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 63487Notes

Reaction equation

HRID 63487 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-6e21cf77083b4e71a87d33b2c0ed18bf
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Reaction notes

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