Reacción #91763

Ecuación de reacción

HCl

3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate

4-fluorophenylisocyanate

triethylamine

→

1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-fluoro-phenyl)-urea

Rendimiento 69.0%

Disolventes

acetonitrile

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroThe product was isolated by filtration
2. 2
   Lavadowashed with 1N aq. HCl (20 mL), acetonitrile (20 mL)
3. 3
   Otrodried overnight in vacuo

Procedimiento

To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.50 g, 1.80 mmol) and 4-fluorophenylisocyanate (0.25 g, 1.80 mmol) in acetonitrile (20 mL), was added triethylamine (0.51 mL, 3.60 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-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-(4-fluoro-phenyl)-urea as an off-white solid (0.51 g, 68% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 2.13 min (98.98%); mp: 262-264° C.; 1H NMR (DMSO-d6) δ 1.92-2.13 (m, 1H), 2.29-2.47 (m, 1H), 2.54-2.69 (m, 1H), 2.82-3.00 (m, 1H), 4.31 (d, J=17.4 Hz, 1H), 4.37-4.55 (m, 3H), 5.11 (dd, J=13.2, 5.1 Hz, 1H), 6.73 (t, J=5.9 Hz, 1H), 7.06 (t, J=8.9 Hz, 2H), 7.37-7.48 (m, 3H), 7.52 (s, 1H), 7.70 (d, J=7.9 Hz, 1H), 8.67 (s, 1H), 10.99 (s, 1H); 13C NMR (DMSO-d6) δ 22.5, 31.2, 42.8, 47.1, 51.6, 115.1 (d, J=22.0 Hz,), 119.4 (d, J=6.6 Hz), 121.9, 122.9, 126.9, 130.3, 136.8, 142.4, 144.9, 155.3 (d, J=4.4 Hz), 158.5, 168.0, 171.0, 172.9; LCMS: MH=411; Anal Calcd for C21H19FN4O4: C, 61.46; H, 4.67; N, 13.65. Found: C, 61.44; H, 4.53; N, 13.46.

Fuente