Benzylethanolamine → (R)-Morpholin-2-ylmethanol 2,2,2-trifluoroacetate salt

Temperatur

10 °C

To a mixture of N-benzylethanolamine (81.7 g, 0.540 mol), 2-propanol (50 ml) and water (50 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (50.0 g, 0.540 mol, 99% ee). After reaction at 15 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 28.1 g, 0.703 mol) was added at 5 to 10° C. After reaction at 25° C. for 20 hr, the reaction mixture was concentrated under reduced pressure to evaporate 2-propanol. To the residue was added toluene (150 ml) and, after partitioning, the organic layer was concentrated under reduced pressure. The residue was distilled (0.5 mmHg, 150 to 180° C.) to give a mixture of N-benzyl-2-hydroxymethylmorpholine and N-benzyl-1,4-oxazepane compound (about 70 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=76:24). To this mixture (50.0 g) were added methanol (150 ml), trifluoroacetic acid (27.5 g, 0.241 mol) and palladium carbon (10.0 g when dry), and the mixture was reacted under hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected twice to azeotropic distillation with dehydrating with 2-propanol (50 ml). To the residue after azeotropic distillation with dehydrating was added ethyl acetate (150 ml) at 40° C., and the mixture was cooled to 10° C. After crystallization, the mixture was further stirred for 1 hr. The crystal was collected by filtration, washed twice with ethyl acetate (76 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate as crystals (about 20 to 25 g). The obtained crystals were used as a seed crystal in the following Examples.

1. customAfter reaction at 15 to 25° C. for 7 hr
2. customAfter reaction at 25° C. for 20 hr
3. concentrationthe reaction mixture was concentrated under reduced pressure
4. customto evaporate 2-propanol
5. additionTo the residue was added toluene (150 ml)
6. customafter partitioning
7. concentrationthe organic layer was concentrated under reduced pressure
8. distillationThe residue was distilled (0.5 mmHg, 150 to 180° C.)
9. customto give
10. customthe mixture was reacted under hydrogen stream at 25° C. for 15 hr
11. filtrationPalladium carbon was filtered off
12. concentrationthe filtrate was concentrated under reduced pressure
13. distillationThe residue was subjected twice to azeotropic distillation
14. distillationTo the residue after azeotropic distillation with dehydrating
15. additionwas added ethyl acetate (150 ml) at 40° C.
16. customAfter crystallization
17. filtrationThe crystal was collected by filtration
18. washwashed twice with ethyl acetate (76 ml)
19. customdried (1 mmHg, 40° C.)

ORD-Eintrag

ord-7256205d7cd34e6ba5201d486c996e20

Quelldatensatz

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08648190B2