8-Hydroxyquinoline → tert-butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

HRID 474928노트

반응식

HRID 474928 반응식
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21][C:7]=3[N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:9]=2[CH:10]=1.[F:33][C:34]([F:49])([F:48])[C:35]1[N:40]=[N:39][C:38]([C:41]2[CH:46]=[CH:45][NH:44][C:43](=[O:47])[CH:42]=2)=[CH:37][CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[O:47]=[C:43]1[CH:42]=[C:41]([C:38]2[N:39]=[N:40][C:35]([C:34]([F:49])([F:48])[F:33])=[CH:36][CH:37]=2)[CH:46]=[CH:45][N:44]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21][C:7]=3[NH:8][C:9]=2[CH:10]=1

참가 물질

7

반응물 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 579502624-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-oneHCID 86649548tert-Butyl 8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

생성물 1

HCID 66874312tert-butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate수율 19.5%

시약·촉매·용매 2

HCID 83717Copper iodide촉매HCID 679Dimethyl Sulfoxide용매

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온도
130 °C

실험 절차

tert-Butyl 8-bromo-6-tosyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.20 g, 0.39 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (0.10 g, 0.43 mmol), and Cs2CO3 (0.14 g, 0.43 mmol) were suspended in DMSO (2.3 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (95 mg, 0.50 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (15 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL), the resulting solution was filtered through silica gel, and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×25 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 12 column volumes) gave tert-butyl 8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (40 mg, 19%) and the title compound (59 mg, 22%) as a yellow film.

후처리

  1. customthe air was removed under vacuum for 15 min
  2. additionwere added to the suspension
  3. customThe evacuation/Ar flushing process
  4. temperatureThe mixture was cooled
  5. additiondiluted with 5:1 MeOH/NH4OH (15 mL)
  6. additionThe reaction was further diluted with CH2Cl2 (75 mL)
  7. filtrationthe resulting solution was filtered through silica gel
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. additionThe residue was diluted with CH2Cl2
  10. washwashed with brine (3×25 mL)
  11. dry with materialThe organic solution was dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated to dryness under reduced pressure
  14. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 12 column volumes)

출처 및 근거

ORD 기록
ord-3cc3c05a9a0541b0bf30e32e0d0dcc61
출처 데이터셋
uspto-grants-2014_01
특허 번호
US08637501B2

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