反应详情

Water (60 g) and toluene (75 g) were added to (S)-3-[2-(4-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (S)-N-benzyl-α-methylbenzylamine salt (22a, 15 g, 30 mmol) and the pH of the resulting mixture was adjusted to 14 using 45% potassium hydroxide (5.6 mL). The mixture was stirred at ambient temperature for about 40 minutes. Agitation was stopped and the layers separated. The aqueous phase was extracted with toluene (2×20 g). Isopropyl acetate (130 g) and ethyl acetate (13 g) were added to the aqueous phase and the pH of the mixture was adjusted to 3 with 37% hydrochloric acid. The organic layer was separated from the aqueous phase and the latter extracted with ethyl acetate (15 g). The combined organic extracts were washed with saturated aqueous sodium chloride solution (25 mL). The organic product solution was heated to reflux and water removed by azeotropic distillation. When no more water was collected, the solution was distilled to afford 136 mL of distillate. The residual product mixture was stirred and cooled to ambient temperature. Stirring was continued for another 12 hours. Heptane (11 g) was added to the mixture. The slurry was cooled to 0-3° C. and held for 1 hour. The mixture was filtered and vacuum dried at 40° C. to give (S)-3-[2-(4-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid (23a) as a white powder: 7.9 g (27 mmol, 90% yield): mp: 119-120° C.; Assay (HPLC): 99.8 area %; Chiral assay (HPLC): 98.9 area % (S) isomer; Water (KF): 0.16%.

1. customthe layers separated
2. extractionThe aqueous phase was extracted with toluene (2×20 g)
3. additionIsopropyl acetate (130 g) and ethyl acetate (13 g) were added to the aqueous phase
4. customThe organic layer was separated from the aqueous phase
5. extractionthe latter extracted with ethyl acetate (15 g)
6. washThe combined organic extracts were washed with saturated aqueous sodium chloride solution (25 mL)
7. temperatureThe organic product solution was heated
8. temperatureto reflux
9. customwater removed by azeotropic distillation
10. customWhen no more water was collected
11. distillationthe solution was distilled
12. customto afford 136 mL of distillate
13. stirringThe residual product mixture was stirred
14. temperaturecooled to ambient temperature
15. stirringStirring
16. waitwas continued for another 12 hours
17. temperatureThe slurry was cooled to 0-3° C.
18. waitheld for 1 hour
19. filtrationThe mixture was filtered
20. customvacuum dried at 40° C.