Acetic Acid → 2-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dione

HRID 10004

Reaction equation

HRID 10004 reaction equation
[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:20])[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:21](=O)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(O)(=O)C.[BH4-].[Na+]>CN(C=O)C>[O:19]=[C:13]1[CH:12]([N:5]2[C:4](=[O:20])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 8130HeptanalHCID 134780PomalidomideHCID 4311764Sodium borohydride2×

Product 1

HCID 99476072-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dioneYield 41.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and heptanal (3.4 mL, 24 mmol) and acetic acid (2 mL) in DMF (20 mL) was heated until all solid was dissolved. To the mixture was added sodium borohydride (605 mg, 16 mmol) and kept at room temperature for 18 h. To the mixture was added sodium borohydride (150 mg, 3.9 mmol) and kept at room temperature for 1 d. The mixture was extracted with ethyl acetate (200 mL) and water (100 mL). The organic layer was washed with water (100 mL), The solvent was removed in vacuo to give an oil. The oil was purified by column chromatography (Silca Gel, 33% EtOAc:CH2Cl2) to give 2-(2,6-Dioxo-piperidin-3-yl)-4-heptylamino-isoindole-1,3-dione as a yellow solid (610 mg, 41% yield): mp, 107–109° C.; 1H NMR (DMSO-d6) δ 0.82–0.87 (m, 3H, CH3), 1.24–1.29 (m, 8H, 4 CH2), 2.00–2.04 (m, 1H, CHH), 2.43–2.62 (m, 2H, CH2), 2.82–2.96 (m, 1H, CHH), 3.23–3.31 (m, 2H, CH2), 5.06 (dd, J=5.3, 12.4 Hz, 1H, NCH), 6.51 (t, J=5.9 Hz, 1H, NH), 7.01 (d, J=7.0 Hz, 1H, Ar), 7.07 (d, J=8.6 Hz, 1H, Ar), 7.57 (dd, J=7.4, 8.4 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.91, 22.03, 22.17, 26.28, 28.42, 28.69, 30.98, 31.22, 34.84, 48.55, 109.03, 110.36, 117.13, 132.18, 136.24, 146.43, 167.29, 168.96, 170.05, 172.77; Anal Calcd for C20H25N3O4: C, 64.67; H, 6.78; N, 11.31. Found: C, 64.62; H, 6.76; N, 11.13.

Workup

  1. temperaturewas heated until all solid
  2. dissolutionwas dissolved
  3. waitkept at room temperature for 1 d
  4. extractionThe mixture was extracted with ethyl acetate (200 mL) and water (100 mL)
  5. washThe organic layer was washed with water (100 mL)
  6. customThe solvent was removed in vacuo
  7. customto give an oil
  8. customThe oil was purified by column chromatography (Silca Gel, 33% EtOAc:CH2Cl2)

Sources & evidence

ORD record
ord-d9ecf58554e04c83a235de2184551fb7
Source dataset
uspto-grants-2006_08
Patent number
US07091353B2

Linked notes

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