Citric Acid → Cbz-L-Phenylalaninal

HRID 744749Notes

Reaction equation

HRID 744749 reaction equation
CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C:19]([NH:21][C@H:22]([CH2:30][OH:31])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.O.C(N(CC)CC)C>[CH2:11]([O:18][C:19]([NH:21][C@H:22]([CH:30]=[O:31])[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[O:20])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1

Participants

8

Reactant 4

HCID 311Citric AcidHCID 679Dimethyl SulfoxideHCID 65578Oxalyl chlorideHCID 853481N-carbobenzoxy-L-phenylalanilol

Product 1

HCID 7021150Cbz-L-Phenylalaninal

Reagents, catalysts & solvents 3

HCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent3×HCID 8471TriethylamineSolvent

Conditions

Temperature
-60 °C

Procedure

A solution of 24.5 ml of anhydrous dimethyl sulfoxide in 870 ml of anhydrous dichloromethane was cooled under N2 atmosphere to -60° C. and treated over a period of 15 min with 131 ml of a 2M solution of oxalyl chloride in dichloromethane in order that the internal temperature remained below -50° C. After addition, the solution was stirred at -60° C. for 15 min and treated over a period of 20 min with a solution of 50 g (0.175 mol) of N-(((benzyl)oxy)-carbonyl)-L-phenylalaninol in 200 ml of dichloromethane. The resulting solution was stirred at -60° C. for 1 h, then treated over a period of 15 min with 97 ml of triethylamine in order that the internal temperature remained below -50° C. After addition the solution was stirred at -60° C. for 15 min, then, with the cooling bath in place, was treated rapidly (over a period of 1 min) with a solution of 163 g of citric acid in 550 ml of water. The resulting slurry was stirred vigorously for 10 min, allowed to warm, diluted to 1 liter with water, and separated. The organic layer was washed with 700 ml of water followed by a mixture of 550 ml of water and 150 ml of saturated aqueous NaHCO3, dried over MgSO4, and concentrated in vacuo at 20° C. to give the crude desired compound as a light yellow solid.

Workup

  1. customremained below -50° C
  2. additionAfter addition
  3. stirringThe resulting solution was stirred at -60° C. for 1 h
  4. customremained below -50° C
  5. additionAfter addition the solution
  6. stirringwas stirred at -60° C. for 15 min
  7. stirringThe resulting slurry was stirred vigorously for 10 min
  8. temperatureto warm
  9. customseparated
  10. washThe organic layer was washed with 700 ml of water
  11. additionfollowed by a mixture of 550 ml of water and 150 ml of saturated aqueous NaHCO3
  12. dry with materialdried over MgSO4
  13. concentrationconcentrated in vacuo at 20° C.

Sources & evidence

ORD record
ord-0b51f8cb454f481ea7f69f451aafdd14
Source dataset
uspto-grants-1996_09
Patent number
US05559158

Reaction notes

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