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Triethylamine → 6-fluoro-2-[(1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]non-3-yl]quinazoline

HRID 1916160
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 1916160
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:15][C@@H:14]3[CH2:16][CH2:17][C@H:10]2[CH2:11][NH:12][C:13]3=O)=[CH:5][CH:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(N(CC)CC)C.Cl[C:33]1[N:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([F:43])[CH:39]=2)[N:34]=1>C1COCC1.CC(N(C)C)=O>[F:43][C:38]1[CH:39]=[C:40]2[C:35](=[CH:36][CH:37]=1)[N:34]=[C:33]([N:12]1[CH2:11][C@@H:10]3[CH2:17][CH2:16][C@@H:14]([CH2:15][N:9]3[C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:13]1)[N:42]=[CH:41]2
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

7

Edukt 4

HCID 8471TriethylamineHCID 179135522-Chloro-6-fluoroquinazolineHCID 21226445Aluminium lithium hydrideHCID 68558737(1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]-nonan-2-one

Produkt 1

HCID 689989426-fluoro-2-[(1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]non-3-yl]quinazoline

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 8028TetrahydrofuranLösungsmittel2×HCID 31374DimethylacetamideLösungsmittel

Reaktionsbedingungen

Temperatur
65 °C

Versuchsvorschrift

To a solution of (1S,5S)-6-(4-methoxyphenyl)-3,6-diazabicyclo[3.2.2]-nonan-2-one (E-4, 0.108 g, 0.438 mmol, 1.0 equiv) in THF (3.0 mL) at ambient temperature was added a solution of lithium aluminum hydride in THF (1.31 mL, 1.31 mmol, 1.0M, 3.0 equiv) and the reaction mixture was heated to 65° C. for 2 h. The reaction was cooled to 0° C. and quenched with water (0.1 mL), 1M NaOH (0.2 mL), and water (0.3 mL). The reaction mixture was stirred a further 0.5 h, diluted with ethyl acetate (50 mL), dried over MgSO4, and concentrated to an oil. To a solution of the residual oil in dimethylacetamide (2.1 mL) was added triethylamine (0.24 mL, 1.72 mmol, ca. 4 equiv), and 2-chloro-6-fluoroquinazoline (0.094 g, 0.52 mmol, ca. 1.2 equiv) and the reaction was heated to 175° C. for 15 minutes in the microwave. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was dried over MgSO4 and concentrated. The residue was purified by column chromatography (0 to 60% ethyl acetate in hexanes) to afford E-5 as a yellow solid. ESI MS [M+H] for C22H23FN4O=379.2.

Aufarbeitung

  1. temperatureThe reaction was cooled to 0° C.
  2. customquenched with water (0.1 mL), 1M NaOH (0.2 mL), and water (0.3 mL)
  3. additiondiluted with ethyl acetate (50 mL)
  4. dry with materialdried over MgSO4
  5. concentrationconcentrated to an oil
  6. temperaturethe reaction was heated to 175° C. for 15 minutes in the microwave
  7. temperatureThe reaction was cooled
  8. custompartitioned between ethyl acetate and water
  9. dry with materialThe organic phase was dried over MgSO4
  10. concentrationconcentrated
  11. customThe residue was purified by column chromatography (0 to 60% ethyl acetate in hexanes)
  12. customto afford E-5 as a yellow solid

Quellen und Nachweise

ORD-Eintrag
ord-6975e32572fa4b8798d03cc994a8776d
Quelldatensatz
uspto-grants-2013_12
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US08618102B2

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