Dichloromethane → (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid hydrochloride

HRID 1178879Notes

Reaction equation

HRID 1178879 reaction equation
FC(F)(F)C(O)=O.[C:8]([N:12]([CH2:18]OC)[CH2:13][Si](C)(C)C)([CH3:11])([CH3:10])[CH3:9].[F:21][C:22]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=1/[CH:29]=[CH:30]/[C:31]([O:33]C)=[O:32].C(=O)(O)[O-].[Na+].C(Cl)[Cl:41]>>[ClH:41].[C:8]([N:12]1[CH2:13][C@@H:29]([C:23]2[CH:24]=[CH:25][C:26]([F:28])=[CH:27][C:22]=2[F:21])[C@H:30]([C:31]([OH:33])=[O:32])[CH2:18]1)([CH3:9])([CH3:10])[CH3:11]

Participants

6

Reactant 5

HCID 6344DichloromethaneHCID 6422Trifluoroacetic acidHCID 516892Sodium BicarbonateHCID 15276473Methyl 3-(2,4-difluorophenyl)acrylateHCID 22228418N-tert-Butyl-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine

Product 1

HCID 67212109(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid hydrochloride

Procedure

Trifluoroacetic acid (116 μL, 1.51 mmol) was added to a solution of N-tert-butyl-N-(methoxymethyl)-N-(trimethylsilylmethyl)amine from Step B (3.07 g, 15.1 mmol) and methyl (2E)-3-(2,4-difluorophenyl)prop-2-enoate (2.99 g, 15.1 mmol) in methylene chloride (60 mL) at ambient temperature. After 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methlene chloride. The combined organic extracs were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification of the residue by normal phase medium pressure liquid chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent) gave the racemic title compound as a colorless liquid. The racemic titled compound was resolved into its enantiomeric components using preparative chiral high pressure liquid chromatography on CHIRALPAK AD Phase (5% isopropanol/heptanes as eluent) to give in order of elution: methyl (3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate enantiomer of the titled compound as a colorless oil followed by the methyl (3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate enantiomer of the title compound as a colorless oil.

Workup

  1. extractionextracted three times with methlene chloride
  2. washThe combined organic extracs were washed with brine
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated in vacuo
  5. customPurification of the residue by normal phase medium pressure liquid chromatography on silica gel (gradient elution; 0-9% methanol (containing 10% v/v ammonium hydroxide)/methylene chloride as eluent)

Sources & evidence

ORD record
ord-b765fd2b38184dd5820a5dae5abfee24
Source dataset
uspto-grants-2007_10
Patent number
US07276520B2

Reaction notes

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