反应详情

A 5-L, 3-necked flask was charged with N-CBZ-L-serine (110 g, 0.46 mole) (CBZ=carbobenzyloxy) followed by dichloromethane (2.1 L). The resulting slurry was stirred under argon and treated with triethylamine (61.7 mL, 0.443 mole) over several minutes. The resulting hazy solution was cooled to an internal temperature of -35° and treated over 10 min with trimethylacetylchloride (51.06 mL, 0.415 mole) such that the internal temperature did not rise above -30°. The reaction was stirred an additional 40 min at -25° to -30°, treated with pyridine (35.2 mL, 0.435 mole) over 5 min and stirred an additional 10 min. Amylamine (51 mL, 0.44 mole) was added over 10 min while maintaining the internal temperature at -25° to -29°. The reaction was stirred for 30 min while warming to -25°. A precipitate formed during this warming. The reaction was further warmed to -10° over 40 min during which time the precipitate redissolved. After stirring an additional 20 min at -10°, the reaction was quenched by the addition of 500 mL of 1N HCl. The biphasic mixture was stirred for 20 min and transferred to a separatory funnel. The aqueous layer was extracted with dichloromethane (2×75 mL). The combined dichloromethane solutions were concentrated in vacuo to a weight of 500 g. Ethyl acetate (EtOAc) (2.25 L) was added and the organic solution was washed with 1N HCl (2×400 mL) and 1N K2CO3 (1×700 mL and 2×500 mL). The organic solution was dried (magnesium sulfate), filtered and concentrated in vacuo to the title compound which was used in the next step without purification.

1. temperatureThe resulting hazy solution was cooled to an internal temperature of -35°
2. customdid not rise above -30°
3. stirringThe reaction was stirred an additional 40 min at -25° to -30°
4. stirringstirred an additional 10 min
5. temperaturewhile maintaining the internal temperature at -25° to -29°
6. stirringThe reaction was stirred for 30 min
7. temperaturewhile warming to -25°
8. customA precipitate formed during this warming
9. temperatureThe reaction was further warmed to -10° over 40 min during which time the precipitate
10. dissolutionredissolved
11. stirringAfter stirring an additional 20 min at -10°
12. customthe reaction was quenched by the addition of 500 mL of 1N HCl
13. stirringThe biphasic mixture was stirred for 20 min
14. customtransferred to a separatory funnel
15. extractionThe aqueous layer was extracted with dichloromethane (2×75 mL)
16. concentrationThe combined dichloromethane solutions were concentrated in vacuo to a weight of 500 g
17. additionEthyl acetate (EtOAc) (2.25 L) was added
18. washthe organic solution was washed with 1N HCl (2×400 mL) and 1N K2CO3 (1×700 mL and 2×500 mL)
19. dry with materialThe organic solution was dried (magnesium sulfate)
20. filtrationfiltered
21. concentrationconcentrated in vacuo to the title compound which
22. customwas used in the next step without purification