Reaktion #562155

Reaktionsgleichung

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one

8-hydroxyquinoline

Cs2CO3

→

title compound

Ausbeute 24.8%

tert-Butyl 10-methyl-2-(2-oxo-4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-1(2H)-yl)-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate

Ausbeute 24.8%

Lösungsmittel

DMSO

Reaktionsbedingungen

Aufarbeitung

1. 1
   Sonstigethe mixture was degassed under vacuum for 15 min
2. 2
   workup.ADDITIONwere added to the suspension
3. 3
   SonstigeThe evacuation/Ar flushing process
4. 4
   TemperaturThe mixture was cooled
5. 5
   workup.ADDITIONdiluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL)
6. 6
   FiltrationThe resulting solids were collected by filtration
7. 7
   workup.DISSOLUTIONdissolved in CH2Cl2(30 mL)
8. 8
   Waschenwashed with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (40 mL) (2×20 mL)
9. 9
   TrocknenThe resulting organic solution was dried over Na2SO4
10. 10
    Filtrationfiltered
11. 11
    Einengenconcentrated to dryness under reduced pressure
12. 12
    TemperaturFlash 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
13. 13
    Temperaturincreased to 0:100 over 20 column volumes

Vorschrift

tert-Butyl 2-bromo-10-methyl-5,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[2,3-d]azepine-7(6H)-carboxylate (0.13 g, 0.35 mmol), 4-(6-(trifluoromethyl)pyridazin-3-yl)pyridin-2(1H)-one (85 mg, 0.35 mmol), and Cs2CO3 (0.13 g, 0.39 mmol) were suspended in DMSO (2.0 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (15 mg, 0.11 mmol) and copper iodide (86 mg, 0.45 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(30 mL) and washed with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (40 mL) (2×20 mL). The resulting organic solution was dried over Na2SO4, filtered and 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, then increased to 0:100 over 20 column volumes and held for 4 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 (47 mg, 24%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 8.71 (d, J=9.0 Hz, 1H), 8.47 (d, J=8.5 Hz, 1H), 8.12 (d, J=7.5 Hz, 1H), 8.05 (d, J=8.0 Hz, 1H), 7.40-7.39 (m, 2H), 7.22 (dd, J=7.0, 2.0 Hz, 1H), 3.73 (s, 3H), 3.71-3.69 (m, 2H), 3.61-3.60 (m, 2H), 3.09-3.08 (m, 2H), 2.99-2.89 (m, 2H), 1.44 (s, 9H).

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