Synthesis
The general procedure for the synthesis of 3-morpholino benzonitrile from 3-hydroxybenzonitrile and morpholine is as follows:
1. 3-hydroxybenzonitrile (1.77 g, 14.9 mmol) and triethylamine (6.30 ml, 45.2 mmol) were dissolved in dichloromethane (75 ml) under argon protection, cooled to -10 °C and stirred.
2. A solution of trifluoroacetic anhydride (3.79 ml, 22.5 mmol) dissolved in dichloromethane (15 ml) was added slowly and dropwise, and the reaction mixture was continued to be stirred at -10 °C for 1.5 hours.
3. After completion of the reaction, the solvent was removed by distillation under reduced pressure. To the concentrated residue, aqueous sodium bicarbonate solution was added and extracted with dichloromethane.
4. The organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The filtrate was concentrated by filtration to remove the desiccant.
5. The concentrated residue was purified using silica gel column chromatography (eluent: chloroform/methanol=100:1) to obtain an oily intermediate.
6. The above oily intermediate was dissolved in acetonitrile (40 ml), morpholine (33.0 ml, 378 mmol) was added and stirred at reflux for 3 days.
7. After completion of the reaction, the solvent and unreacted morpholine were removed by distillation under reduced pressure. Water was added to the concentrated residue and extracted with chloroform.
8. The organic layer was dried with anhydrous sodium sulfate, filtered and the filtrate was concentrated.
9. Finally, the concentrated residue was purified using silica gel column chromatography (eluent: chloroform/hexane=1:2) to afford the target product 3-morpholino benzonitrile as an oil (0.74 g, 26% yield).
The product was characterized by 1H-NMR (CDCl3): δ (ppm) 3.15-3.19 (4H, m), 3.83-3.88 (4H, m), 7.09-7.18 (3H, m), 7.34 (1H, dd, J=7.6Hz, 7.6Hz).
References
[1] Patent: US2002/193389, 2002, A1
[2] Patent: US6127541, 2000, A
