Citric Acid → Ethyl 3-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-3-oxopropionate

HRID 1279644Notes

Reaction equation

HRID 1279644 reaction equation
[CH2:1]([O:8][CH:9]1[CH2:12][C:11]([NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([C:13](O)=[O:14])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=N[CH:33]=[CH:32]2)=O)C=1.C([CH:38](C([O-])=O)[C:39]([O-:41])=[O:40])C.[Mg+2].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)(=O)C>[CH2:1]([O:8][CH:9]1[CH2:10][C:11]([C:13](=[O:14])[CH2:38][C:39]([O:41][CH2:32][CH3:33])=[O:40])([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 311Citric AcidHCID 682631,1'-CarbonyldiimidazoleHCID 107820171-Benzyloxy-3-(tert-butoxycarbonylamino)cyclobutane-3-carboxylic acidHCID 22261989Magnesium ethylmalonate

Product 1

HCID 18427807Ethyl 3-[1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutan-3-yl]-3-oxopropionateYield 85.8%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

A 37.24 g (115.7 mmol) portion of 1-benzyloxy-3-(tert-butoxycarbonylamino)cyclobutane-3-carboxylic acid was dissolved in 300 ml of tetrahydrofuran to which, while cooling in an ice bath with stirring, was added 20.63 g (127.2 mmol) of N,N-carbonyldiimidazole. After 10 minutes of stirring, the ice bath was detached and the reaction mixture was stirred at room temperature for 3 hours. To the reaction solution which was cooled in an ice bath with stirring was added dropwise 200 ml of tetrahydrofuran solution containing 36.45 g (127.2 mmol) of magnesium ethylmalonate. After 1 hour of stirring, the ice bath was detached, and the reaction mixture was stirred at room temperature for 10 hours. While cooling in an ice bath with stirring, the reaction mixture was mixed with 10% citric acid aqueous solution and then with ethyl acetate to effect separation of layers, and the resulting organic layer was washed with saturated sodium bicarbonate aqueous solution. The organic layer was further washed with saturated brine. After extraction of the aqueous layer with ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 38.84 g (85.8%) of the title compound.

Workup

  1. temperaturewhile cooling in an ice bath
  2. stirringAfter 10 minutes of stirring
  3. stirringthe reaction mixture was stirred at room temperature for 3 hours
  4. temperatureTo the reaction solution which was cooled in an ice bath
  5. stirringwith stirring
  6. stirringAfter 1 hour of stirring
  7. stirringthe reaction mixture was stirred at room temperature for 10 hours
  8. temperatureWhile cooling in an ice bath
  9. stirringwith stirring
  10. customseparation of layers
  11. washthe resulting organic layer was washed with saturated sodium bicarbonate aqueous solution
  12. washThe organic layer was further washed with saturated brine
  13. extractionAfter extraction of the aqueous layer with ethyl acetate
  14. dry with materialdried over anhydrous sodium sulfate
  15. filtrationAfter filtration
  16. customthe solvent was evaporated under a reduced pressure
  17. customthe resulting residue was purified by a silica gel column chromatography

Sources & evidence

ORD record
ord-ec7c5648579543e7a96285f710ac1411
Source dataset
uspto-grants-2002_09
Patent number
US06448266B1

Reaction notes

Loading…