反应详情

温度

-2.5 °C

A solution of potassium tert-butoxide (6.6 Kg, 59 mol) in THF (22 liters) was added over 1 hour to a stirred solution of sodium 1-hydroxy-3-(2-methyl-1,1′-biphenyl-4-yl)-1-propanesulfonate (4.55 Kg, 13.8 mol) and 3-(diethoxyphosphoryl)succinic acid 1-tert-butyl ester (4.94 Kg, 15.9 mol) in THF (5.2 liters) and tert-butanol (18.3 liters), from −5 to 0° C., under nitrogen. The mixture was stirred from −5 to 0° C. for 4 hours and then a solution of citric acid (12.0 Kg, 62 mol) in demineralised water (28 liters) was added in one portion. The pH was adjusted to pH4-5 by the addition of aqueous sodium hydroxide solution (40%) and the organic phase was separated. The organic phase was concentrated in vacuo to a volume of approximately 25 liters and then recombined with the aqueous phase. Ethyl acetate (28 liters) was added and the organic phase was separated and then washed with a solution of sodium bicarbonate (3.18 Kg) in demineralised water (45 liters). Demineralised water (15 liters) was added and the pH was adjusted to pH 4-5 by the addition of a solution of citric acid (2.27 Kg) in demineralised water (23 liters). The organic phase was separated, washed with demineralised water (14 liters) and then azeotropically dried by distillation at atmospheric pressure at a constant volume of 56 liters. The reaction was cooled to 35 to 40° C. and cyclohexylamine (1.10 Kg, 11.1 mol) was added in one portion. The mixture was cooled to 20-25° C. and was stirred for 18 hours. The mixture was then cooled to 0° C., and was stirred for 2 hours and then filtered. The residue was washed with ethyl acetate (5 liters), then dried in vacuo at 40-45° C. to leave the title compound as a colourless solid (4.1 Kg, 61% yield, 89% pure by HPLC).

1. customthe organic phase was separated
2. concentrationThe organic phase was concentrated in vacuo to a volume of approximately 25 liters
3. additionEthyl acetate (28 liters) was added
4. customthe organic phase was separated
5. washwashed with a solution of sodium bicarbonate (3.18 Kg) in demineralised water (45 liters)
6. additionDemineralised water (15 liters) was added
7. additionthe pH was adjusted to pH 4-5 by the addition of a solution of citric acid (2.27 Kg) in demineralised water (23 liters)
8. customThe organic phase was separated
9. washwashed with demineralised water (14 liters)
10. customazeotropically dried by distillation at atmospheric pressure at a constant volume of 56 liters
11. temperatureThe reaction was cooled to 35 to 40° C.
12. temperatureThe mixture was cooled to 20-25° C.
13. stirringwas stirred for 18 hours
14. temperatureThe mixture was then cooled to 0° C.
15. stirringwas stirred for 2 hours
16. filtrationfiltered
17. washThe residue was washed with ethyl acetate (5 liters)
18. customdried in vacuo at 40-45° C.