Reaktion #73884

Reaktionsgleichung

(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

Lösungsmittel

triethylamine

Reaktionsbedingungen

Aufarbeitung

1. 1
   workup.ADDITIONwere sequentially added
2. 2
   Sonstigethe solvent was removed in vacuo
3. 3
   workup.DISSOLUTIONthe residue was dissolved in chloroform
4. 4
   WaschenThis solution was washed with a saturated aqueous sodium carbonate solution (×2), aqueous citric acid (0.5M, ×2) and brine (×1)
5. 5
   Trocknendried over magnesium sulphate
6. 6
   Sonstigeevaporated 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
   SonstigeAfter 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
    SonstigeAfter this time, the dioxane was removed in vacuo
14. 14
    workup.DISSOLUTIONthe residue was dissolved in ethyl acetate
15. 15
    WaschenThe solution was washed with citric acid solution (0.5M, ×2), saturated aqueous sodium bicarbonate solution (×1) and brine (×1)
16. 16
    TrocknenThe liquors were then dried over magnesium sulphate and in vacuo
17. 17
    SonstigeThis crude material was purified by Biotage™ (90 g, silica)
18. 18
    Wascheneluting with toluene:ethyl acetate:cyclohexane (5:3:2) with 5% triethylamine

Vorschrift

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)

Quelle