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3,4-Dimethylphenyl isocyanate → 3-(3,4-dimethyl-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea

HRID 240680
Notes
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Reaction equation

HRID 240680 reaction equation
Cl.[O:2]=[C:3]1[CH:8]([N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[CH2:19][NH:20][CH3:21])[C:10]2=[O:22])[CH2:7][CH2:6][C:5](=[O:23])[NH:4]1.[CH3:24][C:25]1[CH:26]=[C:27]([N:32]=[C:33]=[O:34])[CH:28]=[CH:29][C:30]=1[CH3:31]>C(Cl)Cl>[CH3:24][C:25]1[CH:26]=[C:27]([NH:32][C:33](=[O:34])[N:20]([CH2:19][C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[C:17](=[O:18])[N:9]([CH:8]2[CH2:7][CH2:6][C:5](=[O:23])[NH:4][C:3]2=[O:2])[C:10]3=[O:22])[CH3:21])[CH:28]=[CH:29][C:30]=1[CH3:31]
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

4

Reactant 2

HCID 43896633,4-Dimethylphenyl isocyanateHCID 670266492-(2,6-Dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dione hydrochloride

Product 1

HCID 248959023-(3,4-dimethyl-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-ureaYield 59%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a suspension of 2-(2,6-dioxo-piperidin-3-yl)-4-methylaminomethyl-isoindole-1,3-dione hydrochloride (0.65 g, 1.93 mmol) and 3,4-dimethylphenyl isocyanate (0.32 mL, 2.31 mmol) in dry CH2Cl2 (80 ml), was added diidopropylethylamine (0.47 mL g, 2.60 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was quenched with MeOH (1 mL). The suspension was filtered, and the resulting solid cake was rinsed with CH2Cl2 (5 ml). The solid was reslurried with ether (I 5 mL) to give 3-(3,4-dimethyl-phenyl)-1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-1-methyl-urea as a solid (0.51 g, 59%)): mp 202-204° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.23 (99%); 1H NMR (DMSO-d6): δ 2.14 (s, 3H), 2.16 (s, 3H), 2.54-2.64 (m, 2H), 2.85-2.97 (m, 1H), 3.03 (s, 3H), 5.00 (s, 2H), 5.14-5.20 (dd, J=5.3, 12.6 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 7.26 (s, 1H), 7.61 (d, J=7.2 Hz, 1H), 7.89-7.81 (m, 2H), 8.34 (s, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 18.62, 15.54, 21.97, 30.91, 35.10, 47.46, 48.85, 117.61, 121.43, 121.83, 127.54, 129.12, 129.51, 131.78, 132.42, 134.95, 135.63, 137.93, 138.97, 155.79, 16696, 167.58, 169.80, 172.74. Anal Calcd for C24H24N4O5: C, 64.28; H, 5.39; N, 12.49. Found: C, 63.99; H, 5.26; N, 12.39.

Workup

  1. additionwas added diidopropylethylamine (0.47 mL g, 2.60 mmol)
  2. customThe reaction mixture was quenched with MeOH (1 mL)
  3. filtrationThe suspension was filtered
  4. washthe resulting solid cake was rinsed with CH2Cl2 (5 ml)

Sources & evidence

ORD record
ord-7e2196f38e924776b8630647424bf99d
Source dataset
uspto-grants-2014_02
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US08648096B2

Reaction notes

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