N-bromobutanimide → 2-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-9,10-dihydro-phenanthren-2-yl}-2-oxo-ethyl) ester 2-tert-butyl ester

HRID 71901Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 71901
[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([O:15][CH2:16][C:17]([C:19]1[CH:32]=[CH:31][C:30]2[C:29]3[C:24](=[CH:25][C:26](Br)=[CH:27][CH:28]=3)[CH2:23][CH2:22][C:21]=2[CH:20]=1)=[O:18])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:39]([O:41]CC)=[CH2:40])CCC.C1C(=O)N(Br)C(=O)C1.[C:60]([O:64][C:65]([N:67]1[CH:72]([C:73]([OH:75])=[O:74])[CH:71]2[CH2:76][CH:68]1[CH2:69][CH2:70]2)=[O:66])([CH3:63])([CH3:62])[CH3:61].CCN(C(C)C)C(C)C>O1CCOCC1.C(OCC)(=O)C.C(#N)C.O>[C:60]([O:64][C:65]([N:67]1[CH:72]([C:73]([O:75][CH2:40][C:39]([C:26]2[CH:27]=[CH:28][C:29]3[C:30]4[C:21](=[CH:20][C:19]([C:17](=[O:18])[CH2:16][O:15][C:13]([CH:9]5[CH2:10][CH2:11][CH2:12][N:8]5[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:14])=[CH:32][CH:31]=4)[CH2:22][CH2:23][C:24]=3[CH:25]=2)=[O:41])=[O:74])[CH:71]2[CH2:76][CH:68]1[CH2:69][CH2:70]2)=[O:66])([CH3:63])([CH3:61])[CH3:62]

Komponenten

10

Edukt 5

HCID 67184N-bromobutanimideHCID 81531DiisopropylethylamineHCID 619414Stannane, tributyl(1-ethoxyethenyl)-HCID 150563882-(tert-Butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acidHCID 66620898HCID 66620898, Verbindung

Produkt 1

HCID 666206532-Aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-9,10-dihydro-phenanthren-2-yl}-2-oxo-ethyl) ester 2-tert-butyl ester

Reagenzien, Katalysatoren, Lösungsmittel 4

HCID 962WaterLösungsmittelHCID 6342AcetonitrileLösungsmittelHCID 8857Ethyl AcetateLösungsmittel2×HCID 312751,4-DioxaneLösungsmittel

Reaktionsbedingungen

Temperatur
80 °C

Versuchsvorschrift

Pd(Ph3)4 (37 mg, 0.03 mmol) and PdCl2(Ph3)2 (22 mg, 0.03 mmol) were added to a mixture of pyrrolidine-1,2-dicarboxylic acid 2-[2-(7-bromo-9,10-dihydro-phenanthren-2-yl)-2-oxo-ethyl]ester 1-tert-butyl ester (410 mg, 0.8 mmol) and tributyl(1-ethoxyvinyl)tin (0.32 mL, 0.96 mmol) in 8 mL dioxane. The reaction mixture was flushed with nitrogen, heated at 80° C. for 16 hours, then cooled to ambient temperature. Water (2 mL) and NBS (171 mg, 0.96 mmol) were added and the mixture was stirred at room temperature for 40 minutes, then diluted with ethyl acetate (100 mL). Washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. Half of the obtained residue was suspended in acetonitrile (5 mL) To it was added a solution of 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 2-tert-butyl ester (100 mg, 0.41 mmol) and DIPEA (0.068 mL, 0.39 mmol) in 2 mL acetonitrile. The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with NaHCO3 solution and water, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2-aza-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid 3-(2-{7-[2-(1-tert-butoxycarbonyl-pyrrolidine-2-carbonyloxy)-acetyl]-9,10-dihydro-phenanthren-2-yl}-2-oxo-ethyl) ester 2-tert-butyl ester as a white solid (171 mg, 60% over two steps). m/z 717.2 (M+H)+.

Aufarbeitung

  1. customThe reaction mixture was flushed with nitrogen
  2. temperaturecooled to ambient temperature
  3. washWashed with water and brine
  4. dry with materialdried over Na2SO4
  5. filtrationfiltered
  6. concentrationconcentrated in vacuo
  7. stirringThe mixture was stirred at room temperature for 16 hours
  8. washThe organic layer was washed with NaHCO3 solution and water
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe obtained residue was purified by flash chromatography

Quellen und Nachweise

ORD-Eintrag
ord-7793ff03e7b844d2a6a4eeeabfd8788f
Quelldatensatz
uspto-grants-2014_09
Patentnummer
US08822430B2

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