Citric Acid → HCID 53789286, compound

Temperature

10 °C

A mixture of 2-(3,3-bis(4-(trifluoromethyl)phenyl)-2-propen-1-yloxy)ethanol (25.0 g, 64 mmol) and triethylamine (16.2 g, 0.16 mol) in dry toluene (100 ml) kept under a nitrogen atmosphere was cooled to 10° C. and a solution of methanesulphonyl chloride (14.6 g, 0.13 mol) in dry toluene (100 ml) was added dropwise keeping the temperature below 10° C. When addition was complete the reaction mixture was stirred for 45 minutes at 5° C. and then for 30 minutes at 15° C. Water was added (100 ml) and the mixture was stirred at room temperature for 15 minutes. The phases were separated and the aqueous phase was extracted with two small portions of toluene. The combined organic extracts was washed with brine, dried over sodium sulphate and filtered. To the filtrate was added ethyl (R)-3-piperidine carboxylate (20.1 g, 0.13 mol) and potassium carbonate (22.1 g, 0.16 mol) and the mixture was heated at reflux temperature for 2 days and then stirred at room temperature for 2 days. The reaction mixture was filtered and the solvent evaporated in vacuo to give a residue which was dissolved into a mixture of ethyl acetate (125 ml) and water (75 ml). A 10% citric acid solution was added until pH 4 and the phases were separated. The organic phase was evaporated in vacuo to give a residue which was dissolved in toluene (150 ml). A mixture of a 34% citric acid solution (56 ml) and water (150 ml) was added and the phases were separated. The organic phase was extracted once more with a mixture of a 34% citric acid solution (20 ml) and water (50 ml). To the combined aqueous extracts was added ethyl acetate (150 ml) and excess of a 5% aqueous sodium bicarbonate solution. The phases were separated, the organic phase was dried over sodium sulphate and the solvent evaporated in vacuo to give 21.7 g (64%) of (R)-N-(2-(3,3-bis-(4-(trifluoromethyl)phenyl)-2-propen-1-yloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil. TLC: rf=0.60 (SiO2 ; dichloromethane/methanol/acetic acid=20:2:1).

1. customthe temperature below 10° C
2. additionWhen addition
3. waitfor 30 minutes at 15° C
4. stirringthe mixture was stirred at room temperature for 15 minutes
5. customThe phases were separated
6. extractionthe aqueous phase was extracted with two small portions of toluene
7. washThe combined organic extracts was washed with brine
8. dry with materialdried over sodium sulphate
9. filtrationfiltered
10. temperaturethe mixture was heated
11. temperatureat reflux temperature for 2 days
12. stirringstirred at room temperature for 2 days
13. filtrationThe reaction mixture was filtered
14. customthe solvent evaporated in vacuo
15. customto give a residue which
16. customthe phases were separated
17. customThe organic phase was evaporated in vacuo
18. customto give a residue which
19. additionwas added
20. customthe phases were separated
21. extractionThe organic phase was extracted once more with a mixture of a 34% citric acid solution (20 ml) and water (50 ml)
22. additionTo the combined aqueous extracts was added ethyl acetate (150 ml)
23. customThe phases were separated
24. dry with materialthe organic phase was dried over sodium sulphate
25. customthe solvent evaporated in vacuo

ORD record

ord-89dfb690288b48d98b960e48f9e8c419

Source dataset

uspto-grants-1993_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US05198451