Citric Acid → 4-[(R)-2-iodo-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester

HRID 1917284Notes

Reaction equation

HRID 1917284 reaction equation
C(N(CC)CC)C.S(Cl)(C)(=O)=O.[CH3:13][O:14][C:15]([CH:17]1[CH:21]([C@@H:22]([CH3:25])[CH2:23]O)[CH2:20][N:19]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:18]1)=[O:16].C(O)(=O)CC(CC(O)=O)(C(O)=O)O.[I-:49].[Na+]>ClCCl.C(OCC)(=O)C.CO>[CH3:13][O:14][C:15]([CH:17]1[CH:21]([C@@H:22]([CH3:25])[CH2:23][I:49])[CH2:20][N:19]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:18]1)=[O:16]

Participants

9

Reactant 5

HCID 311Citric AcidHCID 5238Sodium IodideHCID 8471TriethylamineHCID 31297Methanesulfonyl chlorideHCID 674908004-[(R)-2-Hydroxy-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester

Product 1

HCID 674908464-[(R)-2-iodo-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl esterYield 90.6%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Triethylamine (2.7 mL, 19.1 mmol) and mesyl chloride (1.2 mL, 15.3 mmol) were added to a solution of 4-[(R)-2-hydroxy-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (4.1 g, 12.8 mmol) in dichloromethane (100 mL) under ice-cooling, and then the mixture was stirred at room temperature for 30 minutes. After adding methanol to the reaction mixture, the mixture was blended with a mixture of ethyl acetate and a 10% citric acid solution. The organic layer was washed with brine and dried over magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the resulting residue was dissolved in acetone (100 mL). Sodium iodide (4.1 g, 27.4 mmol) was added, and the mixture was heated to reflux for 20 hours. The reaction mixture was cooled and then the solvent was evaporated under reduced pressure. The resulting residue was blended with a mixture of ethyl acetate and water. The organic layer was washed with a saturated sodium thiosulfate solution and brine, dried over magnesium sulfate, and then filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3) to give 5.0 g (84%) of the diastereomer mixture title compound as a colorless oil. The diastereomers were used for the next step without separation.

Workup

  1. temperaturecooling
  2. washThe organic layer was washed with brine
  3. dry with materialdried over magnesium sulfate
  4. filtrationAfter filtration
  5. customthe solvent was evaporated under reduced pressure
  6. dissolutionthe resulting residue was dissolved in acetone (100 mL)
  7. temperaturethe mixture was heated
  8. temperatureto reflux for 20 hours
  9. temperatureThe reaction mixture was cooled
  10. customthe solvent was evaporated under reduced pressure
  11. additionThe resulting residue was blended with a mixture of ethyl acetate and water
  12. washThe organic layer was washed with a saturated sodium thiosulfate solution and brine
  13. dry with materialdried over magnesium sulfate
  14. filtrationfiltered
  15. customthe solvent was evaporated under reduced pressure
  16. customThe residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→7:3)

Sources & evidence

ORD record
ord-e737d4f197b44cdb892a219f84ddf851
Source dataset
uspto-grants-2013_12
Patent number
US08618094B2

Reaction notes

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