反应详情

温度

35 °C

A mixture of (R)-tert-butyl 2-(hydroxymethyl)morpholine-4-carboxylate (750 g, 3.45 mol) was stirred with triethylamine (577 mL, 4.14 mol) and toluene (6000 mL) at 3° C. under N2. Methanesulfonyl chloride (321 mL, 4.14 mol) was added over 2.5 hr, keeping the temperature at less than 15° C. When the addition was finished, the temperature was increased to 35° C., and water (2000 mL) was added. The phases were mixed for 10 min and then allowed to settle. The aqueous phase was drawn off and water (1500 mL) was added. The phases were mixed again for 10 min, and then the aqueous phase was removed. Toluene (4000 mL) was added to the vessel, and 2000 mL of distillate was removed under reduced pressure at 50° C. The temperature was then reduced to 20° C., and potassium phthalimide (864 g, 4.66 mol) and tetrabutylammonium bromide (111 g, 0.35 mol) were added. The mixture was stirred at 108° C. for 4 hr, and then cooled to 20° C. Water (1000 mL) and 5% aqueous NaOH (2500 mL) were added. The resulting mixture was stirred for 10 min. The phases were then allowed to settle, and the aqueous phase was removed. Water (2000 mL) was added, and the resulting mixture was stirred for an additional 10 min. The aqueous phase was then removed. A total of 7 L of distillate were removed under reduced pressure at a temperature ranging from 60 to 85° C. The vessel was cooled to 65° C., and heptanes (3000 mL) was added. The temperature was further decreased to 25° C., and the solution was seeded with crystalline sample of the title compound. The mixture was stirred for 1 hr until crystallization was well under way. After adding heptanes (2500 mL), the mixture was cooled to 10° C. and then stirred for an additional 24 hr. Afterward, the mixture was filtered, and the solid was washed with 800 mL of a cold solution of 10% toluene in heptanes and dried under mechanical vacuum oven at 45° C. for 16 hr to produce (S)-tert-butyl 2-((1,3-dioxoisoindolin-2-yl)methyl)morpholine-4-carboxylate (614 g, 51%) as a solid. 1H NMR (500 MHz, chloroform-d) δ ppm 1.38 (s, 9H), 2.69 (br. s., 1H), 2.92 (br. s., 1H), 3.37 (td, J=11.51, 2.76 Hz, 1H), 3.60 (dd, J=13.75, 4.53 Hz, 1H), 3.63-4.01 (m, 5H), 7.66 (dd, J=5.32, 3.03 Hz, 2H), 7.79 (dd, J=5.04, 3.07 Hz, 2H).

1. customat less than 15° C
2. additionWhen the addition
3. additionThe phases were mixed for 10 min
4. additionThe phases were mixed again for 10 min
5. customthe aqueous phase was removed
6. additionToluene (4000 mL) was added to the vessel, and 2000 mL of distillate
7. customwas removed under reduced pressure at 50° C
8. customwas then reduced to 20° C.
9. temperaturecooled to 20° C
10. stirringThe resulting mixture was stirred for 10 min
11. customthe aqueous phase was removed
12. additionWater (2000 mL) was added
13. stirringthe resulting mixture was stirred for an additional 10 min
14. customThe aqueous phase was then removed
15. customA total of 7 L of distillate were removed under reduced pressure at a temperature
16. customranging from 60 to 85° C
17. temperatureThe vessel was cooled to 65° C.
18. additionheptanes (3000 mL) was added
19. customwas further decreased to 25° C.
20. stirringThe mixture was stirred for 1 hr until crystallization
21. additionAfter adding heptanes (2500 mL)
22. temperaturethe mixture was cooled to 10° C.
23. stirringstirred for an additional 24 hr
24. filtrationAfterward, the mixture was filtered
25. washthe solid was washed with 800 mL of a cold solution of 10% toluene in heptanes
26. customdried under mechanical vacuum oven at 45° C. for 16 hr