反应详情

温度

5 °C

CBZ-L-Alanine (6.5 kg, 28.5 mol), HOBT-hydrate (4.8 kg, 34.8 mol), N,O-dimethylhydroxylamine hydrochloride (3.4 kg, 36.2 mol) and THF (32 L) are charged to a clean flask under nitrogen. The mixture is cooled to 0-10° C. and then DIPEA (12.4 L) is slowly added at a temperature less than 20° C. EDC-HCl (7 Kg, 36.2 mol) is then added slowly with slight cooling at 15-25° C. The slurry is aged overnight at 20-25° C. The mixture is then cooled to 0-10° C. and 3 N HCl (13 L) is added slowly. Then IPAC (45.5 L) is added and the layers are separated. The organic layer is washed once with HCl (13 L) and twice with 8% NaHCO3 (13 L). The organic layer is then concentrated under vacuum to <20 L at 50° C. The clear solution is cooled slowly to room temperature, allowing the product to crystallize. Heptane (˜70 L) is then added slowly. The slurry is filtered, washed with heptane (18 L), and dried at room temperature on the filter pot. Product is obtained with >99.9% ee measured by chiral HPLC.

1. temperaturewith slight cooling at 15-25° C
2. temperatureThe mixture is then cooled to 0-10° C.
3. additionThen IPAC (45.5 L) is added
4. customthe layers are separated
5. washThe organic layer is washed once with HCl (13 L) and twice with 8% NaHCO3 (13 L)
6. concentrationThe organic layer is then concentrated under vacuum to <20 L at 50° C
7. temperatureThe clear solution is cooled slowly to room temperature
8. customto crystallize
9. additionHeptane (˜70 L) is then added slowly
10. filtrationThe slurry is filtered
11. washwashed with heptane (18 L)
12. customdried at room temperature on the filter pot
13. customProduct is obtained with >99.9% ee