Ethyl Acetate → 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine

HRID 1621961Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1621961
[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH3:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.Cl[C:26]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1.C([O-])(=O)C.[K+].CCOC(C)=O>O1CCOCC1.O.CC(O)C.C(Cl)(Cl)Cl>[F:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]([N:10]2[CH2:11][CH2:12][O:13][CH2:14][CH2:15]2)[CH3:9])=[CH:4][C:3]=1[C:26]1[N:34]=[C:33]([CH3:35])[N:32]=[C:31]2[C:27]=1[N:28]=[CH:29][N:30]2[CH:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1

Komponenten

8

Edukt 4

HCID 8857Ethyl AcetateHCID 517044Potassium AcetateHCID 595482686-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purineHCID 666111244-(1-(6-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ethyl)morpholine

Produkt 1

HCID 665998534-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholineAusbeute 55 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 962WaterLösungsmittelHCID 312751,4-DioxaneLösungsmittelHCID 21906603Chloroform isopropyl alcoholLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a 5 mL microwave reaction tube was added 4-(1-(6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)ethyl)morpholine (0.523 g, 1.55 mmol), 6-chloro-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Example 3, 0.322 g, 1.28 mmol), Am-Phos (Aldrich, 0.0531 g, 0.075 mmol) and potassium acetate (Aldrich, 0.379 g, 3.87 mmol) in 1,4-dioxane (4 mL) and water (0.4 mL). The mixture was degassed by bubbling argon through for 5 min. The tube was heated in a microwave reactor (Biotage) at 100° C. for 15 min. The reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The layers were separated and saturated NH4Cl (30 mL) was added to the aqueous phase. The aqueous phase was extracted with EtOAc (2×40 mL). The combined organic phases were washed with saturated aqueous sodium chloride (100 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography (50 g, eluent: EtOAc in hexanes 20% to 70% then IPA/CHCl3 0% to 12.5%) to afford 4-(1-(6-fluoro-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)ethyl)morpholine (0.30 g, 55% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.27-8.37 (m, 3H) 5.86 (d, J=10.37 Hz, 1H) 4.15-4.24 (m, 1H) 3.78-3.88 (m, 1H) 3.64-3.75 (m, 4H) 3.53 (q, J=6.72 Hz, 1H) 2.89 (s, 3H) 2.50-2.60 (m, 2H) 2.38-2.48 (m, 2H) 2.01-2.22 (m, 3H) 1.69-1.91 (m, 3H) 1.43 (d, J=6.65 Hz, 3H). m/z (ESI, positive ion) δ 427.1 (M+H)+.

Aufarbeitung

  1. customThe mixture was degassed
  2. customby bubbling argon through for 5 min
  3. customThe reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL)
  4. customThe layers were separated
  5. additionsaturated NH4Cl (30 mL) was added to the aqueous phase
  6. extractionThe aqueous phase was extracted with EtOAc (2×40 mL)
  7. washThe combined organic phases were washed with saturated aqueous sodium chloride (100 mL)
  8. dry with materialThe organic phase was dried over sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customThe crude product was purified by silica gel column chromatography (50 g, eluent

Quellen und Nachweise

ORD-Eintrag
ord-323c505162c84d7caee726c8a280d87e
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08772480B2

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