2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 1-(7-Fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran]

HRID 1618526Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1618526
[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[C:11]3[NH:13][CH2:14][C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[C:10]3=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([F:32])=[CH:29][CH:30]=2)[N:25]=[C:24]([C:33]2[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=2)[C:23]=1[CH3:40].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[F:32][C:28]1[CH:27]=[C:26]2[C:31]([C:22]([N:13]3[C:11]4[C:10](=[CH:9][CH:8]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[CH:12]=4)[C:15]4([CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)[CH2:14]3)=[C:23]([CH3:40])[C:24]([C:33]3[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=3)=[N:25]2)=[CH:30][CH:29]=1

Komponenten

9

Edukt 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 672846616-Morpholino-2',3',5',6'-tetrahydrospiro[indoline-3,4'-pyran]HCID 672852274-Chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline

Produkt 1

HCID 509390771-(7-Fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2',3',5',6'-hexahydrospiro[indole-3,4'-pyran]

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 962WaterLösungsmittelHCID 1140TolueneLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

To a stirred solution of 6-morpholino-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran] (86 mg, 0.31 mmol), 4-chloro-7-fluoro-3-methyl-2-(2-methylpyridin-3-yl)quinoline (90 mg, 0.31 mmol) in toluene (1.7 mL) was added Pd2dba3 (43 mg, 0.047 mmol), XPhos (45 mg, 0.09 mmol) and sodium tert-butoxide (90 mg, 0.94 mmol) and the reaction was heated in the microwave for 1 h at 100° C. After this time the reaction was cooled to rt and treated with EtOAc (100 mL) and water (40 mL). The separated organic layer was washed with NaCl (saturated aqueous solution, 40 mL), dried over MgSO4, filtered and evaporated in vacuo. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 1-(7-fluoro-3-methyl-2-(2-methyl-3-pyridinyl)-4-quinolinyl)-6-(4-morpholinyl)-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]. 1H NMR (400 MHz, chloroform-d) δ ppm 8.59-8.67 (1H, m), 7.84-7.94 (1H, m), 7.76-7.83 (1H, m), 7.59-7.69 (1H, m), 7.27-7.34 (2H, m), 7.11-7.18 (1H, m), 6.28-6.47 (1H, m), 5.48-5.70 (1H, m), 3.97-4.09 (2H, m), 3.85-3.94 (1H, m), 3.68-3.80 (4H, m), 3.48-3.63 (2H, m), 2.89-3.05 (4H, m), 2.36-2.44 (3H, m), 2.09-2.25 (2H, m), 2.05 (4H, dd, J=4.5, 2.3 Hz), 1.90 (1H, dt, J=13.7, 1.2 Hz), 1.72-1.81 (1H, m). Mass Spectrum (ESI) m/e=525 (M+1).

Aufarbeitung

  1. temperatureAfter this time the reaction was cooled to rt
  2. washThe separated organic layer was washed with NaCl (saturated aqueous solution, 40 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. customevaporated in vacuo
  6. customPurification by reverse phase HPLC (10 to 60% acetonitrile in water)

Quellen und Nachweise

ORD-Eintrag
ord-fd0b43b6c0854ecd9f89fbb2a3702c9e
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08765940B2

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