Triethylamine → 3-methyl-3H-imidazole-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide

HRID 448453Notes

Reaction equation

HRID 448453 reaction equation
[CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][N:4]=[CH:3]1.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(CC)CC)C.Cl.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[C:34](=[O:50])[N:35]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[C:36]2=[O:41]>CN(C=O)C>[O:49]=[C:43]1[CH:42]([N:35]2[C:34](=[O:50])[C:33]3[C:37](=[CH:38][CH:39]=[CH:40][C:32]=3[CH2:31][NH:30][C:7]([C:6]3[N:2]([CH3:1])[CH:3]=[N:4][CH:5]=3)=[O:9])[C:36]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 27735071-methyl-1H-imidazole-5-carboxylic acidHCID 5250894Bis-(1H-imidazol-2-YL)-methanoneHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 588273333-methyl-3H-imidazole-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amideYield 28%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A mixture of 1-methyl-1H-imidazole-5-carboxylic acid (0.3 g, 2.6 mmol) and carbonyl diimidazole (0.5 g, 3.0 mmol) in DMF (30 mL) was stirred at room temperature for 3 hours. Triethylamine (0.8 g, 6.0 mmol) was added, followed by 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol). The mixture was stirred at 75° C. (oil bath) for 3 hours. The mixture was cooled to room temperature and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×40 mL) and brine (40 mL), and dried (MgSO4). Solvent was removed, and the residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5) to give 3-methyl-3H-imidazole-4-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-amide (0.2 g. 28%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.50-2.64 (m, 2H), 2.84-2.97 (m, 1H), 3.81 (s, 3H), 4.89 (d, J=5.6 Hz, 2H), 5.13-5.20 (dd, J=5.2 and 12.5 Hz, 1H), 7.68-7.84 (m, 5H), 8.94 (t, J=5.5 Hz, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 21.98, 30.93, 33.51, 37.44, 48.88, 121.88, 125.45, 127.05, 131.52, 132.29, 133.09, 134.83, 139.42, 142.08, 160.25, 166.94, 167.53, 169.82, 172.74; Anal. calcd. for C19H17N5O5+0.13H2O+0.1Et2O: C, 57.52; H, 4.54; N, 17.29. Found: C, 57.23; H, 4.27; N, 16.95.

Workup

  1. stirringThe mixture was stirred at 75° C. (oil bath) for 3 hours
  2. temperatureThe mixture was cooled to room temperature
  3. concentrationconcentrated
  4. dissolutionThe residue was dissolved in EtOAc (100 mL)
  5. washwashed with water (2×40 mL) and brine (40 mL)
  6. dry with materialdried (MgSO4)
  7. customSolvent was removed
  8. customthe residue was purified by chromatography (SiO2, CH2Cl2: CH3OH 97.5:2.5)

Sources & evidence

ORD record
ord-2d87199b26454f9ca2fd24e0dc02a393
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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