Ammonium Hydroxide → Lacosamide

Temperature

2.5 °C

A suspension of (R)-2-amino-N-benzyl-3-methoxypropanamide (2R,3R)-dihydroxysuccinate (358.34 g, 1.0 moL, 1.0 eq) in water (720 mL) was cooled to 0-5° C., and the pH adjusted to 10 to 10.5 by the addition of aqueous 28% NH4OH at below 10° C. The reaction mixture was extracted with dichloromethane (2×720 mL and 1×360 mL). The organic phase was charged with 4-(dimethylamino)pyridine (3.66 g, 0.03 moL), followed by acetic anhydride (112.3 g, 1.1 moL) slowly under constant stirring at 10-15° C. The reaction mixture was stirred at 10-15° C. for 30 to 60 min. The reaction mixture was heated to 20-25° C. and stirred for 1 hour. The reaction mixture was charged with water (1254 mL) and sodium bicarbonate (109.21 g, 1.3 moL) and stirred for 1 hour. The phases were allowed to separate and the aqueous phase was extracted with dichloromethane (2×360 mL) and concentrated to a volume of about 720 mL, charged with ethyl acetate (2.9 L) and concentrated to a volume of about 720 mL. This operation is repeated until the KF is less than 0.5%. The reaction mixture was charged with ethyl acetate (2.9 L) and heated to 60-65° C. Charcoal (3% by weight) was charged and the reaction mixture was heated to reflux and stirred for one hour. The reaction mixture was cooled to 60° C., filtered and the solid was washed with hot (60° C.) ethyl acetate (360 mL). The filtrate was cooled to 45-50° C. and stirred there for at least 4 hours and then cooled at 0-5° C. at a rate of 10° C./hour. The suspension was stirred for at least 3 hours to 0-5° C. and filtered. The resulting solid was washed with ethyl acetate (2×180 mL) and dried under vacuum at below 50° C. until a LOD of NMT 0.5% was obtained, to provide (R)-2-acetamido-N-benzyl-3-methoxypropanamide as a white solid (186.3 g, 75%, HPLC purity=99.8%, HPLC enantiomeric purity=100%).

1. extractionThe reaction mixture was extracted with dichloromethane (2×720 mL and 1×360 mL)
2. additionThe organic phase was charged with 4-(dimethylamino)pyridine (3.66 g, 0.03 moL)
3. stirringThe reaction mixture was stirred at 10-15° C. for 30 to 60 min
4. temperatureThe reaction mixture was heated to 20-25° C.
5. stirringstirred for 1 hour
6. additionThe reaction mixture was charged with water (1254 mL) and sodium bicarbonate (109.21 g, 1.3 moL)
7. stirringstirred for 1 hour
8. customto separate
9. extractionthe aqueous phase was extracted with dichloromethane (2×360 mL)
10. concentrationconcentrated to a volume of about 720 mL
11. additioncharged with ethyl acetate (2.9 L)
12. concentrationconcentrated to a volume of about 720 mL
13. additionThe reaction mixture was charged with ethyl acetate (2.9 L)
14. temperatureheated to 60-65° C
15. additionCharcoal (3% by weight) was charged
16. temperaturethe reaction mixture was heated
17. temperatureto reflux
18. stirringstirred for one hour
19. temperatureThe reaction mixture was cooled to 60° C.
20. filtrationfiltered
21. washthe solid was washed with hot (60° C.) ethyl acetate (360 mL)
22. temperatureThe filtrate was cooled to 45-50° C.
23. stirringstirred there for at least 4 hours
24. temperaturecooled at 0-5° C. at a rate of 10° C./hour
25. stirringThe suspension was stirred for at least 3 hours to 0-5° C.
26. filtrationfiltered
27. washThe resulting solid was washed with ethyl acetate (2×180 mL)
28. customdried under vacuum at below 50° C. until a LOD of NMT 0.5%
29. customwas obtained

ORD record

ord-36404e46ffd34affad255614c9d8e06a

Source dataset

uspto-grants-2015_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09133101B2