Reaktion #10059

Reaktionsgleichung

benzaldehyde

4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione

benzaldehyde

sodium borohydride

sodium borohydride

→

2-(2,6-dioxo(3-piperidyl))-4-[benzylamino]isoindoline-1,3-dione

Ausbeute 16.0%

Lösungsmittel

ethyl acetate

sodium hydrogen carbonate

acetic acid

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturwas heated
2. 2
   Temperaturto reflux for 3 h
3. 3
   TemperaturThe mixture was cooled to room temperature
4. 4
   workup.WAITkept at room temperature for 18 h
5. 5
   TemperaturThe mixture was then heated
6. 6
   Temperaturto reflux for 2 h
7. 7
   Temperaturduring reflux
8. 8
   TemperaturAfter 30 min of reflux the reaction
9. 9
   Temperaturto cool to room temperature
10. 10
    workup.STIRRINGthe mixture stirred at room temperature for 3 days
11. 11
    SonstigeThe solvent was removed in vacuo
12. 12
    Sonstigeto yield an oil
13. 13
    SonstigeThe organic layer was separated
14. 14
    Waschenwas washed with aqueous sodium hydrogen carbonate (sat, 2×100 ml), brine (100 ml)
15. 15
    Trocknendried over MgSO4
16. 16
    SonstigeThe solvent was removed in vacuo
17. 17
    Sonstigeto give a solid
18. 18
    SonstigeThe solid was purified by column chromatography (Silca Gel, 50% EtOAc:CH2Cl2)
19. 19
    Sonstigeto give a yellow solid
20. 20
    SonstigeThe solid was further purified by column chromatography (KP-C18-HS, 35:65 CH3CN:0.1% CF3COOH in water)

Vorschrift

A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.0 g, 3.7 mmol) and benzaldehyde (0.4 ml, 3.9 mmol) in acetic acid (20 ml) was stirred at room temperature for 17 h, then was heated to reflux for 3 h. The mixture was cooled to room temperature. To the stirred mixture was added sodium borohydride (140 mg, 3.7 mmol) and kept at room temperature for 18 h. The mixture was then heated to reflux for 2 h. To the mixture was added additional benzaldehyde (0.4 ml, 3.9 mmol) during reflux. After 30 min of reflux the reaction was allowed to cool to room temperature. To the mixture was added sodium borohydride (180 mg, 4.8 mmol) and the mixture stirred at room temperature for 3 days. The solvent was removed in vacuo to yield an oil. The oil was diluted with ethyl acetate (90 ml) and aqueous sodium hydrogen carbonate (sat, 100 ml). The organic layer was separated and was washed with aqueous sodium hydrogen carbonate (sat, 2×100 ml), brine (100 ml) and dried over MgSO4. The solvent was removed in vacuo to give a solid. The solid was purified by column chromatography (Silca Gel, 50% EtOAc:CH2Cl2) to give a yellow solid. The solid was further purified by column chromatography (KP-C18-HS, 35:65 CH3CN:0.1% CF3COOH in water) to give 2-(2,6-dioxo(3-piperidyl))-4-[benzylamino]isoindoline-1,3-dione as a yellow solid (210 mg, 16% yield): mp, 209–211° C.; 1H NMR (DMSO-d6) δ 2.02–2.08 (m, 1H, CHH), 2.46–2.63 (m, 2H, CH2), 2.82–2.97 (m, 1H, CHH), 4.56 (d, J=6.2 Hz, 2H, CH2), 5.07 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.96 (d, J=8.6 Hz, 1H, Ar), 7.02 (d, J=7.0 Hz, 1H, Ar), 7.19–7.40 (m, 6H, Ar, NH), 7.51 (dd, J=7.5, 8.4 Hz, 1H, Ar), 11.11 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.15, 30.99, 45.44, 48.59, 109.58, 110.74, 117.63, 126.95, 126.99, 132.21, 136.09, 138.95, 146.09, 167.27, 168.78, 170.07, 172.79; Anal Calcd for C20H17N3O4: C, 66.11; H, 4.72; N, 11.56. Found: C, 65.96; H, 4.60; N, 11.49.

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