Citric Acid → HCID 10225438, compound

HRID 495869Notes

Reaction equation

HRID 495869 reaction equation
[Li+].CC([N-]C(C)C)C.[C:9]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])(=[O:11])[CH3:10].C([O:24][C:25](=O)[C@H:26]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[N:27]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)C1C=CC=CC=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.O>[C:13]([O:12][C:9](=[O:11])[CH2:10][C:25](=[O:24])[C@@H:26]([N:27]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([CH3:16])([CH3:15])[CH3:14]

Participants

9

Reactant 4

HCID 311Citric AcidHCID 10908tert-Butyl acetateHCID 2724682Lithium diisopropylamideHCID 10928230Benzyl N,N-dibenzyl-L-phenylalaninate

Product 1

HCID 10225438HCID 10225438, compoundYield 91.3%

Reagents, catalysts & solvents 4

HCID 962WaterSolventHCID 7500EthylbenzeneSolventHCID 8028TetrahydrofuranSolvent4×HCID 8900HeptaneSolvent

Conditions

Temperature
-53 °C

Procedure

A solution (2.0M) (24 ml, 48 mmol) of LDA in heptane, THF and ethyl benzene was dissolved in 64 ml of anhydrous THF, and the mixed solution was cooled to −53° C. in an argon atmosphere. To this solution was added dropwise a solution of 5.8 g (50 mmols) of tert-butyl acetate in 12 ml of THF for approximately 15 minutes, while maintaining the temperature of from −45° C. to −50° C. After the completion of the dropwise addition, the mixture was stirred at −53° C. for 1 hour. Subsequently, a solution of 7.2 g (15 mmols, purity 90%) of N,N-dibenzyl-L-phenylalanine benzyl ester (Ia) in 8 ml of THF was added dropwise thereto for approximately 15 minutes while maintaining the temperature at from −48° C. to −52° C. After the completion of the dropwise addition, the reaction temperature was raised to −5° C. After three hours, a solution of 16.5 g of citric acid in 50 ml of water was added to the reaction solution to stop the reaction. The resulting mixture was extracted twice with ethyl acetate (100 ml and 50 ml), and the organic layer was washed with 20 ml of 10% citric acid, with 10 ml of a saturated aqueous solution of sodium chloride, with 5% sodium hydrogencarbonate aqueous solution (20 ml×4) and with 10 ml of a saturated aqueous solution of sodium chloride in this order. The organic layer was dried over anhydrous magnesium sulfate, and the filtrate was concentrated. The concentrate was purified through silica-gel column chromatography (eluent-mixture of n-hexane and ethyl acetate at a ratio of 4:1) to give 6.09 g (13.7 mmol) of the above-mentioned compound (IIa).

Workup

  1. temperaturewhile maintaining the temperature of from −45° C. to −50° C
  2. additionAfter the completion of the dropwise addition
  3. temperaturefor approximately 15 minutes while maintaining the temperature at from −48° C. to −52° C
  4. additionAfter the completion of the dropwise addition
  5. temperaturethe reaction temperature was raised to −5° C
  6. waitAfter three hours
  7. customthe reaction
  8. extractionThe resulting mixture was extracted twice with ethyl acetate (100 ml and 50 ml)
  9. washthe organic layer was washed with 20 ml of 10% citric acid, with 10 ml of a saturated aqueous solution of sodium chloride, with 5% sodium hydrogencarbonate aqueous solution (20 ml×4) and with 10 ml of a saturated aqueous solution of sodium chloride in this order
  10. dry with materialThe organic layer was dried over anhydrous magnesium sulfate
  11. concentrationthe filtrate was concentrated
  12. customThe concentrate was purified through silica-gel column chromatography (
  13. additioneluent-mixture of n-hexane and ethyl acetate at a ratio of 4:1)

Sources & evidence

ORD record
ord-6bdb764e41d0460b874531f9cd473890
Source dataset
uspto-grants-2005_09
Patent number
USRE038796E1

Reaction notes

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