Ethanol → L-Tartaric acid

Temperature

65 °C

The vessel was charged with (R)-methyl 6,8-difluorochroman-3-ylcarbamate (1.0 wt) and methanol (12.66 vol.), the content temperature was adjusted to 65° C. with stirring. A solution of potassium hydroxide (2.76 wt) in water (4.15 vol.) was transferred to the vessel while maintaining 65° C. and the mixture was stirred for 24 hours. The content was adjusted to 35° C., water (5.6 vol.) was charged and the vessel was set up for atmospheric distillation. The content was distilled off at 70° C. internal temperature and 80° C. in doubled jacket until a residual volume reached 8-10 vol. The content adjusted to 30° C., dichloromethane (6.5 vol.) was charged while cooling the content temperature to 20/25° C. Stirred for 15 min, settled for 15 min, the lower organic phase was separated. Dichloromethane (3.0 vol.) was charged, the mixture stirred for 15 min, settled for 15 min, the lower organic phase was separated. Combined organic phase was washed twice with brine and transferred to a vessel set up for vacuum distillation. The vessel was charged with ethanol (20.0 vol.), 4.3 vol. of distillate was distilled off. The vessel was set up for atmospheric distillation; content of the vessel was distilled off at 65/75° C. internal temperature and 90° C. in doubled jacket until vessel volume was 20.0 vol. and then distilled at constant volume by the addition of ethanol until refractive index showed no dichloromethane was present. A solution of L-tartaric acid (0.647 wt, 1.108 eq) in water (3.0 vol.) was prepared and adjusted to 70° C. The solution was added slowly to previously obtained ethanolic solution at 75° C. The mixture stirred at 75° C. for 5 hours then cooled to 0° C. at 10° C./hour. The content was stirred at 0° C. for 12 hours, ethanol (2.5 vol.) was charged and the temperature was adjusted to 0° C. The content of the vessel was transfer to a filter. The filter cake was washed with ethanol (5.0 vol. and 2.5 vol.) and dried under vacuum at 45° C. Yield of (R)-6,8-difluorochroman-3-amine L-Tartrate salt 90% of theory.

1. customwas adjusted to 65° C.
2. stirringthe mixture was stirred for 24 hours
3. customwas adjusted to 35° C.
4. distillationthe vessel was set up for atmospheric distillation
5. distillationThe content was distilled off at 70° C. internal temperature and 80° C. in doubled jacket until a residual volume
6. customadjusted to 30° C.
7. additiondichloromethane (6.5 vol.) was charged
8. temperaturewhile cooling the content temperature to 20/25° C
9. stirringStirred for 15 min
10. customthe lower organic phase was separated
11. additionDichloromethane (3.0 vol.) was charged
12. stirringthe mixture stirred for 15 min
13. waitsettled for 15 min
14. customthe lower organic phase was separated
15. washCombined organic phase was washed twice with brine
16. customtransferred to a vessel
17. distillationset up for vacuum distillation
18. additionThe vessel was charged with ethanol (20.0 vol.), 4.3 vol. of distillate
19. distillationwas distilled off
20. distillationThe vessel was set up for atmospheric distillation
21. distillationcontent of the vessel was distilled off at 65/75° C. internal temperature and 90° C. in doubled jacket until vessel volume
22. distillationdistilled at constant volume by the addition of ethanol until refractive index
23. customadjusted to 70° C
24. additionThe solution was added slowly to previously obtained ethanolic solution at 75° C
25. stirringThe mixture stirred at 75° C. for 5 hours
26. temperaturethen cooled to 0° C. at 10° C./hour
27. stirringThe content was stirred at 0° C. for 12 hours
28. customwas adjusted to 0° C
29. washThe filter cake was washed with ethanol (5.0 vol. and 2.5 vol.)
30. customdried under vacuum at 45° C

ORD record

ord-7aa88ef2d8594ad1a6d27100803ec72f

Source dataset

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09346751B2