Methyl iodide → Methyl{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}acetate

HRID 10216

Reaktionsgleichung

Reaktionsgleichung von HRID 10216
C(O[C:6]([N:8]1[CH2:11][CH:10]([CH2:12][C:13]([OH:15])=[O:14])[CH2:9]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].[CH3:22]I.[F:24][C:25]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:26]=1[CH2:27]CBr>CN(C)C=O.O>[CH3:22][O:15][C:13](=[O:14])[CH2:12][CH:10]1[CH2:9][N:8]([CH2:6][CH2:27][C:26]2[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:25]=2[F:24])[CH2:11]1

Komponenten

7

Edukt 4

HCID 6328Methyl iodideHCID 11430Potassium Carbonate2×HCID 110959892-(1-(Tert-butoxycarbonyl)azetidin-3-yl)acetic acidHCID 112989892,4-Difluorophenethyl bromide

Produkt 1

HCID 21978392Methyl{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}acetateAusbeute 52,2 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 962WaterLösungsmittel2×HCID 6228DimethylformamideLösungsmittel

Versuchsvorschrift

A mixture of [1-(tert-butoxycarbonyl)azetidin-3-yl]acetic acid (2 g, 9.24 mmol), potassium carbonate (1.54 g, 11.1 mmol) and methyl iodide (2.89 mL, 46.5 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature under nitrogen overnight. The reaction mixture was diluted with water and extracted with dichloromethane (x2). The combined organic layers were washed with saturated sodium hydrogencarbonate solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (5 mL) added. The reaction was stirred at room temperature for 30 minutes. The solvent was removed in vacuo. The residue was dissolved in N,N-dimethylformamide (30 mL). 2,4-Difluorophenethyl bromide (2.26 g, 10.2 mmol) and potassium carbonate (5.14 g, 37.2 mmol) were added and the reaction heated at 60° C. overnight. The cooled reaction mixture was diluted with water and extracted with dichloromethane (x3). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica, eluting with 5% methanol/dichloromethane, to give methyl{1-[2-(2,4-difluorophenyl)ethyl]azetidin-3-yl}acetate (1.3 g, 52%). 1H NMR (360 MHz, CDCl3) δ 7.15–7.09 (1H, m), 6.79–6.71 (2H, m), 3.64 (3H, s), 3.48–3.44 (2H, m), 2.87–2.75 (3H, m), 2.60 (4H, s), 2.57 (2H, d, J=7.1 Hz); m/z (ES+) 270 (M+H)+.

Aufarbeitung

  1. extractionextracted with dichloromethane (x2)
  2. washThe combined organic layers were washed with saturated sodium hydrogencarbonate solution
  3. dry with materialdried over MgSO4
  4. concentrationconcentrated in vacuo
  5. dissolutionThe residue was dissolved in dichloromethane (5 mL)
  6. additiontrifluoroacetic acid (5 mL) added
  7. stirringThe reaction was stirred at room temperature for 30 minutes
  8. customThe solvent was removed in vacuo
  9. dissolutionThe residue was dissolved in N,N-dimethylformamide (30 mL)
  10. temperaturethe reaction heated at 60° C. overnight
  11. customThe cooled reaction mixture
  12. extractionextracted with dichloromethane (x3)
  13. washThe combined organic layers were washed with brine
  14. dry with materialdried over MgSO4
  15. concentrationconcentrated in vacuo
  16. customThe residue was purified by flash column chromatography on silica
  17. washeluting with 5% methanol/dichloromethane

Quellen und Nachweise

ORD-Eintrag
ord-e5d5975d399c45f8b8ff01ba0896422c
Quelldatensatz
uspto-grants-2006_08
Patentnummer
US07094777B2

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