Hydrochloric Acid → 4-(2,2-difluoro-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one

HRID 2208986Notes

Reaction equation

HRID 2208986 reaction equation
[F-].[K+].C1OCCOCCOCCOCCOCCOC1.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C@H:29]([N:31]2[C:35](=[O:36])[CH2:34][C@@H:33]([CH:37]=[O:38])[CH2:32]2)[CH3:30])=[CH:25][CH:24]=1.[F:39][CH:40]([Si](C)(C)C)[F:41].Cl>O.CCOC(C)=O>[F:39][CH:40]([F:41])[CH:37]([CH:33]1[CH2:32][N:31]([C@@H:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH3:30])[C:35](=[O:36])[CH2:34]1)[OH:38]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 2855718-Crown-6HCID 522689Potassium FluorideHCID 11170968(Difluoromethyl)trimethylsilaneHCID 117842859(R)-1-((R)-1-(4-Methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carbaldehyde

Product 1

HCID 1178436304-(2,2-difluoro-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

Under a nitrogen atmosphere, KF (0.28 g, 1.87 mmol) and 18-crown-6 (0.49 g, 1.87 mmol) were added to a solution of (3R)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-5-oxopyrrolidine-3-carbaldehyde 1.07 (420 mg, 1.7 mmol) and (difluoromethyl)trimethylsilane (530 mg, 0.52 mmol, 68 uL), and the mixture was stirred at room temperature for 5 hours. 1M HCl was added, and the reaction was stirred for 15 minutes. EtOAc and water were added and the aqueous layer was extracted with EtOAc. The combined organics were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (0→15% MeOH in EtOAc) to afford 4-(2,2-difluoro-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.24 as a mixture of diastereomers, which were not separated at this stage.

Workup

  1. stirringthe reaction was stirred for 15 minutes
  2. extractionthe aqueous layer was extracted with EtOAc
  3. dry with materialThe combined organics were dried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe residue was purified by flash chromatography (0→15% MeOH in EtOAc)

Sources & evidence

ORD record
ord-5353042470bf4872a60b345b87e45dd5
Source dataset
uspto-grants-2016_06
Patent number
US09376441B2

Reaction notes

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