8-Hydroxyquinoline → tert-Butyl 9-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-b]pyridine-6-carboxylate

HRID 882025Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 882025
Br[C:2]1[N:7]=[C:6]2[N:8]([CH3:22])[C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:5]2=[CH:4][CH:3]=1.[F:23][C:24]([F:39])([F:38])[C:25]1[N:30]=[N:29][C:28]([C:31]2[CH:36]=[CH:35][NH:34][C:33](=[O:37])[CH:32]=2)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:8]1[C:6]2=[N:7][C:2]([N:34]3[CH:35]=[CH:36][C:31]([C:28]4[N:29]=[N:30][C:25]([C:24]([F:38])([F:23])[F:39])=[CH:26][CH:27]=4)=[CH:32][C:33]3=[O:37])=[CH:3][CH:4]=[C:5]2[C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH2:14][C:9]1=2

Komponenten

7

Edukt 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 579502624-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-oneHCID 71551310tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-b]pyridine-6-carboxylate

Produkt 1

HCID 86667078tert-Butyl 9-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,7,8,9-tetrahydro-6H-pyrido[3',4':4,5]pyrrolo[2,3-b]pyridine-6-carboxylateAusbeute 44,3 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 83717Copper iodideKatalysatorHCID 679Dimethyl SulfoxideLösungsmittel

Reaktionsbedingungen

Temperatur
130 °C

Versuchsvorschrift

tert-Butyl 2-bromo-9-methyl-5,7,8,9-tetrahydro-6H-pyrido[3′,4′:4,5]pyrrolo[2,3-b]pyridine-6-carboxylate (0.11 g, 0.30 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (73 mg, 0.30 mmol), and Cs2CO3 (0.11 g, 0.33 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (13 mg, 0.091 mmol) and copper iodide (75 mg, 0.39 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 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (30 mL), and washed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (2×30 mL). Activated charcoal was added to the organic solution, and the resulting suspension was filtered through a Celite® plug 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 4 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 4 column volumes) gave the title compound (70 mg, 43%) as a yellow powder: 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=9.0 Hz, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.13 (d, J=7.5 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 7.22 (dd, J=7.5, 1.5 Hz, 1H), 4.60 (s, 2H), 3.77 (t, J=5.5 Hz, 2H), 3.71 (s, 3H), 2.90 (t, J=5.5 Hz, 2H), 1.45 (s, 9H); ESI MS m/z 527 [M+H]+.

Aufarbeitung

  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 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (70 mL)
  6. filtrationThe resulting solids were collected by filtration
  7. dissolutiondissolved in CH2Cl2 (30 mL)
  8. washwashed with 5.0:3.5:1.5 NH4Cl(aq.)/NH4OH/H2O (2×30 mL)
  9. additionActivated charcoal was added to the organic solution
  10. filtrationthe resulting suspension was filtered through a Celite® plug
  11. concentrationconcentrated to dryness under reduced pressure
  12. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 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 4 column volumes)

Quellen und Nachweise

ORD-Eintrag
ord-f6d4c99e426d400fab668042bac1695d
Quelldatensatz
uspto-grants-2015_03
Patentnummer
US08993765B2

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