5-(Chloromethyl)-2-methoxypyridine → 3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

HRID 1774899Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1774899
Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH3:10])=[N:7][CH:8]=1.Br[C:12]1[CH:13]=[C:14]2[C:19](=[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=13)[N:18]=[CH:17][N:16]([C@H:26]1[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]1[OH:32])[C:15]2=[O:33]>C1COCC1.ClCCl.O.[Zn].CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[OH:32][C@@H:27]1[C@@H:26]([N:16]2[C:15](=[O:33])[C:14]3[C:19](=[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]4=[C:12]([CH2:2][C:3]4[CH:8]=[N:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=4)[CH:13]=3)[N:18]=[CH:17]2)[CH2:31][CH2:30][O:29][CH2:28]1

Komponenten

8

Edukt 2

HCID 137528915-(Chloromethyl)-2-methoxypyridineHCID 699279036-bromo-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one

Produkt 1

HCID 510007023-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-methoxypyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one

Reagenzien, Katalysatoren, Lösungsmittel 5

HCID 23994ZincKatalysatorHCID 178418851HCID 178418851, VerbindungKatalysatorHCID 962WaterLösungsmittelHCID 6344DichloromethaneLösungsmittelHCID 8028TetrahydrofuranLösungsmittel2×

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

To a solution of 5-(chloromethyl)-2-methoxy pyridine (0.158 g, 0.999 mmol) in 0.5 mL of THF under an atmosphere of nitrogen was added Rieke Zn (1.3 mL, 1.0 mmol, 0.76 M in THF). The mixture was heated to reflux for 18 h, then cooled to 0° C. A solution of 6-bromo-3-[(3R,4S)-3-hydroxytetrahydro-2H-pyran-4-yl]benzo[h]quinazolin-4(3H)-one (see Example 1, 0.125 g, 0.333 mmol) in 0.5 mL of THF was added, followed by bis(tri-tert-butylphosphine)palladium(0) (5.1 mg, 0.010 mmol). The mixture was warmed to rt. After 2 h, the reaction was diluted with dichloromethane and water, and the aqueous layer was extracted with additional dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-3% methanol in dichloromethane to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 418.0 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.94-8.92 (m, 1H), 8.27 (s, 1H), 8.03 (s, 1H), 7.91-7.87 (m, 2H), 7.65-7.61 (m, 2H), 7.29 (dd, J=2.4 Hz, 8.5 Hz, 1H), 6.58 (d, J=8.5 Hz, 1H), 4.86-4.79 (m, 1H), 4.28 (s, 2H), 4.23-4.06 (m, 3H), 3.85 (s, 3H), 3.58-3.53 (m, 1H), 3.31 (t, J=10.3 Hz, 1H), 2.96 (d, J=6.7 Hz, 1H), 2.30-2.20 (m, 1H), 2.01-1.97 (m, 1H).

Aufarbeitung

  1. temperatureThe mixture was heated
  2. temperatureto reflux for 18 h
  3. temperatureThe mixture was warmed to rt
  4. extractionthe aqueous layer was extracted with additional dichloromethane
  5. dry with materialThe combined organic fractions were dried over sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified via silica gel chromatography
  9. washeluting with 0-3% methanol in dichloromethane

Quellen und Nachweise

ORD-Eintrag
ord-7c269bc20b7f4618b03aabf19a16084a
Quelldatensatz
uspto-grants-2016_02
Patentnummer
US09260418B2

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