Réaction #91798

Équation de réaction

5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride

propylisocyanate

DIPEA

→

1-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-propyl-urea

Rendement 29.0%

Solvants

THF

Conditions de réaction

Traitement

1. 1
   Températurethen cooled to rt
2. 2
   AutreThe solvent was removed in vacuo
3. 3
   workup.DISSOLUTIONthe residue was dissolved in EtOAc (100 mL)
4. 4
   LavageThe organic layer was washed with dil. aq. HCl (2×150 mL), water (2×150 mL)
5. 5
   Séchagedried (MgSO4)
6. 6
   Concentrationconcentrated
7. 7
   AutreThe crude product was purified by column chromatography (0-5% MeOH CH2Cl2, gradient over 15 min)
8. 8
   Concentrationconcentrated
9. 9
   Autretriturated in Et2OCH2Cl2 (50 mL) for 18 h
10. 10
    AutreThe product was isolated by filtration
11. 11
    Autredried in vacuo

Mode opératoire

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.

Source