Dicyclohexylcarbodiimide → tert-Butyloxycarbonyl-D-isoglutamine benzyl ester

HRID 1526674Notes

Reaction equation

HRID 1526674 reaction equation
[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15](O)=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O[N:26]1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1>O1CCCC1>[NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@@H:2]([C:15]([NH2:26])=[O:16])[CH2:3][CH2:4][C:5](=[O:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1

Participants

5

Reactant 3

HCID 10868DicyclohexylcarbodiimideHCID 80170N-HydroxysuccinimideHCID 7010513N-Boc-D-Glutamic acid 5-benzyl ester

Product 1

HCID 7037012tert-Butyloxycarbonyl-D-isoglutamine benzyl esterYield 75%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

48.6 g (1.0 eq) Boc-D-Glu(OBzl)-OH was dissolved in tetrahydrofuran, 24.8 g (1.5 eq) HOSu and 44.5 g (1.5 eq) DCC were added sequentially. After stirring for 5 hours in ice bath, the reaction was warmed to r.t and stirred for another 20 hours. A large number of white precipitate (DCU) precipitated, the precipitate was filtered out and washed with little tetrahydrofuran. The filtrate was stirred in ice-salt bath, and anhydrous ammonia was introduced to the solution. After 15 minutes, a large number of white precipitate precipitated, and stirred the mixture for another 1.5 hours, no more white solid precipitated out, and the reaction was completed. The precipitate was filtered and washed with tetrahydrofuran, and yellow oil was obtained after removing the tetrahydrofuran filtrate under vacuum. The yellow oil was diluted with AcOEt; and the pH of the solution was adjusted to 7 with 2N HCl aqueous solution in ice bath, and the solution was allowed to stand for 30 minutes. The AcOEt layer was separated, and successively washed with diluted hydrochloric acid, saturated sodium bicarbonate and water. After that, the AcOEt layer was dried with MgSO4 overnight. The mixture was filtered and the filtrate was evaporated to dryness under vacuum, and the residue was recrystallized with ethyl acetate-cyclo hexane to yield 34.2 g target compound with the yield of 75%, m.p.=122˜123° C., [α]=−1.8° (C=9.8 mg/mL, DMF)

Workup

  1. temperaturethe reaction was warmed
  2. stirringstirred for another 20 hours
  3. customA large number of white precipitate (DCU) precipitated
  4. filtrationthe precipitate was filtered out
  5. washwashed with little tetrahydrofuran
  6. stirringThe filtrate was stirred in ice-salt bath
  7. additionanhydrous ammonia was introduced to the solution
  8. waitAfter 15 minutes
  9. customa large number of white precipitate precipitated
  10. stirringstirred the mixture for another 1.5 hours
  11. customno more white solid precipitated out
  12. filtrationThe precipitate was filtered
  13. washwashed with tetrahydrofuran
  14. customyellow oil was obtained
  15. customafter removing the tetrahydrofuran filtrate under vacuum
  16. additionThe yellow oil was diluted with AcOEt
  17. waitto stand for 30 minutes
  18. customThe AcOEt layer was separated
  19. washsuccessively washed with diluted hydrochloric acid, saturated sodium bicarbonate and water
  20. dry with materialAfter that, the AcOEt layer was dried with MgSO4 overnight
  21. filtrationThe mixture was filtered
  22. customthe filtrate was evaporated to dryness under vacuum
  23. customthe residue was recrystallized with ethyl acetate-cyclo hexane
  24. customto yield 34.2 g target compound with the yield of 75%, m.p.=122˜123° C., [α]=−1.8° (C=9.8 mg/mL, DMF)

Sources & evidence

ORD record
ord-b4b7fdcb3d1640e086306063b6252b8f
Source dataset
uspto-grants-2015_07
Patent number
US09085605B2

Reaction notes

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