反应详情

(R)-Methyl 3-(4-amino-3,5-dimethylphenyl)-2-(benzyloxycarbonyl)propanoate (50.0 g, 140 mmol) was weighed into a flame-dried 5 L three neck round bottom flask, followed by the addition of toluene (2400 mL) and glacial acetic acid (120 mL, 2096 mmol). The mixture was mechanically stirred to form a clear solution, and then potassium acetate (103 g, 1048 mmol) was added. To this white suspension, iso-amyl nitrite (20.7 mL, 154 mmol) was added dropwise at room temperature and the resulting mixture was stirred for 16 h. Saturated sodium bicarbonate (1 L) was added, followed by the careful addition of solid sodium bicarbonate to neutralize the acetic acid. The mixture was extracted with a mixture of dichloromethane (2 L) and brine (1.5 L). After separation, the aqueous layer was extracted with dichloromethane (500 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered. Solvents were removed to afford a tan solid, which was washed with hexanes (2.0 L) and toluene (150 mL). The solid was recrystallized from hot acetone (260 mL) and hexanes (700 mL). The slightly cloudy mixture was allowed to cool to room temperature slowly, then to 0° C. for 1.5 h, and finally to −15° C. for 1.5 h. The resulting solid was filtered and washed with ice-cold acetone/hexanes (1:1, 200 mL) to afford 39.1 g (76%). Analytical HPLC showed >98% UV purity. The enantiomeric excess was determined to be 99.8% (conditions: Chiralpak AD column, 4.6×250 mm, 10 μm; A=ethanol, B=0.05% diethylamine/heptane; 85% B@1.0 mL/min. for 55 min. The retention times for R was 44.6 min and for S was 28.8 min). 1H-NMR (DMSO-d6) δ 2.48 (s, 3H), 2.93 (dd, J=13.4, 10.7 Hz, 1H), 3.10 (dd, J=13.7, 4.9 Hz, 1H), 3.63 (s, 3H), 4.32-4.27 (m, 1H), 4.97 (s, 2H), 7.03 (s, 1H), 7.24-7.22 (m, 2H), 7.29-7.27 (m, 3H), 7.41 (s, 1H), 7.83 (d, J=8.2 Hz, 1H), 7.99 (s, 1H), 13.1 (s, 1H); 13C-NMR (DMSO-d6) δ 16.7, 36.5, 51.8, 56.0, 65.3, 117.6, 119.6, 122.7, 127.2, 127.4, 127.6, 128.2, 129.3, 133.4, 136.8, 139.2, 155.9, 172.4. Mass spec.: 368.16 (MH)+.

1. customto form a clear solution
2. stirringthe resulting mixture was stirred for 16 h
3. extractionThe mixture was extracted with a mixture of dichloromethane (2 L) and brine (1.5 L)
4. customAfter separation
5. extractionthe aqueous layer was extracted with dichloromethane (500 mL)
6. dry with materialThe combined organic layers were dried over anhydrous sodium sulfate
7. filtrationfiltered
8. customSolvents were removed
9. customto afford a tan solid, which
10. washwas washed with hexanes (2.0 L) and toluene (150 mL)
11. customThe solid was recrystallized from hot acetone (260 mL) and hexanes (700 mL)
12. waitfinally to −15° C. for 1.5 h
13. filtrationThe resulting solid was filtered
14. washwashed with ice-cold acetone/hexanes (1:1, 200 mL)
15. customto afford 39.1 g (76%)
16. wait85% B@1.0 mL/min. for 55 min
17. waitThe retention times for R was 44.6 min and for S
18. waitwas 28.8 min