Methanol → N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)cyclopropanecarboxamide

HRID 10006

Reaction equation

HRID 10006 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]1([C:24](Cl)=[O:25])[CH2:23][CH2:22]1.CO>C1COCC1.CCOCC>[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][C:24]([CH:21]3[CH2:23][CH2:22]3)=[O:25])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14]1

Participants

6

Reactant 3

HCID 887MethanolHCID 77637Cyclopropanecarbonyl chlorideHCID 134780Pomalidomide

Product 1

HCID 10132095N-(2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)cyclopropanecarboxamideYield 84%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolventHCID 8028TetrahydrofuranSolvent

Procedure

A mixture of 4-amino-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (0.60 g, 2.2 mmol) and cyclopropanecarbonyl chloride (0.4 mL, 4.4 mmol) in THF (20 mL) was heated to reflux for 15 h. To the mixture was added methanol (5 mL). The solvent was removed in vacuo to give a solid. The solid was slurried in ether (30 mL0 for 1 h. The suspension was filtered and washed with ether (30 mL) to give cyclopropanecarboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-yl]-amide as a solid (630 mg, 84% yield): mp, 237–239° C.; 1H NMR (DMSO-d6) δ 0.87–0.90 (m, 4H, 2CH2), 1.93–2.09 (m, 2H, CH, CHH), 2.49–2.65 (m, 2H, CH2), 2.64–2.96 (m, 1H, CHH), 5.15 (dd, J=5.2, 12.6 Hz, 1H, NCH), 7.61 (d, J=7.2 Hz, 1H, Ar), 7.82 (t, J=7.7 Hz, 1H, Ar), 8.41 (d, J=8.3 Hz, 1H, Ar), 9.99 (s, 1H, NH), 11.16 (s, 1H, NH); 13C NMR (DMSO-d6) δ 8.10, 14.93, 22.00, 30.93, 48.92, 117.07, 118.30, 126.69, 131.49, 135.97, 136.43, 166.67, 167.57, 169.77, 172.55, 172.74; Anal Calcd for C17H15N3O5: C, 59.82; H, 4.43; N, 12.31. Found: C, 59.50; H, 4.39; N, 12.04.

Workup

  1. temperaturewas heated
  2. temperatureto reflux for 15 h
  3. customThe solvent was removed in vacuo
  4. customto give a solid
  5. customfor 1 h
  6. filtrationThe suspension was filtered
  7. washwashed with ether (30 mL)

Sources & evidence

ORD record
ord-3cc38ad9cd46421d88aff5f121abcc75
Source dataset
uspto-grants-2006_08
Patent number
US07091353B2

Linked notes

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