Chlorosuccinimide → (S)-1-(1-(3,5-dichloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one

HRID 407989Notes

Reaction equation

HRID 407989 reaction equation
[Cl:1]N1C(=O)CCC1=O.[Cl:9][C:10]1[N:11]=[CH:12][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:36])=[O:35])=[CH:30][C:29]=4[F:38])[C:23]3=[O:39])[CH2:18][CH2:17]2)=[N:14][CH:15]=1>CC(O)=O>[Cl:1][C:12]1[C:13]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([S:34]([CH3:37])(=[O:35])=[O:36])=[CH:30][C:29]=4[F:38])[C:23]3=[O:39])[CH2:18][CH2:17]2)=[N:14][CH:15]=[C:10]([Cl:9])[N:11]=1

Participants

4

Reactant 2

HCID 31398ChlorosuccinimideHCID 54671276(S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one

Product 1

HCID 86688116(S)-1-(1-(3,5-dichloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-oneYield 53.3%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Conditions

Temperature
50 °C

Procedure

N-Chlorosuccinimide (0.016 g, 0.12 mmol) was added to a mixture of (S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (Example 4; 0.042 g, 0.090 mmol) in AcOH (0.3 mL). The mixture was stirred at 50° C. for 1.5 hour and then cooled to ambient temperature. The volatiles were removed by a stream of flowing nitrogen and the resulting residue was stirred in a mixture of saturated aqueous Na2SO3 (1.5 mL) and EtOAc (1.5 mL) for 15 minutes. The mixture was then partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (40 mL). The organic phase was washed successively with water (20 mL), water (20 mL) and brine (20 mL). The combined organic phases were dried over MgSO4, filtered and concentrated. The residue was purified on silica (eluting with 2:1 EtOAc/hexanes) to afford (S)-1-(1-(3,5-dichloropyrazin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.024 g, 0.048 mmol, 53%) as a white solid. Mass spectrum (apci) m/z=502 (M+H).

Workup

  1. temperaturecooled to ambient temperature
  2. customThe volatiles were removed by a stream of flowing nitrogen
  3. stirringthe resulting residue was stirred in a mixture of saturated aqueous Na2SO3 (1.5 mL) and EtOAc (1.5 mL) for 15 minutes
  4. customThe mixture was then partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (40 mL)
  5. washThe organic phase was washed successively with water (20 mL), water (20 mL) and brine (20 mL)
  6. dry with materialThe combined organic phases were dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe residue was purified on silica (eluting with 2:1 EtOAc/hexanes)

Sources & evidence

ORD record
ord-cb7894c222ea4f00a62a12dbdd586059
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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