Potassium Carbonate → HCID 86698498, Verbindung

HRID 75354

Reaktionsgleichung

Reaktionsgleichung von HRID 75354
Cl[C:2]1[C:11]([C@@H:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[CH3:13])=[CH:10][C:9]2[C:4](=[C:5]([F:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][S:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[F:25][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[S:27][CH3:26])[C:11]([C@@H:12]([N:14]1[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]1=[O:24])[CH3:13])=[CH:10]2

Komponenten

6

Edukt 3

HCID 11430Potassium CarbonateHCID 27735432-(Methylthio)benzeneboronic acidHCID 86681380HCID 86681380, Verbindung

Produkt 1

HCID 86698498HCID 86698498, VerbindungAusbeute 84 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 6228DimethylformamideLösungsmittelHCID 8857Ethyl AcetateLösungsmittel

Reaktionsbedingungen

Temperatur
100 °C

Versuchsvorschrift

(S)-2-(1-(2-Chloro-8-fluoroquinolin-3-yl)ethyl)isoindoline-1,3-dione (14.0 g, 39.5 mmol), 2-(methylthio)phenylboronic acid (9.95 g, 59.2 mmol), and potassium carbonate (16.4 g, 118 mmol) were combined in 300 mL of anhydrous DMF under an atmosphere of N2. The solution was sparged with N2 for ˜5 min before adding PdCl2(dppf)CH2Cl2 (3.22 g, 3.95 mmol). The solution was heated at 100° C. for 3 h, and then cooled to 50° C. The solution was concentrated under vacuum to give a brownish residue, which was diluted with EtOAc (600 mL). The organic layers were then washed with H2O (3×80 mL), followed by brine (1×100 mL). The combined aq. layers were extracted with DCM (3×200 mL). The combined organic layers were dried over MgSO4 and then concentrated under vacuum. The residue obtained was purified by silica gel flash chromatography eluting with a gradient of 20% hexane to 40% EtOAc/hexane. The fractions containing the pure product were combined and concentrated under vacuum to give 2-((1S)-1-(8-fluoro-2-(2-(methylthio)phenyl)quinolin-3-yl)ethyl)isoindoline-1,3-dione (14.6 g, 33.0 mmol, 84% yield) as a light yellow foam. The proton NMR reflects a 53/47 ratio of atropisomers at 25° C. 1H NMR (500 MHz, CDCl3) δ ppm 8.71 (br s, 0.53H), 8.65 (br s, 0.47H), 7.79 (m, 1H), 7.66 (s, 4H), 7.55 (m, 1H), 7.45-7.27 (series of m, 3.6; H), 6.87 (m, 1.4H), 5.70 (q J=6.4 Hz, 0.47H), 5.63 (q, J=6.8 Hz, 0.53H), 2.47 (br s, 1.4H), 1.91 (m, 3H), 1.52 (br s, 1.6H). Mass Spectrum (ESI) m/e=443.2 (M+1).

Aufarbeitung

  1. customThe solution was sparged with N2 for ˜5 min
  2. temperaturecooled to 50° C
  3. concentrationThe solution was concentrated under vacuum
  4. customto give a brownish residue, which
  5. washThe organic layers were then washed with H2O (3×80 mL)
  6. extractionThe combined aq. layers were extracted with DCM (3×200 mL)
  7. dry with materialThe combined organic layers were dried over MgSO4
  8. concentrationconcentrated under vacuum
  9. customThe residue obtained
  10. customwas purified by silica gel flash chromatography
  11. washeluting with a gradient of 20% hexane to 40% EtOAc/hexane
  12. additionThe fractions containing the pure product
  13. concentrationconcentrated under vacuum

Quellen und Nachweise

ORD-Eintrag
ord-e02dab7f0477433487d15904608ca1ce
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08835432B2

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