2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → HCID 86709780, Verbindung

HRID 1529393Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1529393
Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:27][CH2:26]3)[CH:20]=[N:19][CH:18]=1.[C:39]([Zn]C#N)#[N:40].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CN(C=O)C.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:39]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[C:5]2[C:17]1[N:22]=[C:21]([O:23][C@H:24]2[CH2:31][N:30]([C:32]([O:34][C:35]([CH3:38])([CH3:36])[CH3:37])=[O:33])[CH2:29][CH2:28][C:25]32[CH2:26][CH2:27]3)[CH:20]=[N:19][CH:18]=1)#[N:40]

Komponenten

7

Edukt 3

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 67959732HCID 67959732, VerbindungHCID 178514179HCID 178514179, Verbindung

Produkt 1

HCID 86709780HCID 86709780, VerbindungAusbeute 91,5 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittelHCID 6228DimethylformamideLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

(4R)-tert-Butyl 4-(6-(5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (124 mg, 0.212 mmol), dicyanozinc (Aldrich, St. Louis, Mo.; 32.4 mg, 0.276 mmol), Pd2(dba)3 (Aldrich, St. Louis, Mo.; 9.71 mg, 10.61 μmol), and XPhos (Strem, Newburyport, Mass.; 10.11 mg, 0.021 mmol) in a mixture of DMF (2.0 mL) and water (0.020 mL) was heated at 100° C. for 19 h. The mixture was concentrated onto silica gel and chromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm) to provide (4R)-tert-butyl 4-(6-(5-cyano-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yloxy)-6-azaspiro[2.5]octane-6-carboxylate (102.8 mg, 0.194 mmol, 91% yield) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ ppm 9.04 (1 H, s), 8.74 (1 H, br. s.), 8.25 (1 H, br. s.), 8.02 (1 H, s), 7.78 (1 H, s), 7.64 (1 H, s), 5.84 (1 H, d, J=6.8 Hz), 4.63 (1 H, br. s.), 4.35-4.44 (1 H, m), 4.21-4.33 (1 H, m), 3.90-4.10 (2 H, m), 3.73-3.85 (2 H, m), 3.34 (2 H, d, J=14.1 Hz), 2.53-2.70 (2 H, m), 2.45 (1 H, m), 2.09-2.30 (2 H, m), 1.68-1.90 (4 H, m), 1.14 (9 H, br. s.). MS (ESI, pos. ion) m/z: 531.3 (M+1).

Aufarbeitung

  1. concentrationThe mixture was concentrated onto silica gel
  2. customchromatographically purified (ISCO, 12 g silica gel column, 0-60% EtOAc/hexanes, 15 min, 254 nm)

Quellen und Nachweise

ORD-Eintrag
ord-d75372780e764bd29a27a4b86787ce1e
Quelldatensatz
uspto-grants-2015_07
Patentnummer
US09090593B2

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