反应详情

温度

5 °C

tert-Butyl methyl ether (2.5 L) and an aqueous solution of sodium carbonate (750 g in 2.2 L water, 7.07 mol) were stirred. Ethyl (3-aminooxetan-3-yl)acetate (Preparation 30, 875 g, 5.5 mol) was added to the reaction followed by further tert-butyl methyl ether (2.5 L). The reaction was cooled to 5° C. and benzyl chloroformate (1.21 Kg, 7.09 mol) added in a controlled manner such as to maintain the temperature below 20° C. A precipitate was observed so further water (5 L) and tert-butyl methyl ether (1.5 L) were added to solubilise the reaction mixture. The biphasic mixture was separated. The organic layer was basified with 2M aqueous solution of sodium hydroxide (3.5 L) and stirred vigorously for 18 hours. The aqueous layer was separated and the remaining organic layer washed with water (1.5 L). The aqueous layers were combined and cooled to 15° C. Isopropyl acetate (5 L) was added followed by controlled addition of a 6M aqueous solution of hydrogen chloride (1.2 L), maintaining the temperature below 17° C. The reaction was stirred for 30 minutes. Solid crystallised out in the reactor so was dissolved in a mixture of ethyl acetate and methanol (˜20 L). The solution was stirred at room temperature for 18 hours. The reaction was concentrated in vacuo to afford solid material. Ethyl acetate (5 L) was added and concentrated in vacuo. Further ethyl acetate (5 L) was added and the slurry heated to reflux to give an orange solution. The solution was cooled to 50° C. and heptane (2.5 L) added. A thick slurry was observed that was stirred at room temperature for 18 hours. The solid was filtered and dried on a sinter for 3 hours before drying in vacuo at 40° C. for 18 hours to afford the title compound as a white crystalline solid (1.07 Kg, 73% yield).

1. temperatureto maintain the temperature below 20° C
2. additionwere added
3. customThe biphasic mixture was separated
4. customThe aqueous layer was separated
5. washthe remaining organic layer washed with water (1.5 L)
6. temperaturecooled to 15° C
7. additionIsopropyl acetate (5 L) was added
8. additionfollowed by controlled addition of a 6M aqueous solution of hydrogen chloride (1.2 L)
9. temperaturemaintaining the temperature below 17° C
10. stirringThe reaction was stirred for 30 minutes
11. customSolid crystallised out in the reactor
12. dissolutionso was dissolved in a mixture of ethyl acetate and methanol (˜20 L)
13. stirringThe solution was stirred at room temperature for 18 hours
14. concentrationThe reaction was concentrated in vacuo
15. customto afford solid material
16. concentrationconcentrated in vacuo
17. additionFurther ethyl acetate (5 L) was added
18. temperaturethe slurry heated
19. temperatureto reflux
20. customto give an orange solution
21. temperatureThe solution was cooled to 50° C.
22. stirringthat was stirred at room temperature for 18 hours
23. filtrationThe solid was filtered
24. customdried on a sinter for 3 hours
25. custombefore drying in vacuo at 40° C. for 18 hours