8-Methyl-8-azabicyclo(3.2.1)octan-3-ol → 8-Azabicyclo(3.2.1)octan-3-ol, 8-methyl-, 3-methanesulfonate

Temperatur

2.799999952316284 °C

Tropine (500 g, 3.54 mol) and triethylamine (590 mL, 430 g, 4.25 mol) were mixed in dichloromethane (10 L) and cooled to <−5° C. under a stream of nitrogen. A solution of methane sulphonyl chloride (329 mL, 487 g, 4.25 mol) in dichloromethane (2 L) was added over 4.33 h between −10.4 and −4.9° C. The mixture was stirred for 15 min, the cooling bath removed, and potassium carbonate solution (2.5 L, GB98596-043)) and deionised water (1.25 L) were added. The additions took 4 min and caused an exotherm raising the temperature to 2.8° C. The mixture was warmed to 15 to 20° C., filtered and the phases allowed to separate. The aqueous phase was extracted further with dichloromethane (2.5 L). The combined organic phases were heated to distil off dichloromethane at atmospheric pressure; 10 L were collected over 1.75 h reaching a base temp. of 42.8° C. and vapour temperature of 42° C. Hexane (7.5 L) was added and after allowing the mixture to cool (overnight) the mixture was filtered and the filtrate returned to a clean flask. The solution was reheated to distil at atmospheric pressure; 7.5 L were collected up to base and vapour temperatures of 60.5 and 62° C. respectively. The mixture was cooled to 0 to 5° C., stirred for 1 h, the product filtered off and washed with hexane (1.5 L). The product was dried under vacuum in a dessicator. Crystallisation from ethyl acetate/hexane or dichloromethane/hexane gave crystalline title compound which was then used in Step 3.

1. temperaturecooled to <−5° C. under a stream of nitrogen
2. customthe cooling bath removed
3. additionpotassium carbonate solution (2.5 L, GB98596-043)) and deionised water (1.25 L) were added
4. waitThe additions took 4 min
5. temperatureThe mixture was warmed to 15 to 20° C.
6. filtrationfiltered
7. customto separate
8. extractionThe aqueous phase was extracted further with dichloromethane (2.5 L)
9. temperatureThe combined organic phases were heated
10. customto distil off dichloromethane at atmospheric pressure
11. custom10 L were collected over 1.75 h
12. customof 42.8° C.
13. customvapour temperature of 42° C
14. additionHexane (7.5 L) was added
15. temperatureto cool (overnight) the mixture
16. filtrationwas filtered
17. customthe filtrate returned to a clean flask
18. customto distil at atmospheric pressure
19. custom7.5 L were collected up to base and vapour temperatures of 60.5 and 62° C. respectively
20. temperatureThe mixture was cooled to 0 to 5° C.
21. stirringstirred for 1 h
22. filtrationthe product filtered off
23. washwashed with hexane (1.5 L)
24. customThe product was dried under vacuum in a dessicator
25. customCrystallisation from ethyl acetate/hexane or dichloromethane/hexane

ORD-Eintrag

ord-6eb7279bb503469caee431d3e0178074

Quelldatensatz

uspto-grants-2012_06

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08207191B2