Diisopropylethylamine → 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(3-methoxy-phenyl)-urea

HRID 63519

Reaction equation

HRID 63519 reaction equation
Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1.CCN(C(C)C)C(C)C>C1COCC1>[O:21]=[C:15]1[CH:14]([N:8]2[C:7](=[O:22])[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([CH2:3][NH:2][C:32]([NH:31][C:27]4[CH:28]=[CH:29][CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)=[O:33])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

5

Reactant 3

HCID 81531DiisopropylethylamineHCID 878433-Methoxyphenyl isocyanateHCID 670197065-(Aminomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride

Product 1

HCID 577304861-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(3-methoxy-phenyl)-ureaYield 6.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
40 °C

Procedure

To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 3-methoxyphenylisocyanate (0.45 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The residue was triturated in Et2O (50 mL) for 3 h at rt, then refluxed in acetone (50 mL) for 1 h. The product was isolated by filtration and dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(3-methoxy-phenyl)-urea as a white solid (0.08 g, 6% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 8.01 min (99.44%); mp: 323-325° C.; 1H NMR (DMSO-d6) δ 2.03-2.09 (m, 1H, CHH), 2.49-2.63 (m, 2H, CHH, CHH), 2.85-2.91 (m, 1H, CHH), 3.70 (s, 3H, CH3), 4.47 (d, J=6.0 Hz, 2H, CH2), 5.15 (dd, J=5.4, 13.5 Hz, 1H, CH), 6.47-6.50 (m, 1H, Ar or NH), 6.82-6.91 (m, 2H, Ar or NH), 7.09-7.15 (m, 2H, Ar or NH), 7.78-7.91 (m, 3H, Ar or NH), 8.74 (s, 1H, NH), 11.12 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.98, 30.90, 42.57, 48.96, 54.81, 103.52, 106.72, 110.14, 121.63, 123.47, 129.36, 129.65, 131.57, 133.17, 141.49, 143.07, 148.75, 155.16, 159.60, 167.02, 167.18, 169.80, 172.72; LCMS: MH=437; Anal Calcd for C22H20N4O6: C, 58.38; H, 4.85; N, 12.38. Found: C, 58.36; H, 4.45; N, 11.98.

Workup

  1. temperaturethen cooled to rt
  2. customThe solvent was removed in vacuo
  3. dissolutionthe residue was dissolved in EtOAc (100 mL)
  4. washThe organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. customThe residue was triturated in Et2O (50 mL) for 3 h at rt
  8. temperaturerefluxed in acetone (50 mL) for 1 h
  9. customThe product was isolated by filtration
  10. customdried in vacuo

Sources & evidence

ORD record
ord-3007e7f74e3f400ea9c92527d552a600
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Linked notes

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