反应详情

To a cooled (0-5° ) solution of N-benzyloxycarbonyl-L-valine (450.0 g) in dry N,N-dimethylformamide (3.0 liter) was added 1-hydroxybenzotriazole hydrate (483.3 g): and the reaction mixture was stirred for 20 min, followed by the addition of a slurry of L-proline methyl ester hydrochloride (296.4 g) and triethylamine (186.6 g) in N,N-dimethylformamide (1.5 liter). After the resulting mixture was cooled to 0°, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (377.6 g, 1.97 mol) in N,N-dimethylformamide (500 ml) was added. The reaction mixture was stirred at 0°-5° for 3 hr and then allowed to warm gradually to room temperature. Stirring was continued for 65 hr, and the mixture was filtered and evaporated. The residue was partitioned between ether and lN HCl, and the precipitate which formed was removed by filtration. The etheral layer was then separated: washed with water, saturated aqueous NaHCO3 and brine; dried (MgSO4); and evaporated. The crude ester was purified by flash chromatography using a gradient elution of methylene chloride, then methanol:methylene chloride (1:99), (2.5:79.5), and, finally, (5:95). The impure material from the first column was rechromatographed using a gradient elution of methylene chloride:hexanes (1:3), methylene chloride, and, finally, methanol:methylene chloride (2:98). The combined chromatographies afforded the ester (596.9 g, 92%) as a colorless oil; TLC, Rf =0.45-0.60, methanol:methylene chloride (5:95); MS, m/e=363(M+1, base), 319, 255, 130, 91.

1. temperatureAfter the resulting mixture was cooled to 0°
2. stirringThe reaction mixture was stirred at 0°-5° for 3 hr
3. stirringStirring
4. waitwas continued for 65 hr
5. filtrationthe mixture was filtered
6. customevaporated
7. customThe residue was partitioned between ether and lN HCl
8. customthe precipitate which formed
9. customwas removed by filtration
10. customThe etheral layer was then separated
11. washwashed with water, saturated aqueous NaHCO3 and brine
12. dry with materialdried (MgSO4)
13. customand evaporated
14. customThe crude ester was purified by flash chromatography
15. washa gradient elution of methylene chloride
16. customThe impure material from the first column was rechromatographed
17. washa gradient elution of methylene chloride:hexanes (1:3), methylene chloride