Benzoic Acid → (3R,4S)-[1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol

HRID 424731Notes

Reaction equation

HRID 424731 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)(=O)C1C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([OH:16])[C@@H:13]([CH2:17][OH:18])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 243Benzoic AcidHCID 11776TriphenylphosphineHCID 220568ethyl N-ethoxycarbonyliminocarbamateHCID 66704861(3R,4R)-(1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl)methanol

Product 1

HCID 66704867(3R,4S)-[1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanolYield 81.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

(3R,4R)-[1-Benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol (2.50 g), triphenylphosphine (5.74 g) and benzoic acid (2.55 g) were dissolved in tetrahydrofuran (60 mL). While this solution was chilled in a salt/ice bath, diethyl azodicarboxylate (40% toluene solution, 9.53 mL) was added dropwise. The mixture was stirred at 0° C. or below for 1 hour and then at room temperature for 2 hours and was subsequently concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1). The eluted pale brown tar-like material was dissolved in ethanol (60 mL). To this solution, potassium carbonate (4.07 g) in water (30 mL) was added and the mixture was refluxed for 3 hours while being stirred. Subsequently, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane (200 mL). This solution was washed with saturated brine (2×50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate:methanol=10:1) to give (3R,4S)-[1-benzyloxycarbonyl-4-hydroxypyrrolidin-3-yl]methanol as a milky white syrup (2.04 g).

Workup

  1. additionwas added dropwise
  2. waitat room temperature for 2 hours
  3. concentrationwas subsequently concentrated under reduced pressure
  4. customThe resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1)
  5. dissolutionThe eluted pale brown tar-like material was dissolved in ethanol (60 mL)
  6. additionTo this solution, potassium carbonate (4.07 g) in water (30 mL) was added
  7. temperaturethe mixture was refluxed for 3 hours
  8. stirringwhile being stirred
  9. concentrationSubsequently, the reaction mixture was concentrated under reduced pressure
  10. dissolutionthe residue was dissolved in dichloromethane (200 mL)
  11. washThis solution was washed with saturated brine (2×50 mL)
  12. dry with materialdried over anhydrous sodium sulfate
  13. concentrationconcentrated under reduced pressure
  14. customThe resulting residue was purified by silica gel column chromatography (eluant: ethyl acetate:methanol=10:1)

Sources & evidence

ORD record
ord-bb4afb6aee90455ebf4001360b37f182
Source dataset
uspto-grants-2012_01
Patent number
US08106072B2

Reaction notes

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