Benzaldehyde → 3-{1-Oxo-4-[benzylamino]isoindolin-2-yl}piperidine-2,6-dione

HRID 906706Notes

Reaction equation

HRID 906706 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[O:11]=[C:6]1[C:7]2[C:3](=[C:2]([NH:1][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:10]=[CH:9][CH:8]=2)[CH2:4][N:5]1[CH:12]1[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]

Participants

6

Reactant 3

HCID 240BenzaldehydeHCID 216326LenalidomideHCID 4311764Sodium borohydride

Product 1

HCID 102914653-{1-Oxo-4-[benzylamino]isoindolin-2-yl}piperidine-2,6-dioneYield 60.1%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidSolventHCID 887MethanolSolvent

Procedure

A stirred mixture of 3-(4-amino-1-oxoisoindolin-2-yl)piperidine-2,6-dione (518 mg, 2.0 mmol) and benzaldehyde (0.21 ml, 2.0 mmol) in methanol (20 ml) was heated to reflux for 5 h. The solvent was removed in vacuo to give a solid. The solid was re-dissolved in acetic acid (20 ml). The stirred solution was heated to reflux for 1 h, and was then allowed to cool to room temperature. To the stirred solution was added sodium borohydride (90 mg, 2.3 mmol) and stirring continued at room temperature for 18 h. The resulting suspension was filtered and washed with acetic acid (10 ml) and ether (20 ml) to give 3-{1-oxo-4-[benzylamino]isoindolin-2-yl}piperidine-2,6-dione as an off-white solid (420 mg, 60% yield): mp, 257-259° C.; 1H NMR (DMSO-d6) δ 2.01-2.07 (m, 1H, CHH), 2.23-2.30 (m, 1H, CHH), 2.49-2.65 (m, 1H, CHH), 2.85-3.00 (m, 1H, CHH), 4.19 (d, J=17 Hz, 1H, CHH), 4.31 (d, J=17 Hz, 1H, CHH), 4.39 (d, J=5.7 Hz, 2H, CH2), 5.12 (dd, J=5.1, 13 Hz, 1H, NCH), 6.37 (t, J=5.9 Hz, 1H, NH), 6.62 (d, J=8.0 Hz, 1H, Ar), 6.91 (d, J=7.3 Hz, 1H, Ar), 7.19-7.40 (m, 6H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.79, 31.25, 45.79, 46.09, 51.56, 110.32, 112.34, 126.72, 127.05, 128.32, 129.07, 132.08, 139.72, 143.33, 168.82, 171.22, 172.90; Anal Calcd for C20H19N3O3: C, 68.75; H, 5.48; N. 12.03. Found C, 68.73; H, 5.41; N, 12.04.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 5 h
  3. customThe solvent was removed in vacuo
  4. customto give a solid
  5. temperatureThe stirred solution was heated
  6. temperatureto reflux for 1 h
  7. filtrationThe resulting suspension was filtered
  8. washwashed with acetic acid (10 ml) and ether (20 ml)

Sources & evidence

ORD record
ord-a1499ca61d35409d98e9c26ef661c9eb
Source dataset
uspto-grants-2011_09
Patent number
US08012997B2

Reaction notes

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