Dimethylformamide → N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methylsulfanyl-acetamide

HRID 2103525Notes

Reaction equation

HRID 2103525 reaction equation
[CH3:1][S:2][CH2:3][C:4]([OH:6])=O.C(Cl)(=O)C(Cl)=O.CN(C=O)C.[NH2:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21](=[O:37])[N:22]([CH:29]1[CH2:34][CH2:33][C:32](=[O:35])[NH:31][C:30]1=[O:36])[C:23]2=[O:28]>CCOCC.CO.C1COCC1>[O:36]=[C:30]1[CH:29]([N:22]2[C:21](=[O:37])[C:20]3[C:24](=[CH:25][CH:26]=[CH:27][C:19]=3[NH:18][C:4](=[O:6])[CH2:3][S:2][CH3:1])[C:23]2=[O:28])[CH2:34][CH2:33][C:32](=[O:35])[NH:31]1

Participants

8

Reactant 4

HCID 6228DimethylformamideHCID 65578Oxalyl chlorideHCID 75551(Methylthio)acetic acidHCID 134780Pomalidomide

Product 1

HCID 21988527N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-2-methylsulfanyl-acetamideYield 69.2%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of (methylthio)acetic acid (0.77 mL, 8.9 mmol) and oxalyl chloride (0.7 mL, 8.0 mmol) in ether (5 mL) was added DMF (0.02 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-methylsulfanyl-acetamide as a white solid (1.0 g, 69% yield): mp, 228-230° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H, CHH), 2.18 (s, 3H, CH3), 2.46-2.65 (m, 2H, CH2), 2.82-2.95 (m, 1H, CHH), 3.53 (s, 2H, CH2), 5.17 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.63 (d, J=7.2 Hz, 1H, Ar), 7.86 (t, J=7.5 Hz, 1H, Ar), 8.61 (d, J=8.4 Hz, 1H, Ar), 10.39 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 15.62, 21.96, 30.93, 37.99, 48.94, 116.69, 118.46, 125.28, 131.44, 136.31, 166.67, 167.88, 168.63, 169.78, 172.75; Anal Calcd for C16H15N3O5S: C, 53.18; H, 4.18; N, 11.63. Found: C, 53.26; H, 4.17; N, 11.52.

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-486dbede120645e08b66105297285b85
Source dataset
uspto-grants-2009_08
Patent number
US07576104B2

Reaction notes

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