反应详情

N-((N-Methyl-N-((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl)-L-valine (4.13 g, 13.18 mmole) and hydroxybenztriazole (2.23 g, 16.48 mmoles) were dissolved in 70 mL THF and then dicyclohexyl-carbodiimide(2.71 g, 13.18 mmoles) was added in one portion to the stirred solution under nitrogen atmosphere. This mixture was stirred for 4h at room temperature and then filtered to remove dicyclohexylurea precipitate. The product of Example 69B (5.1 g, 11.99 mmoles) was dissolved in 100 mL THF under nitrogen atmosphere. To this stirred solution was added the filtrate of HOBT-active ester and the resulting solution was stirred at room temperature for 4 h, and the solvent removed via rotary evaporation. The residue was dissolved in 150 mL ethyl acetate and washed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueous KHSO4 and the solvent was removed by rotary evaporation to afford a residue. The residue was dissolved in 175 mL 1N HCL, and the solution filtered to remove the small quantity of dicyclohexylurea. The filtrate solution was added to 175 mL ethyl acetate and the two phase mixture rapidly mixed. The pH of this rapidly stirred mixture was adjusted to pH=7 by dropwise addition of cold 3N NaOH. The organic layer was isolated, washed with 100 mL brine, dried over Na2SO4, filtered, and the solvent was removed to afford 8.6 g of a colorless foam. This material was crystallized from 42 mL EtOAc and 21 mL hexane to give 7.85 g of the desired product as a white solid. mp=122°-123° C. CIMS m/z 721 (M+H)+.

1. filtrationfiltered
2. customto remove dicyclohexylurea precipitate
3. customthe solvent removed via rotary evaporation
4. dissolutionThe residue was dissolved in 150 mL ethyl acetate
5. washwashed with 2×100 mL 1N NaOH, 100 mL brine, 100 mL of 1% w/w aqueous KHSO4
6. customthe solvent was removed by rotary evaporation
7. customto afford a residue
8. dissolutionThe residue was dissolved in 175 mL 1N HCL
9. filtrationthe solution filtered
10. customto remove the small quantity of dicyclohexylurea
11. additionThe filtrate solution was added to 175 mL ethyl acetate
12. additionthe two phase mixture rapidly mixed
13. additionThe pH of this rapidly stirred mixture was adjusted to pH=7 by dropwise addition of cold 3N NaOH
14. customThe organic layer was isolated
15. washwashed with 100 mL brine
16. dry with materialdried over Na2SO4
17. filtrationfiltered
18. customthe solvent was removed