反应详情

温度

6 °C

(2S,3S)-3-Amino-2-hydroxy-4-phenyl-butyric acid (which can be prepared according to the method of Pedrosa et al., Tetrahedron Asymm. 2001, 12, 347; M. Shibasaki et al., Tetrahedron Lett. 1994, 35, 6123; and Ikunaka, M. et al. Tetrahedron Asymm. 2002, 13, 1201; 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 contaminated with ˜7 mol % Et3N.HCl: 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+); elemental analysis calcd for C20H21NO6.0.07 Et3N.HCl: C, 64.34; H, 5.86; N, 3.95; Cl, 0.70; found: C, 64.27; H, 5.79; N, 3.96; Cl; 0.86.

1. addition948 mmol) was added to a 5-L flask
2. customOne-half hour
3. customthe ice bath was then removed
4. stirringthe mixture was stirred vigorously
5. temperaturewhile warming to room temperature
6. customthe lower aqueous phase was then removed
7. distillationThe organic fraction was transferred to a 5-L distillation flask
8. additionwas then diluted with fresh THF (2.5 L)
9. customThe solution was azeotropically dried
10. concentrationconcentrated to a volume of 1.3 L by distillation of THF at one atmosphere
11. additionwas added
12. concentrationthe solution was concentrated to 1.85 L by distillation at one atmosphere
13. customwas then held at 55° C.
14. additionwas added dropwise via addition funnel
15. customAfter crystallization
16. additionadditional n-heptane (95 mL) was added dropwise
17. stirringThe resulting crystal slurry was stirred vigorously for 7 min
18. additionAdditional n-heptane (1.52 L) was then added as a slow stream
19. temperatureto cool to room temperature slowly
20. stirringstir overnight
21. filtrationThe suspension was vacuum-filtered
22. washthe filter cake was then washed with 1:1 THF/n-heptane (700 mL)
23. customAfter drying in a vacuum oven at 45–50° C.