4-Chlorophenyl Isocyanate → 1-(4-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea

HRID 448304Notes

Reaction equation

HRID 448304 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.Cl.[NH2:12][CH2:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH2:16][N:17]([CH:24]1[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]1=[O:31])[C:18]2=[O:23].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH2:16][N:17]([CH:24]2[CH2:29][CH2:28][C:27](=[O:30])[NH:26][C:25]2=[O:31])[C:18]3=[O:23])=[O:10])=[CH:4][CH:3]=1

Participants

5

Reactant 3

HCID 76934-Chlorophenyl IsocyanateHCID 8471TriethylamineHCID 219885683-(4-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

Product 1

HCID 161174801-(4-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-ureaYield 78.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
5 °C

Procedure

4-Chlorophenyl isocyanate (0.4 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL) at 5-10° C. After stirring at 5° C. for 10 minutes, the mixture was stirred at room temperature overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1NHCl (30 mL) for 30 minutes. The mixture was filtered, and the solid was slurried with hot acetone (10 mL) to give 1-(4-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.7 g, 73%) as a white solid: mp>260° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.33-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.36-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=5.0 and 12.5 Hz, 1H, CH), 6.77 (t, J=5.0 Hz, 1H, NH), 7.27 (d, J=10.0 Hz, 2H, Ar), 7.40 (d, J=10 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.77 (s, 1H, NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 45.19, 51.58, 119.29, 121.56, 124.66, 128.30, 128.44, 130.35, 131.64, 135.46, 139.31, 139.92, 155.08, 168.07, 171.00, 172.84; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.85; H, 4.35; N, 12.97; Cl, 8.19.

Workup

  1. stirringthe mixture was stirred at room temperature overnight
  2. customThe reaction was quenched with methanol (1 mL)
  3. concentrationconcentrated
  4. stirringThe residue was stirred with 1NHCl (30 mL) for 30 minutes
  5. filtrationThe mixture was filtered

Sources & evidence

ORD record
ord-4d4345cceb4f4c00a650605fa45ef757
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

Loading…