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

HRID 1917293Notes

Reaction equation

HRID 1917293 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 67491014HCID 67491014, compound

Product 1

HCID 674908134-[(S)-2-Iodo-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl esterYield 94.2%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

Triethylamine (3.4 mL, 24 mmol) and mesyl chloride (1.5 mL, 19.2 mmol) were added to a solution of 4-[(S)-2-hydroxy-1-(methyl)ethyl]pyrrolidine-1,3-dicarboxylic acid 1-benzyl ester 3-methyl ester (5.1 g, 16 mmol) in dichloromethane (50 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 then the residue was dissolved in acetone (100 mL). Sodium iodide (4.8 g, 32 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. Then, 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 6.5 g (94%) 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 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. customThen, the 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-d14d7cfad48b49339fac10196e1c3a37
Source dataset
uspto-grants-2013_12
Patent number
US08618094B2

Reaction notes

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