Methanesulfonic Acid → (1S,2S)-1-(4-hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol mesylate trihydrate

Temperature

52.5 °C

Five percent palladium on carbon catalyst (0.75 g, 50% water-wet), (1S,2S)-1-(4-benzyloxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-1-propanol (5.0 g, 12.0 mmol), ethanol (62.5 mL), and methanesulfonic acid (1.15 g, 12.0 mmol) were combined in a Parr pressure reactor under a nitrogen atmosphere. The nitrogen atmosphere was exchanged for hydrogen (3×25 psi) and then the hydrogen pressure was increased to 50 to 55 psi. The mixture was heated and stirred at 50 to 55° C. for 5 hours when HPLC indicated that the reaction was complete. The hydrogen gas was slowly vented, the reactor flushed with nitrogen, and then the warm (50° C.) reaction mixture was filtered through Celite. The Celite filter cake was washed with ethanol (5 mL). The combined wash and filtrate were concentrated in vacuo to 10 mL. Water (17.5 mL) was added and the solution was concentrated at atmospheric pressure until a distillate temperature of 76° C. was obtained. The clear solution was slowly cooled over 1 hour to 15 to 20° C. and then cooled further to 0 to 5° C. After granulating for 1 hour at 0 to 5° C., the thick slurry was filtered and the cake washed with cold water (5° C., 2.5 mL). The solid was dried for 18 hours at 20 to 25° C. to give 4.71 g of the title compound for an 83% yield. The product was identical to an authentic sample of the title compound. If low-pyrogen water and pyrogen-free conditions are employed in the above procedure, isolated title compound is suitable for parenteral applications.

1. temperatureThe mixture was heated
2. customthe reactor flushed with nitrogen
3. temperaturethe warm
4. custom(50° C.) reaction mixture
5. filtrationwas filtered through Celite
6. filtrationThe Celite filter cake
7. washwas washed with ethanol (5 mL)
8. washThe combined wash
9. concentrationfiltrate were concentrated in vacuo to 10 mL
10. additionWater (17.5 mL) was added
11. concentrationthe solution was concentrated at atmospheric pressure until a distillate temperature of 76° C.
12. customwas obtained
13. temperatureThe clear solution was slowly cooled over 1 hour to 15 to 20° C.
14. temperaturecooled further to 0 to 5° C
15. waitAfter granulating for 1 hour at 0 to 5° C.
16. filtrationthe thick slurry was filtered
17. washthe cake washed with cold water (5° C., 2.5 mL)
18. customThe solid was dried for 18 hours at 20 to 25° C.

ORD record

ord-913d3ea41d2242af8f49ab75a25fbe30

Source dataset

uspto-grants-2003_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06570018B2