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 1431723노트

반응식

HRID 1431723 반응식
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

참가 물질

7

반응물 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

생성물 1

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

시약·촉매·용매 2

HCID 9811564Bis(dibenzylideneacetone)palladium촉매HCID 1140Toluene용매

실험 절차

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).

후처리

  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

출처 및 근거

ORD 기록
ord-43c4593d22de434ebb16ae390b13719c
출처 데이터셋
uspto-grants-2015_01
특허 번호
US08940724B2

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