Benzylethanolamine → (R)-2-hydroxymethylmorpholine p-nitrobenzoate

Temperature

10 °C

To a mixture of N-benzylethanolamine (302.4 g, 2.0 mol), 2-propanol (185 ml) and water (185 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (185.0 g, 2.0 mol, 99% ee). After reaction at 15 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 104 g, 2.6 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 (555 ml) and, after partitioning, the organic layer was concentrated under reduced pressure to give a mixture of N-benzyl-2-hydroxymethylmorpholine, N-benzyl-1,4-oxazepane and other byproducts (410.4 g, N-benzyl-2-hydroxymethylmorpholine:N-benzyl-1,4-oxazepane compound=75.2:24.8). To this mixture were added methanol (830 ml) and palladium carbon (40.0 g when dry), and the mixture was reacted under a hydrogen stream at 25° C. for 15 hr. Palladium carbon was filtered off, methanol was evaporated under reduced pressure to give a mixture of 2-hydroxymethylmorpholine and a 1,4-oxazepane compound (265.7 g, 2-hydroxymethylmorpholine:1,4-oxazepane compound=75.8:24.2). To the mixture (20.0 g) were added methanol (100 ml) and p-nitrobenzoic acid (25.2 g, 0.151 mol) and the mixture was stirred for 30 min. Then, methanol was evaporated under reduced pressure. To the residue was added 2-propanol (50 ml) and the mixture was subjected twice to azeotropic distillation with dehydrating. To the residue after azeotropic distillation with dehydrating was added ethyl acetate (100 ml) at 40° C., and the mixture was cooled to 10° C. 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 (25 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine p-nitrobenzoate (17.7 g) (yield from (S)-epichlorohydrin 41.3%). The obtained (R)-2-hydroxymethylmorpholine p-nitrobenzoate was analyzed by HPLC to find an optical purity of 99% ee.

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 (555 ml)
6. customafter partitioning
7. concentrationthe organic layer was concentrated under reduced pressure
8. customto give
9. customthe mixture was reacted under a hydrogen stream at 25° C. for 15 hr
10. filtrationPalladium carbon was filtered off
11. custommethanol was evaporated under reduced pressure
12. customto give
13. customThen, methanol was evaporated under reduced pressure
14. additionTo the residue was added 2-propanol (50 ml)
15. distillationthe mixture was subjected twice to azeotropic distillation with dehydrating
16. distillationTo the residue after azeotropic distillation with dehydrating
17. additionwas added ethyl acetate (100 ml) at 40° C.
18. customAfter crystallization
19. temperaturethe mixture was cooled to 0° C.
20. stirringstirred for 1 hr
21. filtrationThe crystals were collected by filtration
22. washwashed
23. customdried (1 mmHg, 40° C.)

ORD record

ord-e06117f8b4bd4563a576b8c749873d86

Source dataset

uspto-grants-2014_02

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08648190B2