Benzaldehyde → E3 ligase Ligand 23

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.

1. temperaturewas heated
2. temperatureto reflux for 3 h
3. temperatureThe mixture was cooled to room temperature
4. waitkept at room temperature for 18 h
5. temperatureThe mixture was then heated
6. temperatureto reflux for 2 h
7. temperatureduring reflux
8. temperatureAfter 30 min of reflux the reaction
9. temperatureto cool to room temperature
10. stirringthe mixture stirred at room temperature for 3 days
11. customThe solvent was removed in vacuo
12. customto yield an oil
13. customThe organic layer was separated
14. washwas washed with aqueous sodium hydrogen carbonate (sat, 2×100 ml), brine (100 ml)
15. dry with materialdried over MgSO4
16. customThe solvent was removed in vacuo
17. customto give a solid
18. customThe solid was purified by column chromatography (Silca Gel, 50% EtOAc:CH2Cl2)
19. customto give a yellow solid
20. customThe solid was further purified by column chromatography (KP-C18-HS, 35:65 CH3CN:0.1% CF3COOH in water)

ORD 기록

ord-ea6cf2a4adb041cdad97be0ac9ef9740

출처 데이터셋

uspto-grants-2006_08

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US07091353B2