8-Hydroxyquinoline → tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

HRID 474991노트

반응식

HRID 474991 반응식
Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][NH:36][C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[F:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][N:36]([C:2]3[CH:3]=[CH:4][C:5]4[C:9]5[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=5[N:7]([CH3:22])[C:6]=4[N:23]=3)[C:35](=[O:39])[CH:34]=2)=[N:29][CH:30]=1

참가 물질

7

반응물 4

HCID 19238-HydroxyquinolineHCID 10796Cesium carbonateHCID 579503414-((5-Fluoropyridin-2-yl)methoxy)pyridin-2(1H)-oneHCID 86649551tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate

생성물 1

HCID 66873230tert-butyl 2-(4-((5-fluoropyridin-2-yl)methoxy)-2-oxopyridin-1(2H)-yl)-10-methyl-7,8,9,10-tetrahydropyrido[3',2':4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate수율 45%

시약·촉매·용매 2

HCID 83717Copper iodide촉매HCID 679Dimethyl Sulfoxide용매

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온도
130 °C

실험 절차

tert-Butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (0.21 g, 0.56 mmol), 4-((5-fluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (0.12 g, 0.56 mmol), and Cs2CO3 (0.12 g, 0.61 mmol) were suspended in DMSO (3.2 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (24 mg, 0.17 mmol) and copper iodide (0.13 g, 0.67 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 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (40 mL) and washed with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (2×30 mL). The resulting organic solution was dried over Na2SO4 and filtered. Activated charcoal was added to the filtrate; the resulting suspension was filtered through a celite plug with 80:18:2 CH2Cl2/MeOH/NH4OH; and the filtrate was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) gave the title compound (130 mg, 45%) as an off-white foam: 1H NMR (500 MHz, DMSO-d6) δ 8.62 (d, J=3.0 Hz, 1H), 7.97 (dd, J=7.5, 7.5 Hz, 1H), 7.84-7.80 (m, 2H), 7.67-7.64 (m, 1H), 7.28 (dd, J=8.5, 8.5 Hz, 1H), 6.17 (dd, J=7.5, 2.5 Hz, 1H), 5.98 (d, J=2.5 Hz, 1H), 5.23 (s, 2H), 4.58 (s, 2H), 3.71 (s, 3H), 3.66 (t, J=5.0 Hz, 2H), 3.03 (t, J=6.0 Hz, 2H), 1.94-1.91 (m, 2H), 1.35-1.27 (m, 9H).

후처리

  1. customthe mixture was degassed 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 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL)
  6. filtrationThe resulting solids were collected by filtration
  7. dissolutiondissolved in CH2Cl2 (40 mL)
  8. washwashed with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (2×30 mL)
  9. dry with materialThe resulting organic solution was dried over Na2SO4
  10. filtrationfiltered
  11. additionActivated charcoal was added to the filtrate
  12. filtrationthe resulting suspension was filtered through a celite plug with 80:18:2 CH2Cl2/MeOH/NH4OH
  13. concentrationand the filtrate was concentrated to dryness under reduced pressure
  14. temperatureFlash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes)

출처 및 근거

ORD 기록
ord-fa8778ad32fa425890620a3bf2972b68
출처 데이터셋
uspto-grants-2014_01
특허 번호
US08637501B2

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