8-Hydroxyquinoline → tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

HRID 474979Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 474979
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[N:37][NH:36][C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[N:37][N:36]([C:2]3[CH:3]=[CH:4][C:5]4[C:14]5[CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1

Komponenten

7

Edukt 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 580922585-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-oneHCID 58093388tert-butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

Produkt 1

HCID 58093420tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-6-oxopyridazin-1(6H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylateAusbeute 56 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 83717Copper iodideKatalysatorHCID 679Dimethyl SulfoxideLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.18 g, 0.48 mmol), 5-((5-fluoropyridin-2-yl)methoxy)pyridazin-3(2H)-one (0.11 g, 0.51 mmol), and Cs2CO3 (0.20 g, 0.63 mmol) were suspended in DMSO (2.8 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (21 mg, 0.15 mmol) and copper iodide (0.23 mg, 1.2 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 110° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (20 mL), and the resulting solution was stirred at ambient temperature for 6 h. The resulting solution was diluted with CH2Cl2, the resulting layers were separated, and the aqueous phase was extracted with CH2Cl2 (3×25 mL). Activated charcoal was added to the combined organic extracts, and the resulting suspension was filtered through a silica gel plug. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 10 column volumes and held for 4 column volumes, then increased to 0:100 over 10 column volumes and held for 4 column volumes) gave the title compound (0.12 mg, 56%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 8.63 (d, J=3.0 Hz, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.96 (d, J=3.0 Hz, 1H), 7.86-7.82 (m, 1H), 7.72-7.67 (m, 1H), 7.09 (d, J=8.5 Hz, 1H), 6.51 (d, J=3.0 Hz, 1H), 5.30 (s, 2H), 3.69-3.67 (m, 5H), 3.60-3.57 (m, 2H), 3.08-3.05 (m, 2H), 2.98-2.96 (m, 2H), 1.44-1.42 (m, 9H).

Aufarbeitung

  1. customthe mixture was degassed 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 (20 mL)
  6. additionThe resulting solution was diluted with CH2Cl2
  7. customthe resulting layers were separated
  8. extractionthe aqueous phase was extracted with CH2Cl2 (3×25 mL)
  9. additionActivated charcoal was added to the combined organic extracts
  10. filtrationthe resulting suspension was filtered through a silica gel plug
  11. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 2 column volumes, increased to 50:50 over 10 column volumes
  12. temperatureincreased to 0:100 over 10 column volumes

Quellen und Nachweise

ORD-Eintrag
ord-e543b18f1c1c4025b2ccb8ff3c925a9d
Quelldatensatz
uspto-grants-2014_01
Patentnummer
US08637501B2

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