8-Hydroxyquinoline → tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

HRID 474912ノート

反応式

HRID 474912 の反応式
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]=3[N:8]([CH3:11])[C:9]=2[CH:10]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[N:31]=[N:30][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:11][N:8]1[C:9]2[CH:10]=[C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[N:30]=[N:31][C:26]([C:25]([F:39])([F:24])[F:40])=[CH:27][CH:28]=4)=[CH:33][C:34]3=[O:38])[CH:3]=[CH:4][C:5]=2[C:6]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:13][CH2:12][C:7]1=2

参加物

7

反応物 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 579502624-(6-(Trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-oneHCID 66874851tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate

生成物 1

HCID 66873164tert-butyl 6-methyl-8-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate収率 37%

試薬・触媒・溶媒 2

HCID 83717Copper iodide触媒HCID 679Dimethyl Sulfoxide溶媒

反応条件

温度
130 °C

実験手順

tert-Butyl 8-bromo-6-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.21 g, 0.56 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (0.16 g, 0.68 mmol) and Cs2CO3 (0.20 g, 0.61 mmol) were suspended in DMSO (2.0 mL), and the air was removed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (24 mg, 0.17 mmol) and copper iodide (0.14 g, 0.72 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5:1 MeOH/NH4OH (20 mL), and the resulting solution was stirred at ambient temperature for 30 min. The reaction was further diluted with CH2Cl2 (75 mL). The resulting solution was filtered through silica gel and the filtrate was concentrated under reduced pressure. The residue was diluted with CH2Cl2 and washed with brine (3×20 mL). The organic solution was dried over Na2SO4, filtered and concentrated to dryness. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes) followed by preparative HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) gave the title compound (110 mg, 37%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 8.70 (d, J=9.0 Hz, 1H), 8.45 (d, J=9.0 Hz, 1H), 7.91 (d, J=7.0 Hz, 1H), 7.55-7.54 (m, 2H), 7.37 (d, J=1.5 Hz, 1H), 7.16 (dd, J=7.0, 1.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 1H), 4.60 (s, 2H), 3.70-3.66 (m, 5H), 3.01-3.00 (m, 2H), 1.95-1.91 (m, 2H), 1.36-1.30 (m, 9H); ESI MS m/z 540 [M+H]+.

後処理

  1. customthe air was removed under vacuum for 15 min
  2. additionwere added to the suspension
  3. customThe evacuation/Ar flushing process
  4. temperatureThe mixture was cooled
  5. additiondiluted with 5:1 MeOH/NH4OH (20 mL)
  6. additionThe reaction was further diluted with CH2Cl2 (75 mL)
  7. filtrationThe resulting solution was filtered through silica gel
  8. concentrationthe filtrate was concentrated under reduced pressure
  9. additionThe residue was diluted with CH2Cl2
  10. washwashed with brine (3×20 mL)
  11. dry with materialThe organic solution was dried over Na2SO4
  12. filtrationfiltered
  13. concentrationconcentrated to dryness
  14. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 5 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes and held for 5 column volumes)

出典と根拠

ORDレコード
ord-891d38f16d4d4cd280baa8402befc804
出典データセット
uspto-grants-2014_01
特許番号
US08637501B2

反応ノート

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