1-[2-Chloro-1-hydroxy-3-(6-quinolinyl)propyl]-2,5-pyrrolidinedione → 6-((2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline

HRID 1396522Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 1396522
Cl[CH:2]([CH2:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][CH:17]=[CH:16]2)[CH:3]([N:5]1[C:9](=O)CCC1=O)O.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[N:34]C(N)=[N:32][CH:31]=2)=[CH:26][C:25]=1[F:37]>C(O)CCC>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[N:32][C:9]3[N:34]([C:2]([CH2:12][C:13]4[CH:14]=[C:15]5[C:20](=[CH:21][CH:22]=4)[N:19]=[CH:18][CH:17]=[CH:16]5)=[CH:3][N:5]=3)[N:35]=2)=[CH:26][C:25]=1[F:37]

Komponenten

4

Edukt 2

HCID 445128971-[2-Chloro-1-hydroxy-3-(6-quinolinyl)propyl]-2,5-pyrrolidinedioneHCID 575165236-(4-Bromo-3-fluorophenyl)-1,2,4-triazin-3-amine

Produkt 1

HCID 579711886-((2-(4-Bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinolineAusbeute 6,7 %

Reagenzien, Katalysatoren, Lösungsmittel 1

HCID 2631-ButanolLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

1-(2-Chloro-1-hydroxy-3-(quinolin-6-yl)propyl)pyrrolidine-2,5-dione (11, 228 g, 0.74 mol, 1.1 equiv) and 6-(4-bromo-3-fluorophenyl)-1,2,4-triazin-3-amine (7, 181 g, 0.673 mol) were suspended in 1-butanol (1800 mL) and the resulting suspension was heated to 110° C. and stirred at 110° C. for 18 h (the reaction mixture becomes homogeneous at this point). The reaction mixture was then gradually cooled down to room temperature before being further cooled down to 10° C. in an ice bath. The resulting yellow solid was collected by filtration (save the 1-butanol filtrates), washed with cold 1-butanol (3×100 mL) and dried by suction. This solid was then suspended in the saturated aqueous sodium bicarbonate solution (NaHCO3, 500 mL) and the resulting suspension was stirred at room temperature for 1 h to neutralize the corresponding hydrochloride salt. The free base was then filtered, washed with water (500 mL) and dried in a vacuum oven at 45° C. for 18 h to afford the first crop of the crude 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (12, 125.1 g, 292.3 g theoretical, 42.8% yield). The 1-butanol filtrates were then concentrated under the reduced pressure and the resulting solids were dissolved in dichloromethane (CH2Cl2, 2 L). The solution was wash with the saturated aqueous sodium bicarbonate solution (NaHCO3, 1 L), dried over sodium sulfates (Na2SO4), and concentrated under the reduced pressure. The residue was then purified by flash column chromatography (SiO2, 0-10% MeOH—CH2Cl2 gradient elution) to afford the second crop of 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)-quinoline (12, 19.7 g, 292.3 g theoretical, 6.7% yield; total 144.8 g, 292.3 g theoretical, 49.5% yield) as yellow solids. For 12: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 9.11 (dd, 1H, J=4.98, 1.55 Hz), 8.85 (d, 1H, J=8.09 Hz), 8.25-8.18 (m, 2H), 8.12-8.00 (m, 3H), 7.93-7.86 (m, 3H), 4.70 (s, 2H); C21H13BrFN5 (MW 434.26), LCMS (EI) m/e 434.00/435.95 (M++H).

Aufarbeitung

  1. temperatureThe reaction mixture was then gradually cooled down to room temperature
  2. temperaturebefore being further cooled down to 10° C. in an ice bath
  3. filtrationThe resulting yellow solid was collected by filtration (save the 1-butanol filtrates),
  4. washwashed with cold 1-butanol (3×100 mL)
  5. customdried by suction
  6. stirringthe resulting suspension was stirred at room temperature for 1 h
  7. filtrationThe free base was then filtered
  8. washwashed with water (500 mL)
  9. customdried in a vacuum oven at 45° C. for 18 h
  10. customto afford the first crop of the crude 6-((2-(4-bromo-3-fluorophenyl)imidazo[1,2-b][1,2,4]triazin-7-yl)methyl)quinoline (12, 125.1 g, 292.3 g theoretical, 42.8% yield)
  11. concentrationThe 1-butanol filtrates were then concentrated under the reduced pressure
  12. dissolutionthe resulting solids were dissolved in dichloromethane (CH2Cl2, 2 L)
  13. washThe solution was wash with the saturated aqueous sodium bicarbonate solution (NaHCO3, 1 L)
  14. dry with materialdried over sodium sulfates (Na2SO4)
  15. concentrationconcentrated under the reduced pressure
  16. customThe residue was then purified by flash column chromatography (SiO2, 0-10% MeOH—CH2Cl2 gradient elution)

Quellen und Nachweise

ORD-Eintrag
ord-e884d8679d2d4eb6b1de79167223bde7
Quelldatensatz
uspto-grants-2014_12
Patentnummer
US08901123B2

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