Reaktion #1463469

Reaktionsgleichung

(2S,3S)-3-Amino-2-hydroxy-4-phenyl-butyric acid

NaCl

HCl

NEt3

acetic acid 3-chlorocarbonyl-2-methyl-phenyl ester

→

(2S,3S)-3-(3-acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyric acid

Ausbeute 92.0%

Lösungsmittel

THF

H2O

THF

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITION948 mmol) was added to a 5-L flask
2. 2
   SonstigeOne-half hour
3. 3
   Sonstigethe ice bath was then removed
4. 4
   workup.STIRRINGthe mixture was stirred vigorously
5. 5
   Temperaturwhile warming to room temperature
6. 6
   Sonstigethe lower aqueous phase was then removed
7. 7
   workup.DISTILLATIONThe organic fraction was transferred to a 5-L distillation flask
8. 8
   workup.ADDITIONwas then diluted with fresh THF (2.5 L)
9. 9
   SonstigeThe solution was azeotropically dried
10. 10
    Einengenconcentrated to a volume of 1.3 L by distillation of THF at one atmosphere
11. 11
    workup.ADDITIONwas added
12. 12
    Einengenthe solution was concentrated to 1.85 L by distillation at one atmosphere
13. 13
    Sonstigewas then held at 55° C.
14. 14
    workup.ADDITIONwas added dropwise via addition funnel
15. 15
    SonstigeAfter crystallization
16. 16
    workup.ADDITIONadditional n-heptane (95 mL) was added dropwise
17. 17
    workup.STIRRINGThe resulting crystal slurry was stirred vigorously for 7 min
18. 18
    workup.ADDITIONAdditional n-heptane (1.52 L) was then added as a slow stream
19. 19
    Temperaturto cool to room temperature slowly
20. 20
    workup.STIRRINGstir overnight
21. 21
    FiltrationThe suspension was vacuum-filtered
22. 22
    Waschenthe filter cake was then washed with 1:1 THF/n-heptane (700 mL)
23. 23
    SonstigeAfter drying in a vacuum oven at 45–50° C.

Vorschrift

(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.

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