Pyrazole → 3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one

HRID 1774898Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1774898
Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.[NH:31]1[CH:35]=[CH:34][CH:33]=[N:32]1.C(=O)([O-])[O-].[K+].[K+].CN(C)[C@@H]1CCCC[C@H]1N.CN[C@@H]1CCCC[C@H]1NC>CS(C)=O.C(OCC)(=O)C.O.[Cu]I>[OH:29][C@@H:24]1[C@@H:23]([N:13]2[C:12](=[O:30])[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]4=[C:9]([CH2:8][C:5]4[CH:6]=[N:7][C:2]([N:31]5[CH:35]=[CH:34][CH:33]=[N:32]5)=[CH:3][CH:4]=4)[CH:10]=3)[N:15]=[CH:14]2)[CH2:28][CH2:27][O:26][CH2:25]1

Komponenten

10

Edukt 5

HCID 1048PyrazoleHCID 11430Potassium CarbonateHCID 2733821trans-N,N'-dimethyl-1,2-cyclohexanediamineHCID 11275066(1R,2R)-N1,N1-Dimethylcyclohexane-1,2-diamineHCID 510006176-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one

Produkt 1

HCID 510016033-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-{[6-(1H-pyrazol-1-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 24350Copper(1+) iodide; Copper(I) iodide; Cuprous iodide; Cuprous iodide (CuI)Katalysator2×HCID 679Dimethyl SulfoxideLösungsmittelHCID 962WaterLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
120 °C

Versuchsvorschrift

To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (Example 1, 0.080 g, 0.19 mmol) and pyrazole (0.052 g, 0.15 mmol) in 2 mL of DMSO under an atmosphere of nitrogen was added potassium carbonate (0.57 mL, 1 N aqueous, 0.57 mmol), trans-N,N-dimethylcyclohexane-1,2-diamine (21.6 mg, 0.152 mmol), and copper(I) iodide (0.014 g, 0.076 mmol). The mixture was heated at 120° C. for 20 h, cooled to rt, and additional trans-N,N′-dimethylcyclohexane-1,2-diamine (21.6 mg, 0.152 mmol) and copper(I) iodide (0.014 g, 0.076 mmol) were added. The reaction was heated at 150° C. for 24 h, cooled to rt, and diluted with ethyl acetate and water. The aqueous layer was extracted 3× with ethyl acetate, and the combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-5% methanol in dichloromethane, to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 453.51 for [M+H]+: 1H NMR (400 MHz, CD3OD) δ 8.93 (d, J=7.3 Hz, 1H), 8.46 (s, 1H), 8.30 (s, 1H), 8.26 (s, 1H), 7.90 (s, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.66-7.57 (m, 2H), 7.50 (d, J=8.5 Hz, 1H), 6.39 (s, 1H), 6.30 (s, 1H), 4.86-4.84 (m, 1H), 4.36 (s, 2H), 4.23-4.13 (m, 2H), 4.12-4.04 (m, 1H), 3.56-3.50 (m, 1H), 3.34-3.32 (m, 1H), 2.24-2.19 (m, 1H), 2.00-1.97 (m, 1H).

Aufarbeitung

  1. temperaturecooled to rt
  2. temperatureThe reaction was heated at 150° C. for 24 h
  3. temperaturecooled to rt
  4. extractionThe aqueous layer was extracted 3× with ethyl acetate
  5. washthe combined organic fractions were washed with brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe residue was purified via silica gel chromatography
  10. washeluting with 0-5% methanol in dichloromethane

Quellen und Nachweise

ORD-Eintrag
ord-824f2ce7f8244a6cb2262a7019f3d84e
Quelldatensatz
uspto-grants-2016_02
Patentnummer
US09260418B2

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