Chloroacetyl chloride → Benzyl 4-(3-oxo-4-morpholinyl)piperidin-1-carboxylate

Temperature

0 °C

Benzyl 4-[(2-hydroxyethyl)amino]piperidin-1-carboxylate (7.5 g) obtained in Example 7a) and triethylamine (4.1 mL) were dissolved in THF (70 mL), chloroacetyl chloride (2.2 mL) was added dropwise thereto with cooling at 0° C., and the mixture was stirred at 0° C. for 2 hours. The solvent was distilled off under reduced pressure, the residue was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous citric acid solution and a saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in DMF (60 mL), the solution was cooled to 0° C., and then sodium hydride (60% in oil; 1.2 g) was added to the reaction mixture. The mixture was stirred at 0° C. for one hour, at room temperature for one hour and at 80° C. for 15 hours. The reaction mixture was concentrated under reduced pressure, water was added thereto, the solution was acidified with 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline solution, and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1 to ethyl acetate) to obtain the title compound (3.8 g, 44%) as a colorless oil.

1. distillationThe solvent was distilled off under reduced pressure
2. additionthe residue was diluted with water
3. extractionthe mixture was extracted with ethyl acetate
4. washThe extract was washed with a 5% aqueous citric acid solution
5. dry with materiala saturated saline solution, and dried over anhydrous sodium sulfate
6. distillationthe solvent was distilled off under reduced pressure
7. dissolutionThe residue was dissolved in DMF (60 mL)
8. temperaturethe solution was cooled to 0° C.
9. additionsodium hydride (60% in oil; 1.2 g) was added to the reaction mixture
10. stirringThe mixture was stirred at 0° C. for one hour, at room temperature for one hour and at 80° C. for 15 hours
11. concentrationThe reaction mixture was concentrated under reduced pressure, water
12. additionwas added
13. extractionthe mixture was extracted with ethyl acetate
14. washThe extract was washed with water and saturated saline solution
15. dry with materialdried over anhydrous sodium sulfate
16. distillationthe solvent was distilled off under reduced pressure
17. customThe residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1 to ethyl acetate)

ORD record

ord-7b0af3fb11b44308bfdb629418017cc1

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08697865B2