2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinolin-4-amine

HRID 1431723Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1431723
C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:42]=[C:43]([NH2:47])[CH:44]=[N:45][CH:46]=2)[CH2:37][CH2:36]1.Cl[C:49]1[C:58]2[C:53](=[CH:54][C:55]([F:60])=[CH:56][C:57]=2[F:59])[N:52]=[C:51]([C:61]2[CH:62]=[N:63][C:64]([N:67]3[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]3)=[CH:65][CH:66]=2)[C:50]=1[CH3:73].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]>[F:59][C:57]1[CH:56]=[C:55]([F:60])[CH:54]=[C:53]2[C:58]=1[C:49]([NH:47][C:43]1[CH:44]=[N:45][CH:46]=[C:41]([N:38]3[CH2:39][CH2:40][O:35][CH2:36][CH2:37]3)[CH:42]=1)=[C:50]([CH3:73])[C:51]([C:61]1[CH:62]=[N:63][C:64]([N:67]3[CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]3)=[CH:65][CH:66]=1)=[N:52]2

Komponenten

7

Edukt 4

HCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 23676156Sodium t-butoxideHCID 583477375-Morpholinopyridin-3-amineHCID 596310544-Chloro-5,7-difluoro-3-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)quinoline

Produkt 1

HCID 596312325,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinolin-4-amine

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 1140TolueneLösungsmittel

Versuchsvorschrift

The Buchwald coupled product was prepared according to Procedure S using of dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.043 mmol), 5-morpholinopyridin-3-amine (0.058 g, 0.32 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)quinoline (0.1 g, 0.27 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.064 g, 0.67 mmol) in toluene (2.7 mL) at 100° C. for 23.3 h. The crude product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were concd then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution, the solvent was removed under reduced pressure to yield the desired product 5,7-difluoro-3-methyl-N-(5-morpholinopyridin-3-yl)-2-(6-(piperidin-1-yl)pyridin-3-yl)quinolin-4-amine. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.43-8.47 (2H, m), 7.86 (1H, dd, J=8.9, 2.6 Hz), 7.79 (1H, d, J=2.4 Hz), 7.56-7.61 (2H, m), 7.37 (1H, ddd, J=12.5, 9.5, 2.7 Hz), 6.93 (1H, d, J=8.8 Hz), 6.55 (1H, t, J=2.3 Hz), 3.66-3.74 (4H, m), 3.59-3.66 (4H, m), 3.04-3.11 (4H, m), 2.19 (3H, s). Mass Spectrum (ESI) m/e=517.2 (M+1).

Aufarbeitung

  1. customwas prepared
  2. customThe crude product was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution)
  3. additionThe desired fractions were concd then diluted with EtOAc
  4. washAfter washing twice with satd aq. sodium bicarbonate solution
  5. customthe solvent was removed under reduced pressure

Quellen und Nachweise

ORD-Eintrag
ord-43c4593d22de434ebb16ae390b13719c
Quelldatensatz
uspto-grants-2015_01
Patentnummer
US08940724B2

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