Triethylamine → 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-urea

HRID 448420Notes

Reaction equation

HRID 448420 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17](=[O:33])[N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[O:32]=[C:26]1[CH:25]([N:18]2[C:17](=[O:33])[C:16]3[C:20](=[CH:21][CH:22]=[CH:23][C:15]=3[CH2:14][NH:13][C:10]([NH:9][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[O:11])[C:19]2=[O:24])[CH2:30][CH2:29][C:28](=[O:31])[NH:27]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 794431-Isocyanato-4-methoxybenzeneHCID 219885254-(aminomethyl)-2-(2,6-dioxopiperidin-3-yl)-2,3-dihydro-1H-isoindole-1,3-dione hydrochloride

Product 1

HCID 588273231-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-ureaYield 59%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

4-Methoxyphenyl isocyanate (0.4 g, 2.6 mmol) was added to a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.0 mmol) and triethylamine (0.3 g, 2.8 mmol) in THF (30 mL) at 5-10° C. After 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL), and the mixture was concentrated. The residue was stirred with 1N HCl (30 mL) for one hour and then filtered. The solid was slurried with hot ethanol (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-urea (0.5 g, 59%) as a white solid: mp 205-207° C.; 1H NMR (DMSO-d6) δ 2.05-2.09 (m, 1H), 2.49-2.65 (m, 2H), 2.84-2.97 (m, 1H), 3.68 (s, 3H, OCH3), 4.70 (d, J=5.7 Hz, 2H, CH2), 5.13-5.20 (dd, J=5.2 and 12.4 Hz, 1H, CH), 6.66 (t, J=5.7 Hz, 1H, NH), 6.79 (d, J=9.0 Hz, 2H, Ar), 7.27 (d, J=9.0 Hz, 2H, Ar), 7.75-7.88 (m, 3H, Ar), 8.59 (a, 1H, NH), 11.65 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.94, 48.86, 55.10, 113.86, 119.50, 121.82, 127.15, 131.59, 133.38, 133.62, 134.70, 140.46, 154.03, 155.45, 167.02, 167.60, 169.84, 172.22; Anal. calcd. for C22H20N4O6: C, 60.55; H, 4.62; N, 12.84. Found: C, 60.43; H, 4.42; N, 12.58.

Workup

  1. customThe reaction was quenched with methanol (1 mL)
  2. concentrationthe mixture was concentrated
  3. stirringThe residue was stirred with 1N HCl (30 mL) for one hour
  4. filtrationfiltered

Sources & evidence

ORD record
ord-418f8e1f32d84019878735145e15cf23
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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