2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 3-((4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-quinolinyl)-methyl)benzonitrile

HRID 1618665Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1618665
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH2:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[C:3]=1[CH3:23].[CH3:24][C:25]1([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=[C:28]2[NH:27][CH2:26]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH3:24][C:25]1([CH3:40])[C:29]2=[N:30][CH:31]=[C:32]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[CH:33]=[C:28]2[N:27]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([CH2:14][C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[C:3]=2[CH3:23])[CH2:26]1

Komponenten

7

Edukt 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 672844994-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-morpholineHCID 672854223-((4-Chloro-5,7-difluoro-3-methylquinolin-2-yl)methyl)benzonitrile

Produkt 1

HCID 672846823-((4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-quinolinyl)-methyl)benzonitrile

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 1140TolueneLösungsmittel

Versuchsvorschrift

3-((4-Chloro-5,7-difluoro-3-methylquinolin-2-yl)methyl)benzonitrile (42.3 mg, 0.129 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-morpholine (30 mg, 0.129 mmol), Pd2dba3 (11.8 mg, 0.013 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (12.3 mg, 0.026 mmol), sodium tert-butoxide (37.1 mg, 0.386 mmol), and toluene (1.29 mL) were stirred at 105° C. for 2 h. The reaction mixture was then concentrated and the resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine and water, then dried (MgSO4) and concentrated. Purification of the crude product by reverse-phase HPLC (0-70% acetonitrile in water) gave 3-((4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-quinolinyl)-methyl)benzonitrile. 1H NMR (400 MHz, chloroform-d) δ ppm 7.55-7.63 (2H, m), 7.47-7.53 (2H, m), 7.38-7.46 (1H, m), 7.24 (1H, br. s.), 6.91-7.03 (1H, m), 5.53-5.59 (1H, m), 4.39-4.47 (2H, m), 3.77-3.82 (1H, m), 3.68-3.77 (4H, m), 3.58 (1H, d, J=9.0 Hz), 2.89-3.02 (4H, m), 2.19-2.26 (3H, m), 1.39-1.58 (6H, m). Mass Spectrum (ESI) m/e=526.0 (M+1).

Aufarbeitung

  1. concentrationThe reaction mixture was then concentrated
  2. customthe resulting residue partitioned between EtOAc and saturated aqueous sodium bicarbonate solution
  3. washThe organic layer was washed with brine and water
  4. dry with materialdried (MgSO4)
  5. concentrationconcentrated
  6. customPurification of the crude product by reverse-phase HPLC (0-70% acetonitrile in water)

Quellen und Nachweise

ORD-Eintrag
ord-6083a6ef45ab48769e427c0b6a3c3ce9
Quelldatensatz
uspto-grants-2014_07
Patentnummer
US08765940B2

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