Dimethylformamide → N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-2-ethoxy-acetamide

HRID 10011

Reaction equation

HRID 10011 reaction equation
[CH2:1]([O:3][CH2:4][C:5]([OH:7])=O)[CH3:2].C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:19][C:20]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:21]=1[C:22](=[O:38])[N:23]([CH:30]1[CH2:35][CH2:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])[C:24]2=[O:29]>CCOCC.CO.C1COCC1>[O:37]=[C:31]1[CH:30]([N:23]2[C:22](=[O:38])[C:21]3[C:25](=[CH:26][CH:27]=[CH:28][C:20]=3[NH:19][C:5](=[O:7])[CH2:4][O:3][CH2:1][CH3:2])[C:24]2=[O:29])[CH2:35][CH2:34][C:33](=[O:36])[NH:32]1

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 12301Ethoxyacetic acidHCID 65578Oxalyl chlorideHCID 134780Pomalidomide

Product 1

HCID 21988552N-[2-(2,6-dioxo-3-piperidyl)-1,3-dioxo-isoindolin-4-yl]-2-ethoxy-acetamideYield 90.4%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of ethoxyacetic acid (0.8 mL, 8.5 mmol) and oxalyl chloride (0.7 mL, 8.0 mmol) in ether (5 mL) was added DMF (0.03 mL) at room temperature. After 3 h, 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (1.1 g, 4.0 mmol) and THF (40 mL) was added to the mixture. Then the mixture was heated to reflux for 15 h. To the mixture was added methanol (10 mL) to give a suspension. The suspension was filtered and washed with methanol (10 mL) to give N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-ethoxy-acetamide as a white solid (1.3 g, 87% yield): mp, 253–255° C.; 1H NMR (DMSO-d6) δ 1.27 (t, J=7.0 Hz, 3H, CH3), 2.06–2.10 (m, 1H, CHH), 2.46–2.64 (m, 2H, CH2), 2.84–2.98 (m, 1H, CHH), 3.66 (q, J=7.0 Hz, 2H, CH2), 4.14 (s, 2H, CH2), 5.17 (dd, J=5.2, 12.7 Hz, 1H, NCH), 7.62 (d, J=7.2 Hz, 1H, Ar), 7.87 (t, J=8.2 Hz, 1H, Ar), 8.75 (d, J=8.4 Hz, 1H, Ar), 10.39 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.88, 21.93, 30.92, 48.98, 66.89, 69.49, 116.00, 118.28, 124.25, 131.31, 135.99, 136.53, 166.69, 168.31, 169.49, 169.73, 174.71; Anal Calcd for C17H17N3O6: C, 56.82; H, 4.77; N, 11.69. Found: C, 56.82; H, 4.71; N, 11.60.

Workup

  1. temperatureThen the mixture was heated
  2. temperatureto reflux for 15 h
  3. customto give a suspension
  4. filtrationThe suspension was filtered
  5. washwashed with methanol (10 mL)

Sources & evidence

ORD record
ord-0aec7bc16da1406f8e6c49d1bdaea733
Source dataset
uspto-grants-2006_08
Patent number
US07091353B2

Linked notes

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