반응 #73884

반응 방정식

(2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid

isopropylisocyanide

(D)-leucine methyl ester hydrochloride

4-fluorobenzaldehyde

methanol

→

(2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide

용매

triethylamine

반응 조건

후처리

1. 1
   workup.ADDITIONwere sequentially added
2. 2
   기타the solvent was removed in vacuo
3. 3
   workup.DISSOLUTIONthe residue was dissolved in chloroform
4. 4
   세척This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1)
5. 5
   건조dried over magnesium sulphate
6. 6
   기타evaporated in vacuo
7. 7
   workup.DISSOLUTIONThe residue was dissolved in dichloromethane (2 ml)
8. 8
   workup.STIRRINGtrifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature
9. 9
   기타After this time, the solvent was removed in vacuo
10. 10
    workup.ADDITIONThe residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml)
11. 11
    workup.WAITwas left
12. 12
    workup.STIRRINGto stir overnight
13. 13
    기타After this time, the dioxane was removed in vacuo
14. 14
    workup.DISSOLUTIONthe residue was dissolved in ethyl acetate
15. 15
    세척The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1)
16. 16
    건조The liquors were then dried over magnesium sulphate and in vacuo
17. 17
    기타This crude material was purified by Biotage™ (90 g, silica)
18. 18
    세척eluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine

실험 절차

To a solution of (D)-leucine methyl ester hydrochloride (300 mg) in methanol (4 ml) was added triethylamine (230 μl) and 4-fluorobenzaldehyde (177 μl). The mixture was stirred for 2.5 hours before (2R)-[(tert-butoxycarbonyl)amino](2,3-dihydro-1H-inden-2-yl)ethanoic acid (481 mg) and isopropylisocyanide (225 μl) were sequentially added. After stirring for 16 hr, the solvent was removed in vacuo and the residue was dissolved in chloroform. This solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1), dried over magnesium sulphate and evaporated in vacuo. The residue was dissolved in dichloromethane (2 ml) and trifluoroacetic acid (5 ml) and stirred for 3 hours at ambient temperature. After this time, the solvent was removed in vacuo and the residue co-evaporation with toluene (×3) and cyclohexane/ether (1:1, ×2). The residue was treated with a solution of triethylamine in dioxane (2% solution, 10 ml) and was left to stir overnight. After this time, the dioxane was removed in vacuo and the residue was dissolved in ethyl acetate. The solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1). The liquors were then dried over magnesium sulphate and in vacuo and were then co-evaporated with cyclohexane:ether (1:1, ×2). This crude material was purified by Biotage™ (90 g, silica) eluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine to give (2R)-2-(4-fluorophenyl)-2-[(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-isobutyl-2,5-dioxopiperazin-1-yl]-N-isopropylethanamide (149 mg)

출처