Triethylamine → (R)-N-(2-(3-(3-methoxyphenyl)-3-phenyl-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester

Temperature

5 °C

A mixture of 2-(3-(3-methoxyphenyl)-3-phenyl-2-propen-1-yloxy)ethanol (52 g, 0.18 mol) and triethylamine (46 g, 0.46 mol) in dry toluene (200 ml) kept under a nitrogen atmosphere was cooled below 10 C and a solution of methanesulphonyl chloride (41.7 g, 0.36 mol) in dry toluene (200 ml) was added dropwise keeping the temperature below 10° C. When addition was complete the reaction mixture was stirred for 1 h at 5° C. and then for 0.5 h at approximately 15° C. Water was added (250 ml) and the mixture was stirred at room temperature for 0.5 h. The separated organic phase was washed with a 5% sodium bicarbonate solution, brine and dried (Na2SO4). The mixture was filtered and the filtrate was reduced to approximately 500 ml in vacuo. Ethyl (R)-3-piperidinecarboxylate (57.2 g, 0.36 mol) and potassium carbonate (62.8 g, 0.46 mol) were added and the mixture was heated at reflux temperature for 48 h. The cooled reaction mixture was filtered and the solid was washed with toluene and ethyl acetate successively. The combined organic filtrates was evaporated in vacuo to an oily residue which was dissolved into ethyl acetate (250 ml). Water (150 ml) was added and pH was adjusted to 4 with 10% citric acid solution. The phases were separated and the organic phase was washed with water (150 ml). The combined aqueous phases was extracted with ethyl acetate (150 ml) and then discarded. The combined organic phases was washed with a 5% sodium bicarbonate solution, brine, dried (Na2SO4) and the solvent evaporated in vacuo. The residue was dissolved in toluene (150 ml) and a solution of tartaric acid (42 g) in water (120 ml) was added. The phases were separated and the organic phase was extracted with another solution of tartaric acid (12 g) in water (50 ml). The combined aqueous extracts was extracted with ethyl acetate (200 ml) which was discarded. Ethyl acetate (200 ml) was added to the acidic aqueous phase which was made alkaline with excess of a sodium bicarbonate solution. The separated organic phase was washed with brine and dried (Na2SO4). The solvent was evaporated in vacuo to give 46.6 g (60%) of (R)-N-(2-(3-(3-methoxyphenyl)-3-phenyl-2-propen1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.

1. temperaturewas cooled below 10 C
2. customthe temperature below 10° C
3. additionWhen addition
4. waitfor 0.5 h at approximately 15° C
5. stirringthe mixture was stirred at room temperature for 0.5 h
6. washThe separated organic phase was washed with a 5% sodium bicarbonate solution, brine
7. dry with materialdried (Na2SO4)
8. filtrationThe mixture was filtered
9. temperaturethe mixture was heated
10. temperatureat reflux temperature for 48 h
11. customThe cooled reaction mixture
12. filtrationwas filtered
13. washthe solid was washed with toluene and ethyl acetate successively
14. customThe combined organic filtrates was evaporated in vacuo to an oily residue which
15. dissolutionwas dissolved into ethyl acetate (250 ml)
16. additionWater (150 ml) was added
17. customThe phases were separated
18. washthe organic phase was washed with water (150 ml)
19. extractionThe combined aqueous phases was extracted with ethyl acetate (150 ml)
20. washThe combined organic phases was washed with a 5% sodium bicarbonate solution, brine
21. dry with materialdried (Na2SO4)
22. customthe solvent evaporated in vacuo
23. dissolutionThe residue was dissolved in toluene (150 ml)
24. additiona solution of tartaric acid (42 g) in water (120 ml) was added
25. customThe phases were separated
26. extractionthe organic phase was extracted with another solution of tartaric acid (12 g) in water (50 ml)
27. extractionThe combined aqueous extracts was extracted with ethyl acetate (200 ml) which
28. additionEthyl acetate (200 ml) was added to the acidic aqueous phase which
29. washThe separated organic phase was washed with brine
30. dry with materialdried (Na2SO4)
31. customThe solvent was evaporated in vacuo

ORD record

ord-27e7ce89ddc1458eaf4cd4f175959e68

Source dataset

uspto-grants-2001_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06174898B1