Trifluoroacetic acid → HCID 67257610, compound

A mixture of (3R,4R)-3-(3-Ethoxy-4-methoxy-phenyl)-N-[(1R)-1-(4-methoxy-phenyl)-ethyl]-tetrahydro-2H-thiopyran-4-amine hydrochloride (1.0 g; compound C14) and trifluoroacetic acid (2 ml) is stirred at reflux temperature for 30 min yielding a dark red solution. Cooled to RT the solution is evaporated, the dark viscous residue is dissolved in a mixture of diethylether (5 ml) and water (5 ml) and the pH of the solution is increased up to 10 by adding some drops of a 40% aqueous solution of sodium hydroxide. The mixture is extracted with diethylether, the organic phase is washed with a saturated aqueous solution of NaHCO3 and then extracted two times with a 20% aqueous solution of citric acid. The pH of the collected aqueous acid solutions of about 2.4 is increased up to 10 by adding a 40% NaOH solution and the basic mixture is extracted with diethylether. The organic phase is washed two times with water, dried over sodium sulfate and then evaporated to give an oily residue. This is dissolved in 2-propanol (10 ml) and to the stirred solution a 5-6 M solution of hydrogen chloride in 2-propanol (1 ml) is added dropwise at RT inducing a spontaneous crystallization. The slurry is concentrated to about half of the volume and stirred for 15 h at RT. The crystals are filtered off, washed with 2-propanol (2 ml), dried in vacuo at 40° C. to give the title compound. M.p. 233° C. (decomposition).

1. temperatureat reflux temperature for 30 min
2. customyielding a dark red solution
3. customis evaporated
4. dissolutionthe dark viscous residue is dissolved in a mixture of diethylether (5 ml) and water (5 ml)
5. temperaturethe pH of the solution is increased up to 10
6. additionby adding some drops of a 40% aqueous solution of sodium hydroxide
7. extractionThe mixture is extracted with diethylether
8. washthe organic phase is washed with a saturated aqueous solution of NaHCO3
9. extractionextracted two times with a 20% aqueous solution of citric acid
10. temperatureThe pH of the collected aqueous acid solutions of about 2.4 is increased up to 10
11. additionby adding a 40% NaOH solution
12. extractionthe basic mixture is extracted with diethylether
13. washThe organic phase is washed two times with water
14. dry with materialdried over sodium sulfate
15. customevaporated
16. customto give an oily residue
17. additionis added dropwise at RT
18. customa spontaneous crystallization
19. concentrationThe slurry is concentrated to about half of the volume
20. stirringstirred for 15 h at RT
21. filtrationThe crystals are filtered off
22. washwashed with 2-propanol (2 ml)
23. customdried in vacuo at 40° C.

ORD record

ord-39da8ffcde134ee195b38a2064f2211c

Source dataset

uspto-grants-2015_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09018175B2