反应详情

温度

6 °C

(2S,3S)-3-Amino-2-hydroxy-4-phenyl-butyric acid (185 g; 948 mmol) was added to a 5-L flask and was suspended in THF (695 mL). H2O (695 mL) was poured in, followed by NEt3 (277 mL; 1990 mmol). After stirring for 45 min, the solution was cooled to 6° C. A solution of acetic acid 3-chlorocarbonyl-2-methyl-phenyl ester (201 g; 948 mmol) in THF (350 mL) was then added dropwise. One-half hour later, the pH was adjusted from 8.7 to 2.5 with 6 N HCl (˜170 mL). Solid NaCl (46 g) was added, the ice bath was then removed and the mixture was stirred vigorously while warming to room temperature. The mixture was transferred to 4-L separatory funnel, using 1:1 THF/H2O (50 mL) for the transfer, and the lower aqueous phase was then removed. The organic fraction was transferred to a 5-L distillation flask, and was then diluted with fresh THF (2.5 L). The solution was azeotropically dried and concentrated to a volume of 1.3 L by distillation of THF at one atmosphere. To complete the azeotropic drying, fresh THF (2.0 L) was added and the solution was concentrated to 1.85 L by distillation at one atmosphere and was then held at 55° C. n-Heptane (230 mL) was added dropwise via addition funnel and the solution was then immediately seeded. After crystallization had initiated, additional n-heptane (95 mL) was added dropwise. The resulting crystal slurry was stirred vigorously for 7 min. Additional n-heptane (1.52 L) was then added as a slow stream. The crystal slurry was then allowed to cool to room temperature slowly and stir overnight. The suspension was vacuum-filtered and the filter cake was then washed with 1:1 THF/n-heptane (700 mL). After drying in a vacuum oven at 45–50° C., 324 g (92%) of (2S,3S)-3-(3-acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyric acid was obtained as a crystalline solid: mp=189–191° C., 1H NMR (300 MHz, DMSO-d6) δ 12.65 (br s, 1H), 3.80 (d, J=9.7 Hz, 1H), 7.16–7.30 (m, 6H), 7.07 (dd, J=1.1, 8.0 Hz, 1H), 7.00 (dd, J=1.1, 7.5 Hz), 4.40–4.52 (m, 1H), 4.09 (d, J=6.0 Hz, 1H), 2.92 (app dd, J=2.9, 13.9 Hz, 1H), 2.76 (app dd, J=11.4, 13.9 Hz, 1H), 2.29 (s, 3H), 1.80 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 174.4, 169.3, 168.1, 149.5, 139.7, 139.4, 129.5, 128.3, 127.9, 126.5, 126.3, 124.8, 123.3, 73.2, 53.5, 35.4, 20.8, 12.6; MS (CI) m/z 372.1464 (372.1447 calcd for C20H22NO6, M+H+).

1. customOne-half hour
2. customthe ice bath was then removed
3. stirringthe mixture was stirred vigorously
4. temperaturewhile warming to room temperature
5. customthe lower aqueous phase was then removed
6. distillationThe organic fraction was transferred to a 5-L distillation flask
7. additionwas then diluted with fresh THF (2.5 L)
8. customThe solution was azeotropically dried
9. concentrationconcentrated to a volume of 1.3 L by distillation of THF at one atmosphere
10. additionwas added
11. concentrationthe solution was concentrated to 1.85 L by distillation at one atmosphere
12. customwas then held at 55° C.
13. additionwas added dropwise via addition funnel
14. customAfter crystallization
15. additionadditional n-heptane (95 mL) was added dropwise
16. stirringThe resulting crystal slurry was stirred vigorously for 7 min
17. additionAdditional n-heptane (1.52 L) was then added as a slow stream
18. temperatureto cool to room temperature slowly
19. stirringstir overnight
20. filtrationThe suspension was vacuum-filtered
21. washthe filter cake was then washed with 1:1 THF/n-heptane (700 mL)
22. customAfter drying in a vacuum oven at 45–50° C.