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

Temperature

20 °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 10 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 (76.3 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=76.5:23.5). To this mixture were added methanol (153 ml), trifluoroacetic acid (44.1 g, 0.387 mol) and palladium carbon (15.3 g when dry), and the mixture was reacted under a 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 (76 ml). To the residue after azeotropic distillation with dehydrating was added ethyl acetate (382 ml) at 40° C., and the mixture was cooled to 20° C. Seed crystal was added and, after crystallization, the mixture was cooled to 0° C. and stirred for 1 hr. The crystals were collected by filtration, washed withed twice with ethyl acetate (76 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (50.22 g) (yield from (S)-epichlorohydrin: 40.2%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee.

1. customAfter reaction at 10 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 a 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 (382 ml) at 40° C.
16. additionSeed crystal was added
17. customafter crystallization
18. temperaturethe mixture was cooled to 0° C.
19. filtrationThe crystals were collected by filtration
20. washwashed
21. customdried (1 mmHg, 40° C.)

ORD record

ord-aae43acaf5234a91a2c693cebfc9c68a

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08648190B2