Dicyclohexylcarbodiimide → benzyloxycarbonyl-L-valyl-L-proline t-butyl ester

HRID 373499Notes

Reaction equation

HRID 373499 reaction equation
[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.[C:29]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][NH:36]1)([CH3:32])([CH3:31])[CH3:30].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O.C(Cl)(Cl)Cl.C(OCC)(=O)C>[C:29]([O:33][C:34](=[O:40])[C@@H:35]1[CH2:39][CH2:38][CH2:37][N:36]1[C:16](=[O:18])[C@H:12]([CH:13]([CH3:14])[CH3:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])([CH3:32])([CH3:30])[CH3:31]

Participants

7

Reactant 4

HCID 10868DicyclohexylcarbodiimideHCID 757711-HydroxybenzotriazoleHCID 726987N-Carbobenzoxy-L-valineHCID 6453108L-Proline 1,1-dimethylethyl ester

Product 1

HCID 10549214benzyloxycarbonyl-L-valyl-L-proline t-butyl esterYield 106.8%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent3×HCID 21584013Chloroform ethylacetateSolvent

Procedure

N-Benzyloxycarbonyl-L-valine (121.3 g), 1-hydroxybenzotriazole (130.5 g) and dry dimethylformamide (DMF) (800 ml) were placed in a 5 liter, 3-necked flask equipped with a mechanical stirrer, thermometer, and a calcium sulfate drying tube, under nitrogen atmosphere. The mixture was cooled to 0° for 15 min and proline t-butyl ester (82.6 g) in dry DMF (800 ml) was added at a fast dropwise rate over 2 h while the temperature of the reaction mixture was maintained at 0°. Dicyclohexylcarbodiimide (109.4 g) in dry DMF (400 ml) then was added in one portion to the reaction mixture. The reaction was stirred at 0° for 3 h, allowed to warm to room temperature gradually over 1 h, and stirred for 48 h, whereupon the reaction was shown to be complete by TLC [Rf =0.55, chloroform:ethyl acetate (85:15)]. The reaction mixture was chilled in ice/water and filtered cold to remove the precipitated dicyclohexyl urea. The DMF was evaporated using a mechanical vacuum pump and at a maximum bath temperature of 40°. The remaining oil was diluted with ethyl acetate (2 liter), chilled, and refiltered to remove additional dicyclohexyl urea. The ethyl acetate solution was washed (20% (w/v) citric acid solution (twice), saturated sodium chloride solution, saturated sodium bicarbonate solution (twice), and saturated sodium chloride solution), dried (MgSO4), and evaporated to afford crude benzyloxycarbonyl-L-valyl-L-proline t-butyl ester as an amber oil (208.3 g, 100%).

Workup

  1. customequipped with a mechanical stirrer
  2. temperatureThe mixture was cooled to 0° for 15 min
  3. temperaturewas maintained at 0°
  4. stirringstirred for 48 h, whereupon the reaction
  5. filtrationfiltered cold
  6. customto remove the precipitated dicyclohexyl urea
  7. customThe DMF was evaporated
  8. customtemperature of 40°
  9. additionThe remaining oil was diluted with ethyl acetate (2 liter)
  10. temperaturechilled
  11. customto remove additional dicyclohexyl urea
  12. washThe ethyl acetate solution was washed (20% (w/v) citric acid solution (twice), saturated sodium chloride solution, saturated sodium bicarbonate solution (twice), and saturated sodium chloride solution),
  13. dry with materialdried (MgSO4)
  14. customevaporated

Sources & evidence

ORD record
ord-570da986bedc4087801fe0f80db04828
Source dataset
uspto-grants-1992_11
Patent number
US05164371

Reaction notes

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