Water → 6-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-5H-pyrrolo[2,3-b]pyrazine

HRID 273056

Reaktionsgleichung

Reaktionsgleichung von HRID 273056
[CH3:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C([N-]C(C)C)(C)C.[Li+].[N:16]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3([C:37]#[N:38])[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1.O>C1COCC1>[N:16]1([CH2:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3([C:37]4[NH:38][C:7]5=[N:6][CH:5]=[CH:4][N:3]=[C:2]5[CH:1]=4)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][CH:26]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1

Komponenten

6

Edukt 4

HCID 962WaterHCID 79762-MethylpyrazineHCID 2724682Lithium diisopropylamideHCID 598373944-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile

Produkt 1

HCID 598374606-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-yl}-5H-pyrrolo[2,3-b]pyrazineAusbeute 6 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 8028TetrahydrofuranLösungsmittel2×

Versuchsvorschrift

A solution of 2-methyl-pyrazine (580 μL, 6.4 mmol) in THF (4 mL) was added to 4.7 mL of 1.5M lithium diisopropylamide:THF complex in hexanes at −40° C. and the resulting deep red solution stirred at −40° C. for 0.5 hours. A solution of 4-[4-(3-Pyrrolidin-1-yl-propoxy)-phenyl]-tetrahydro-pyran-4-carbonitrile (1.00 g, 3.2 mmol) in THF (5 mL) was added at −40° C. and the reaction mixture stirred at this temperature for 0.5 hours, then at room temperature for 18 hours. A further 1 equivalent of lithium diisopropylamide complex was then added and the reaction mixture stirred at reflux for 24 hours. The mixture was cooled to room temperature, water (10 mL) added and the mixture concentrated in vacuo. The residue was partitioned between water (60 mL) and DCM (2×60 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1, by volume) to provide the title compound (65 mg, 6%) as a brown oil. 1H NMR (400 MHz, CDCl3) δ 1.74-1.80 (m, 6H), 2.00 (m, 2H), 2.42-2.55 (m, 6H), 2.60 (t, 2H), 3.80 (m, 4H), 4.00 (t, 2H), 6.60 (s, 1H), 6.86 (d, 2H), 7.21 (d, 2H), 8.05 (d, 1H), 8.39 (d, 1H). HRMS ESI+ m/z 407.2437 [MH]+.

Aufarbeitung

  1. waitat room temperature for 18 hours
  2. additionA further 1 equivalent of lithium diisopropylamide complex was then added
  3. stirringthe reaction mixture stirred
  4. temperatureat reflux for 24 hours
  5. concentrationthe mixture concentrated in vacuo
  6. customThe residue was partitioned between water (60 mL) and DCM (2×60 mL)
  7. dry with materialdried over sodium sulphate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1, by volume)

Quellen und Nachweise

ORD-Eintrag
ord-b984cd5339b844d0860728ac333cb6da
Quelldatensatz
uspto-grants-2008_11
Patentnummer
US07456164B2

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