Dimethyl Sulfoxide → N,N'-Dicyclohexylurea

Temperature

23 °C

In a 200 mL round-bottomed flask, ethyl 4-(4-hydroxypiperidin-1-yl)benzoate 390A (0.878 g, 3.52 mmol), DCC (2.202 g, 10.67 mmol), and DMSO (5.0 mL, 70.5 mmol) were taken up in benzene (9.52 mL) to give a colorless solution. The mixture was then cooled in an ice/brine bath. Pyridine (0.26 mL, 3.21 mmol) and TFA (0.12 mL, 1.558 mmol) were added sequentially and in a drop-wise manner, while maintaining the reaction mixture at <5° C. Once the additions were complete, the reaction was allowed to stir at the cooler temperature and then slowly warmed to 23° C. over a 24 hr period. The reaction was diluted with EtOAc (50 mL) and stirred at 23° C. overnight. The undissolved white solid (dicyclohexylurea) was removed by filtration and rinsed with additional EtOAc. The organic layer was washed with brine, dried with MgSO4, filtered, and concentrated to clear oil. The oil was triturated with hexanes and gently stirred overnight. A white solid was collected by filtration and dried in vacuo. Re-crystallization in CCl4 gave a fine solid (dicyclohexylurea impurity) that was removed by vacuum filtration. The CCl4 filtrate was concentrated to yellow oil and dried in vacuo to afford the title compound as a yellow solid (0.575 g, 66.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.29 (t, J=7.07 Hz, 3H) 2.45 (t, J=6.06 Hz, 4H) 3.74 (t, J=6.06 Hz, 4H) 4.24 (q, J=7.07 Hz, 2H) 6.97-7.09 (m, 2H) 7.75-7.86 (m, 2H). ESI-MS: m/z 248.2 (M+H)+.

1. customto give a colorless solution
2. temperatureThe mixture was then cooled in an ice/brine bath
3. temperaturewhile maintaining the reaction mixture at <5° C
4. stirringstirred at 23° C. overnight
5. customThe undissolved white solid (dicyclohexylurea) was removed by filtration
6. washrinsed with additional EtOAc
7. washThe organic layer was washed with brine
8. dry with materialdried with MgSO4
9. filtrationfiltered
10. concentrationconcentrated to clear oil
11. customThe oil was triturated with hexanes and gently stirred overnight
12. filtrationA white solid was collected by filtration
13. customdried in vacuo

ORD record

ord-38b415c8f2e04bec9d0e3a06b6f8bb78

Source dataset

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08669249B2