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Potassium Carbonate → (1R,5S)-3-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)-3-azabicyclo[3.1.0]hexan-1-ol

HRID 712390
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Druckvorschau

Reaktionsgleichung

Reaktionsgleichung von HRID 712390
[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][C@H:37]2[C@:35]([OH:39])([CH2:36]2)[CH2:34]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:30][CH2:31][CH2:32][N:33]4[CH2:38][C@H:37]5[C@:35]([OH:39])([CH2:36]5)[CH2:34]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
KomponentenReaktionsbedingungenVersuchsvorschriftAufarbeitungQuellen und NachweiseNotizen zur Reaktion

Komponenten

5

Edukt 3

HCID 11430Potassium CarbonateHCID 104712174-[(3-Chloro-4-fluorophenyl)amino]-7-methoxyquinazolin-6-olHCID 86729461(1R,5S)-3-(3-chloropropyl)-3-azabicyclo[3.1.0]hexan-1-ol

Produkt 1

HCID 71525472(1R,5S)-3-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)propyl)-3-azabicyclo[3.1.0]hexan-1-olAusbeute 46,7 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 6228
Dimethylformamide
Lösungsmittel
2×

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

To a mixture of 4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-ol (136 mg, 0.42 mmol, 1.0 eq) and anhydrous K2CO3 (290 mg, 2.10 mmol, 5.0 eq) in DMF (3 mL) was added a solution of (1R,5S)-3-(3-chloropropyl)-3-azabicyclo[3.1.0]hexan-1-ol (92 mg, 0.52 mmol, 1.2 eq) in DMF (2 mL) at rt. The mixture was heated at 80° C. for 7 h, then cooled to room temperature and quenched with H2O (10 mL). The mixture was diluted with EtOAc (20 mL). The water layer was then extracted with EtOAc (5 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (10:1 (v/v) CH2Cl2/CH3OH) to give the crude product, which was recrystallized from CH2Cl2/PE to afford the title compound as a pale yellow solid (90 mg, 46.70%), HPLC:91.67%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 459.2 (M+1); 1H NMR (400 MHz, CDCl3) δ: 0.83 (2H, m), 1.09 (1H, t, J=4.8 Hz), 1.36 (1H, m), 2.57 (2H, m), 2.72 (1H, d, J=8.8 Hz), 3.05 (1H, d, J=8.4 Hz), 3.56 (2H, m), 3.80 (2H, m), 3.99 (3H, s), 4.12 (2H, t, J=6.8 Hz), 7.14 (1H, t, J=8.8 Hz), 7.23 (1H, s), 7.29 (1H, d, J=15.8 Hz), 7.60 (1H, m), 7.89 (1H, dd, J=2.5, 6.5 Hz), 8.63 (1H, s) ppm.

Aufarbeitung

  1. temperaturecooled to room temperature
  2. customquenched with H2O (10 mL)
  3. additionThe mixture was diluted with EtOAc (20 mL)
  4. extractionThe water layer was then extracted with EtOAc (5 mL×3)
  5. dry with materialThe combined organic phases were dried over anhydrous Na2SO4
  6. concentrationconcentrated in vacuo
  7. customThe residue was chromatographed with a silica gel column (10:1 (v/v) CH2Cl2/CH3OH)
  8. customto give the crude product, which
  9. customwas recrystallized from CH2Cl2/PE

Quellen und Nachweise

ORD-Eintrag
ord-a0e0f24d58bb454daabd77c18a1afa58
Quelldatensatz
uspto-grants-2015_11
DOI
10.6084/m9.figshare.5104873.v1
Patentnummer
US09181277B2

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