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

HRID 448290Notes

Reaction equation

HRID 448290 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=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:3]=[C:4]([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:5]=[CH:6][CH:7]=1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 17968Benzene, 1-chloro-3-isocyanato-HCID 219885683-(4-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

Product 1

HCID 161173401-(3-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-ureaYield 91%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
5 °C

Procedure

3-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 then concentrated. The residue was stirred with 1N HCl (30 mL) for 1 hour and filtered. The solid was slurried with hot methanol (15 mL) to give 1-(3-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.8 g, 91%): mp 250-252° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-2.98 (m, 1H), 4.37 (d, J=5.3 Hz, 2H, CH2), 4.44 (d, J=17.2 Hz, 1H), 4.51 (d, J=17.3 Hz, 1H), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.82 (t, J=5.4 Hz, 1H, NH), 6.92-6.95 (m, 1H, Ar), 7.18-7.27 (m, 2H, Ar), 7.48-7.65 (m, 4H, Ar), 8.84 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.57, 31.18, 39.68, 46.20, 51.59, 116.15, 117.13, 120.78, 121.57, 128.30, 130.21, 130.35, 131.64, 133.06, 135.37, 139.90, 141.86, 154.99, 168.07, 171.00, 172.82; Anal. calcd. for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 59.06; H, 4.39; N, 13.24; Cl, 7.95.

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 1N HCl (30 mL) for 1 hour
  5. filtrationfiltered

Sources & evidence

ORD record
ord-830f13f7810a463b8d67e44e6fc92046
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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