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

HRID 448288Notes

Reaction equation

HRID 448288 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].C(N(CC)CC)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([N:37]=[C:38]=[O:39])=[CH:33][CH:32]=1>C1COCC1>[O:21]=[C:15]1[CH:14]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH2:3][NH:2][C:38]([NH:37][C:34]3[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=3)=[O:39])[C:8]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 794431-Isocyanato-4-methoxybenzeneHCID 219885683-(4-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione hydrochloride

Product 1

HCID 161172111-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-ureaYield 93%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
5 °C

Procedure

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, 2.7 mmol) in THF (30 mL) was cooled to 5° C. 4-Methoxyphenyl isocyanate (0.4 g, 2.7 mmol) was added, and 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 one hour then filtered. The solid was slurried with hot methanol (20 mL) to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-3-(4-methoxy-phenyl)-urea (0.8 g, 93%) as a white solid: mp 320-322° C.; 1H NMR (DMSO-d6) δ 2.00-2.04 (m, 1H), 2.36-2.64 (m, 2H), 2.86-3.00 (m, 1H), 3.68 (s, 3H, OCH3), 4.35-4.57 (m, 4H, 2CH2), 5.12-5.19 (dd, J=4.6 and 13.0 Hz, 1H, CH), 6.61 (t, J=5.5 Hz, 1H, NH), 6.83 (d, J=8.9 Hz, 2H, Ar), 7.27 (d, J=8.9 Hz, 2H, Ar), 7.47-7.64 (m, 3H, Ar), 8.40 (s, 1H, NH), 11.03 (s, 1H); 13C NMR (DMSO-d6) δ 22.58, 31.18, 46.20, 51.58, 55.11, 113.86, 119.70, 121.49, 128.27, 130.34, 131.62, 133.36, 135.76, 139.88, 154.08, 155.47, 168.10, 171.00, 172.84; Anal. calcd. for C22H22N4O5: C, 62.55; H, 5.25; N, 13.26. Found: C, 62.61; H, 4.95; N, 13.59.

Workup

  1. customThe reaction was quenched with methanol (1 mL)
  2. concentrationconcentrated
  3. stirringThe residue was stirred with 1N HCl (30 mL) for one hour
  4. filtrationthen filtered

Sources & evidence

ORD record
ord-61b1ca114c944f1798b374e4995e5ba6
Source dataset
uspto-grants-2013_07
Patent number
US08481568B2

Reaction notes

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