反应详情

A solution of Z-Leu-OSu (122.5 g, 0.338 mol) in DMF (1.2 L) was stirred at 0° in a 3 L, 3-necked round bottom flask fitted with a mechanical stirrer and thermometer. The H-Lys(Boc)-OH (83.26 g, 0.338 mol) was added and the solution stirred at 0° for 15 min. Triethylamine (47.6 mL, 0.338 mol) was added and the reaction mixture stirred at 0° for 30 min and 25° for 3 h. Additional triethylamine (20 mL) was added to maintain the pH at 8 and the reaction mixture stirred for an additional 20 h. At the end of this time, tlc showed some unreacted H-Lys(Boc)-OH and the reaction mixture was stirred for an additional 24 h (pH 8). The reaction mixture was cooled (0°), acidified with glacial acetic acid (160 mL) and evaporated in vacuo. The residue (oil) was dissolved in EtOAc (1.5 L) and washed with 1M citric acid (2×600 mL) and 10% NaCl (2×700 mL), dried (MgSO4), filtered and concentrated in vacuo. The oily residue was dissolved in anhydrous ether (4 L) and dicyclohexylamine (70.7 mL) added followed by the addition of 1 L of ether. After standing in the cold room for 72 h, the white salt was collected and dried to yield 210.8 g (90%); m.p. 125°-128° (recrystallization of an analytical sample increased the m.p. to 143°-146°); [α]D25 -4.17 (c 1, MeOH); Rf 0.39 (CHCl3 :MeOH:AcOH; 85:10:5). The free acid was generated from the DCHA salt in the following manner: Z-Leu-Lys(Boc)-OH.DCHA (201.9 g, 0.291 mol) was stirred in EtOAC:0.5N H2SO4 (2 L:727 mL) until all the solid dissolved. The organic layer was separated, washed with 0.5N H2SO4 (730 mL), dried (MgSO4) and evaporated in vacuo. Yield: 150.6 g (100%); [α]D25 +3.38° (c 1, CHCl3); Rf 0.64 (CHCl3 :MeOH:AcOH; 85:10:5).

1. customfitted with a mechanical stirrer
2. stirringthe reaction mixture stirred at 0° for 30 min and 25° for 3 h
3. temperatureto maintain the pH at 8
4. stirringthe reaction mixture stirred for an additional 20 h
5. stirringthe reaction mixture was stirred for an additional 24 h (pH 8)
6. temperatureThe reaction mixture was cooled (0°)
7. customevaporated in vacuo
8. dissolutionThe residue (oil) was dissolved in EtOAc (1.5 L)
9. washwashed with 1M citric acid (2×600 mL) and 10% NaCl (2×700 mL)
10. dry with materialdried (MgSO4)
11. filtrationfiltered
12. concentrationconcentrated in vacuo
13. dissolutionThe oily residue was dissolved in anhydrous ether (4 L)
14. additiondicyclohexylamine (70.7 mL) added
15. additionfollowed by the addition of 1 L of ether
16. waitAfter standing in the cold room for 72 h
17. customthe white salt was collected
18. customdried
19. customto yield 210.8 g (90%)
20. customm.p. 125°-128° (recrystallization of an analytical sample
21. temperatureincreased the m.p. to 143°-146°)
22. customThe organic layer was separated
23. washwashed with 0.5N H2SO4 (730 mL)
24. dry with materialdried (MgSO4)
25. customevaporated in vacuo