Propyl isocyanate → HCID 57730517, compound

HRID 63520Notes

Reaction equation

HRID 63520 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].[CH2:23]([N:26]=[C:27]=[O:28])[CH2:24][CH3:25].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:27]([NH:26][CH2:23][CH2:24][CH3:25])=[O:28])[CH:5]=3)[C:9]2=[O:13])[CH2:19][CH2:18][C:17](=[O:20])[NH:16]1

Participants

5

Reactant 3

HCID 61033Propyl isocyanateHCID 81531DiisopropylethylamineHCID 670197065-(Aminomethyl)-2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione hydrochloride

Product 1

HCID 57730517HCID 57730517, compoundYield 29%

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 propylisocyanate (0.26 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 (2×150 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH CH2Cl2, gradient over 15 min). The product fractions were combined, concentrated and triturated in Et2OCH2Cl2 (50 mL) for 18 h. The product was isolated by filtration dried in vacuo to give 1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-propyl-urea as a white solid (0.24 g, 29% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 1.63 min (98.92%); mp: 166-168° C.; 1H NMR (DMSO-d6) δ 0.83 (t, J=7.3 Hz, 3H, CH3), 1.31-1.46 (m, 2H, CH2), 2.03-2.08 (m, 1H, CHH), 2.45-2.62 (m, 2H, CHH, CHH), 2.82-3.01 (m, 3H, CHH, CH2), 4.36 (d, J=5.9 Hz, 2H, CH2), 5.14 (dd, J=5.3, 12.6 Hz, 1H, CH), 6.10 (t, J=5.7 Hz, 1H, NH), 6.53 (t, J=6.0 Hz, 1H, NH), 7.71-7.89 (m, 3H, Ar), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 11.31, 22.01, 23.16, 30.94, 41.20, 42.74, 48.98, 121.54, 123.39, 129.51, 131.53, 133.07, 149.53, 158.03, 167.06, 167.24, 169.84, 172.74; LCMS: MH=373; Anal Calcd for C18H20N4O5+0.1H2O: C, 57.78; H, 5.44; N, 14.97. Found: C, 57.52; H, 5.37; N, 14.76.

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 (2×150 mL)
  5. dry with materialdried (MgSO4)
  6. concentrationconcentrated
  7. customThe crude product was purified by column chromatography (0-5% MeOH CH2Cl2, gradient over 15 min)
  8. concentrationconcentrated
  9. customtriturated in Et2OCH2Cl2 (50 mL) for 18 h
  10. customThe product was isolated by filtration
  11. customdried in vacuo

Sources & evidence

ORD record
ord-48b650012f5a4190bc0096b103ee120b
Source dataset
uspto-grants-2016_09
Patent number
US09447070B2

Reaction notes

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