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 1618665ノート

反応式

HRID 1618665 の反応式
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

参加物

7

反応物 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

生成物 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

試薬・触媒・溶媒 2

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 1140Toluene溶媒

実験手順

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).

後処理

  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)

出典と根拠

ORDレコード
ord-6083a6ef45ab48769e427c0b6a3c3ce9
出典データセット
uspto-grants-2014_07
特許番号
US08765940B2

反応ノート

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