Citric Acid → (3S)-1-Benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-vinylpyrrolidine

HRID 1010566Notes

Reaction equation

HRID 1010566 reaction equation
[CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]([N:16]1[CH2:20][CH:19]([CH:21]=O)[C@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH2:6]([O:13][C:14]([N:16]1[CH2:20][CH:19]([CH:21]=[CH2:1])[C@H:18]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17]1)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1

Participants

7

Reactant 3

HCID 311Citric AcidHCID 86618514(3S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-formylpyrrolidineHCID 178418339Butyllithium

Product 1

HCID 67307498(3S)-1-Benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-vinylpyrrolidine

Reagents, catalysts & solvents 3

HCID 74505Methyltriphenyliphosphonium bromideCatalystHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

Butyl lithium (3.56 mL, 1.58 M, toluene solution) was added dropwise under cooling with ice to a suspension of methyltriphenylphosphonium bromide (2.15 g, 6.03 mmol) in tetrahydrofuran (20 mL), followed by stirring at room temperature for 20 minutes, and further at 40° C. for 5 minutes. Subsequently, a solution of (3S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-formylpyrrolidine [an isomer mixture of (4S)-form: (4R)-form (1:3)] (700 mg, 2.01 mmol) in tetrahydrofuran (7.0 mL) was added under cooling with ice to the resultant mixture, followed by stirring at room temperature for 10 hours. The reaction mixture was poured to a 10% aqueous citric acid solution (20 mL), and the resultant mixture was diluted with ethyl acetate (100 mL). The obtained aqueous layer was extracted with ethyl acetate (100 mL×2). The combined organic layer was washed sequentially by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The obtained residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:4), to thereby yield the title compound (an isomer mixture of (4S)-form and (4R)-form (1:4)) as a colorless oily substance (250 mg, 36%).

Workup

  1. waitfurther at 40° C. for 5 minutes
  2. stirringby stirring at room temperature for 10 hours
  3. extractionThe obtained aqueous layer was extracted with ethyl acetate (100 mL×2)
  4. washThe combined organic layer was washed sequentially by saturated sodium hydrogencarbonate (100 mL) and saturated brine (100 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationAfter filtration
  7. concentrationthe filtrate was concentrated under reduced pressure
  8. customThe obtained residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:4)

Sources & evidence

ORD record
ord-8a009df44bb640389e79d066e9121682
Source dataset
uspto-grants-2011_07
Patent number
US07977327B2

Reaction notes

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