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

HRID 474969Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 474969
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.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2.C>CS(C)=O.C(Cl)Cl.[Cu](I)I>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:2]2[CH:3]=[CH:4][C:5]3[C:14]4[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]=4[N:7]([CH3:22])[C:6]=3[N:23]=2)[C:34](=[O:38])[CH:33]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1

Komponenten

9

Edukt 5

HCID 297MethaneHCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 36077244-Benzyloxy-2(1H)-pyridoneHCID 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 58093462tert-butyl 2-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-10-methyl-5,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylateAusbeute 33,8 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 83717Copper iodideKatalysatorHCID 679Dimethyl SulfoxideLösungsmittelHCID 6344DichloromethaneLösungsmittel

Reaktionsbedingungen

Temperatur
130 °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 (0.27 g, 0.71 mmol), 4-benzyloxy pyridinone (0.16 g, 0.78 mmol), and Cs2CO3 (0.25 g, 0.776 mmol) were suspended in DMSO (4.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (31 mg, 0.21 mmol) and copper iodide (0.17 g, 0.92 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 (30 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 (40 mL) (2×20 mL). The resulting 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 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes) gave a crude product that was dissolved in CH2Cl2 (5 mL). Activated charcoal was added to the solution, and the resulting suspension was filtered through celite. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 75:25 over 20 column volumes and held for 4 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (0.12 g, 33%) as a clear film: 1H NMR (500 MHz, DMSO-d6) δ 7.94 (d, J=8.0 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.48-7.41 (m, 4H), 7.38-7.37 (m, 1H), 7.25 (d, J=8.0 Hz, 1H), 6.15 (dd, J=7.5, 2.5 Hz, 1H), 5.97 (d, J=2.5 Hz, 1H), 5.16 (s, 2H), 3.69-3.67 (m, 5H), 3.59-3.58 (m, 2H), 3.06-3.05 (m, 2H), 2.96-2.95 (m, 2H), 1.43-1.42 (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 (30 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 (40 mL) (2×20 mL)
  9. dry with materialThe resulting organic solution was dried over Na2SO4
  10. filtrationfiltered
  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)
  13. customgave a crude product that
  14. filtrationthe resulting suspension was filtered through celite
  15. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 75:25 over 20 column volumes and held for 4 column volumes)

Quellen und Nachweise

ORD-Eintrag
ord-e220ff6b18004c16ae831a8719cd4a83
Quelldatensatz
uspto-grants-2014_01
Patentnummer
US08637501B2

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