Sodium Carbonate → Azd 7009

Temperature

75 °C

Aqueous sodium carbonate solution (1M, 53 mL) was added to a solution of [2-(9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl)-ethyl]-carbamic acid tert-butyl ester 2,4,6-trimethylbenzenesulfonic acid salt (50.0 g) in water (100 mL). Solid 4-[(2S)-oxiranylmethoxy]benzonitrile (19.1 g) was added and was rinsed into the reaction flask with water (50 mL). The reaction was heated to 75° C. for 3 hours and then left to stir at ambient temperature overnight. Toluene (350 mL) was added followed by aqueous sodium hydroxide (2M, 90 mL). The mixture was stirred for 5 minutes and then the phases were separated. The aqueous phase was discarded and the toluene phase washed with aqueous citric acid (10% w/v, 180 mL). The toluene phase was discarded. MIBC (240 mL) and aqueous sodium hydroxide (5M, 180 mL) were added to the citric acid phase. After mixing well the phases were separated and the aqueous discarded. The MIBC was washed with aqueous sodium chloride (20% w/v, 50 mL). The MIBC was concentrated under vacuum at <55° C. Solvent was collected (water 13 mL, MIBC 29 mL). The MIBC solution was cooled to ambient temperature and filtered, washing through with MIBC (50 mL). Solvent (152 mL) was distilled under vacuum at <66° C. and then distillation was stopped. IPE (360 mL) was added causing the temperature to fall from 65° C. to 37° C. After stirring for 15 minutes T fell by 2° C. to 35° C. and crystallisation started. The mixture was left to cool to ambient temperature overnight with stirring. The mixture was cooled to 5° C. and the product collected by filtration. The solid was washed on the filter with IPE (150 mL) and sucked dry. Further drying in vacuo at 55° C. gave the title compound as a white solid (41.2 g, 87%).

1. washwas rinsed into the reaction flask with water (50 mL)
2. waitleft
3. additionToluene (350 mL) was added
4. stirringThe mixture was stirred for 5 minutes
5. customthe phases were separated
6. washthe toluene phase washed with aqueous citric acid (10% w/v, 180 mL)
7. additionMIBC (240 mL) and aqueous sodium hydroxide (5M, 180 mL) were added to the citric acid phase
8. additionAfter mixing well the phases
9. customwere separated
10. washThe MIBC was washed with aqueous sodium chloride (20% w/v, 50 mL)
11. concentrationThe MIBC was concentrated under vacuum at <55° C
12. customSolvent was collected (water 13 mL, MIBC 29 mL)
13. temperatureThe MIBC solution was cooled to ambient temperature
14. filtrationfiltered
15. washwashing through with MIBC (50 mL)
16. distillationSolvent (152 mL) was distilled under vacuum at <66° C.
17. distillationdistillation
18. additionIPE (360 mL) was added
19. customto fall from 65° C. to 37° C
20. stirringAfter stirring for 15 minutes T
21. customfell by 2° C. to 35° C.
22. customcrystallisation
23. waitThe mixture was left
24. temperatureto cool to ambient temperature overnight
25. stirringwith stirring
26. temperatureThe mixture was cooled to 5° C.
27. filtrationthe product collected by filtration
28. washThe solid was washed on the
29. filtrationfilter with IPE (150 mL)
30. customsucked dry
31. customFurther drying in vacuo at 55° C.

ORD record

ord-8ea12aedc16244d0849e142a011157d7

Source dataset

uspto-grants-2008_01

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07314931B2