Citric Acid → [(1S,5S)-7-Methylene-4-oxo-3-[(1R)-1-phenylethyl]-3-aza-bicyclo[3.3.0]octan-1-yl]carboxylic acid tert-butyl ester

HRID 1917407Notes

Reaction equation

HRID 1917407 reaction equation
C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([C@@:18]1([CH2:32][C:33](=[CH2:36])[CH2:34]Br)[CH2:22][C:21](=[O:23])[N:20]([C@@H:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH3:25])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[C:11]([O:15][C:16]([C@@:18]12[CH2:32][C:33](=[CH2:36])[CH2:34][C@@H:22]1[C:21](=[O:23])[N:20]([C@@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25])[CH2:19]2)=[O:17])([CH3:14])([CH3:13])[CH3:12]

Participants

5

Reactant 3

HCID 311Citric AcidHCID 2733832Lithium HexamethyldisilazideHCID 67491103HCID 67491103, compound

Product 1

HCID 67490877[(1S,5S)-7-Methylene-4-oxo-3-[(1R)-1-phenylethyl]-3-aza-bicyclo[3.3.0]octan-1-yl]carboxylic acid tert-butyl esterYield 94.9%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A 1 M solution of lithium hexamethyldisilazide in THF (9.15 ml, 9.15 mmol) was added to a solution of (3S)-3-(3-bromo-2-methylene-1-propyl)-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (3.22 g, 7.62 mmol) in tetrahydrofuran (76.2 ml) under cooling with ice-acetone in a nitrogen atmosphere, and the mixture was stirred for 10 minutes. A 10% citric acid solution (120 ml) was added to the reaction solution, followed by extraction with ethyl acetate (100 ml×2). The organic layer was washed with brine (200 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→83:17→80:20→75:25) to give 2.47 g of the title compound as white crystals.

Workup

  1. extractionfollowed by extraction with ethyl acetate (100 ml×2)
  2. washThe organic layer was washed with brine (200 ml)
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationAfter filtration
  5. concentrationthe filtrate was concentrated under reduced pressure
  6. customThe resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→95:5→90:10→83:17→80:20→75:25)

Sources & evidence

ORD record
ord-9e932542790c4ba9b3f94a4281aec0d8
Source dataset
uspto-grants-2013_12
Patent number
US08618094B2

Reaction notes

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