تفاعل #328482

معادلة التفاعل

N-benzylethanolamine

trifluoroacetic acid

(S)-epichlorohydrin

2-hydroxymethylmorpholine

1,4-oxazepane

NaOH

→

(R)-2-hydroxymethylmorpholine trifluoroacetate

المردود 42.4%

المذيبات

water

2-propanol

methanol

ظروف التفاعل

المعالجة

1. 1
   أخرىAfter reaction at 15 to 25° C. for 7 hr
2. 2
   أخرىAfter reaction at 25° C. for 20 hr
3. 3
   تركيزthe reaction mixture was concentrated under reduced pressure
4. 4
   أخرىto evaporate 2-propanol
5. 5
   workup.ADDITIONTo the residue was added toluene (75 ml)
6. 6
   أخرىafter partitioning
7. 7
   تركيزthe organic layer was concentrated under reduced pressure
8. 8
   workup.ADDITIONTo the obtained residue (53.9 g) were added methanol (161.8 ml) and palladium carbon (18.9 g when dry)
9. 9
   أخرىthe mixture was reacted under a hydrogen stream at 40° C. for 30 hr
10. 10
    ترشيحPalladium carbon was filtered off
11. 11
    تركيزthe filtrate was concentrated under reduced pressure
12. 12
    workup.DISTILLATIONthe residue was distilled (0.5 mmHg, 115 to 135° C.)
13. 13
    أخرىto give
14. 14
    workup.ADDITIONwas added dropwise at 0 to 25° C
15. 15
    تركيزthe mixture was concentrated under reduced pressure
16. 16
    workup.ADDITIONTo the residue was added ethyl acetate (108 ml) at 40° C.
17. 17
    درجة الحرارةthe mixture was cooled to 20° C
18. 18
    workup.ADDITIONSeed crystal was added
19. 19
    أخرىafter crystallization
20. 20
    درجة الحرارةthe mixture was cooled to 0° C.
21. 21
    workup.STIRRINGstirred for 1 hr
22. 22
    ترشيحThe crystals were collected by filtration
23. 23
    غسيلwashed
24. 24
    أخرىdried (1 mmHg, 40° C.)

الإجراء التجريبي

To a mixture of N-benzylethanolamine (40.9 g, 0.270 mol), 2-propanol (25 ml) and water (25 ml) was added dropwise at 15 to 25° C. (S)-epichlorohydrin (25.0 g, 0.270 mol, 99% ee). After reaction at 15 to 25° C. for 7 hr, aqueous 24% NaOH solution (NET 14.05 g, 0.351 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 (75 ml) and, after partitioning, the organic layer was concentrated under reduced pressure. To the obtained residue (53.9 g) were added methanol (161.8 ml) and palladium carbon (18.9 g when dry), and the mixture was reacted under a hydrogen stream at 40° C. for 30 hr. Palladium carbon was filtered off, and the filtrate was concentrated under reduced pressure and the residue was distilled (0.5 mmHg, 115 to 135° C.) to give a mixture of 2-hydroxymethylmorpholine and 1,4-oxazepane compound (21.6 g, 2-hydroxymethylmorpholine: 1,4-oxazepane compound=79.0:21.0). To this mixture was added methanol (22 ml), and trifluoroacetic acid (22.1 g, 0.194 mol) was added dropwise at 0 to 25° C. After stirring at 25° C. for 1 hr, the mixture was concentrated under reduced pressure. To the residue was added ethyl acetate (108 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 (22 ml) and dried (1 mmHg, 40° C.) to give (R)-2-hydroxymethylmorpholine trifluoroacetate (26.49 g) (yield from (S)-epichlorohydrin 42.4%). The obtained (R)-2-hydroxymethylmorpholine trifluoroacetate was analyzed by HPLC to find an optical purity of 99% ee.

المصدر