ 421.1846 found 421.1844. 1H-NMR (300 MHz, DMSO-d6) δ ppm 10.87 (s, 1H), 8.01 (t, J=8.6 Hz, 2H), 7.68-7.81 (m, 1H), 7.54 (d, J=1.9 Hz, 1H), 6.39 (d, J=1.9 Hz, 1H), 5.02-5.15 (m, 1H), 5.03 (d, J=18.5 Hz, 1H), 4.71 (d, J=18.5 Hz, 1H), 3.73 (s, 3H), 0.98-2.12 (m, 11H).

후처리

  1. temperatureAt this time, the solution was warmed to room temperature
  2. stirringstirred for 30 min
  3. concentrationThe reaction was then concentrated in vacuo
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue was then dissolved in methylene chloride (1 mL)
  6. temperatureto gradually warm to room temperature
  7. stirringwas stirred at room temperature overnight
  8. washwas washed with a 1N aqueous hydrochloric acid solution (2×100 mL)
  9. dry with materiala saturated aqueous sodium bicarbonate solution (2×100 mL) and water (1×100 mL), dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo

출처 및 근거

ORD 기록
ord-b254df38c6c941f3931942d158762bb5
출처 데이터셋
uspto-grants-2014_04
특허 번호
US08697705B2

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