Hydrochloric Acid → 1-(3,4-Dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-urea

HRID 331625Notes

Reaction equation

HRID 331625 reaction equation
CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[CH3:26][C:27]1[CH:28]=[C:29]([N:34]=[C:35]=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33].C(N(CC)CC)C.Cl>C(#N)C>[CH3:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:36])[CH:30]=[CH:31][C:32]=1[CH3:33]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 43896633,4-Dimethylphenyl isocyanateHCID 866307653-(5-(Aminomethyl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione methanesulfonate

Product 1

HCID 445387291-(3,4-Dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1h-isoindol-5-ylmethyl]-ureaYield 71.4%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.37 g, 1.00 mmol) and 3,4-dimethylphenylisocyanate (0.15 g, 1.00 mmol) in acetonitrile (10 mL), was added triethylamine (0.28 mL, 2.00 mmol) at room temperature under nitrogen. After 1 h, 1N aq. HCl (20 mL) was added and the mixture was stirred for 10 min. The product was isolated by filtration, washed with 1N aq. HCl (20 mL), acetonitrile (20 mL) and dried overnight in vacuo to give 1-(3,4-dimethyl-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.30 g, 71% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 3.02 min (97.86%); mp: 254-256° C.; 1H NMR (DMSO-d6) δ 1.93-2.06 (m, 1H), 2.12 (s, 3H), 2.15 (s, 3H), 2.30-2.47 (m, 1H), 2.60 (d, J=17.2 Hz, 1H), 2.82-3.00 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.36-4.50 (m, 3H), 5.11 (dd, J=5.0, 13.3 Hz, 1H), 6.66 (t, J=5.9 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 7.11 (dd, J=1.7, 8.1 Hz, 1H), 7.18 (s, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.51 (s, 1H), 7.69 (d, J=7.7 Hz, 1H), 8.41 (s, 1H), 10.98 (s, 1H); 13C NMR (DMSO-d6) δ 18.60, 19.62, 22.49, 31.20, 42.77, 47.10, 51.56, 115.35, 119.15, 121.86, 122.91, 126.89, 128.67, 129.49, 130.26, 136.08, 138.03, 142.36, 144.96, 155.26, 167.95, 170.98, 172.85; Anal Calcd for C23H24N4O4: C, 65.70; H, 5.75; N, 13.33. Found: C, 65.48; H, 5.62; N, 13.20.

Workup

  1. customThe product was isolated by filtration
  2. washwashed with 1N aq. HCl (20 mL), acetonitrile (20 mL)
  3. customdried overnight in vacuo

Sources & evidence

ORD record
ord-58ac79c79e274278aa8d15c179492f0d
Source dataset
uspto-grants-2014_11
Patent number
US08877780B2

Reaction notes

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