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

HRID 448289Notes

Reaction equation

HRID 448289 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([N:9]=[C:10]=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][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>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 27333153-IsocyanatobenzonitrileHCID 219885683-(4-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

Product 1

HCID 161172121-(3-cyano-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-ureaYield 38%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
5 °C

Procedure

3-Cyanophenyl 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 min, the mixture was warmed to room temperature and stirred overnight. The reaction was quenched with methanol (1 mL) and concentrated. The residue was stirred with 1N HCl (30 mL) for 30 minutes and filtered. The solid was slurried with hot methanol (15 mL) to give 1-(3-cyano-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.33 g, 38%) as a white solid: mp 330-333° C.; 1H NMR (DMSO-d6) δ 2.01-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.37-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.92 (t, J=5.5 Hz, 1H, NH), 7.32-7.65 (m, 6H, Ar), 7.93 (s, 1H, Ar), 9.00 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.55, 31.17, 39.67, 46.18, 51.57, 111.41, 118.91, 120.24, 121.59, 122.36, 124.64, 128.30, 130.02, 130.35, 131.63, 135.27, 139.92, 141.21, 154.98, 168.05, 171.00, 172.82; Anal. calcd. for C22H19N5O4+0.1H2O: C, 63.03; H, 4.62; N, 16.71. Found: C, 62.69, H, 4.48; N, 16.41.

Workup

  1. temperaturethe mixture was warmed to room temperature
  2. stirringstirred overnight
  3. customThe reaction was quenched with methanol (1 mL)
  4. concentrationconcentrated
  5. stirringThe residue was stirred with 1N HCl (30 mL) for 30 minutes
  6. filtrationfiltered

Sources & evidence

ORD record
ord-e14d4b36494442a9b9066eae43f706be
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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