Sodium Carbonate → tert-butyl 4-((S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate

HRID 408024Notes

Reaction equation

HRID 408024 reaction equation
[NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C:8]2([CH3:21])[CH3:20])[C:3]1=[O:22].F[C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=1[F:34].C([O-])([O-])=O.[Na+].[Na+]>CS(C)=O>[F:34][C:25]1[CH:26]=[C:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=[CH:29][C:24]=1[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:9][C:8]2([CH3:21])[CH3:20])[C:3]1=[O:22]

Participants

5

Reactant 3

HCID 10340Sodium CarbonateHCID 27827431,2-Difluoro-4-(methylsulfonyl)benzeneHCID 67469742tert-butyl 4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate

Product 1

HCID 67469764tert-butyl 4-((S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylateYield 16.2%

Reagents, catalysts & solvents 1

HCID 679Dimethyl SulfoxideSolvent

Conditions

Temperature
120 °C

Procedure

tert-Butyl 4-((S)-3-amino-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (0.40 g, 1.3 mmol) was dissolved in DMSO (5 mL). 1,2-Difluoro-4-(methylsulfonyl)benzene (0.32 g, 1.7 mmol) and powdered Na2CO3 (0.18 g, 1.7 mmol) were added. The reaction mixture was bubbled under nitrogen for 15 minutes. The mixture stirred overnight at 120° C. The reaction mixture was cooled to ambient temperature and partitioned between brine and ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated. Flash chromatography of the crude material on silica gel followed by reverse phase HPLC purification gave tert-butyl 4-((S)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)-3,3-dimethylpiperidine-1-carboxylate (0.10 g, 0.21 mmol, 16% yield) as a white solid.

Workup

  1. customThe reaction mixture was bubbled under nitrogen for 15 minutes
  2. temperatureThe reaction mixture was cooled to ambient temperature
  3. custompartitioned between brine and ethyl acetate
  4. washThe organic layer was washed with brine
  5. dry with materialdried over MgSO4
  6. concentrationconcentrated
  7. customFlash chromatography of the crude material on silica gel followed by reverse phase HPLC purification

Sources & evidence

ORD record
ord-0fa575c4b3cc42ea9c6dbbaae148a9be
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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