Diethyl Ether → (S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one

HRID 407891Notes

Reaction equation

HRID 407891 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[C:5]([F:12])=[CH:4][C:3]=1[NH:13][C@H:14]1[CH2:18][CH2:17][N:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:15]1=[O:25].CCN(C(C)C)C(C)C.[Cl:35][C:36]1[CH:41]=[N:40][C:39](Cl)=[CH:38][N:37]=1.CCOCC>CN(C=O)C.[Cl-].[Na+].O>[Cl:35][C:36]1[N:37]=[CH:38][C:39]([N:22]2[CH2:23][CH2:24][CH:19]([N:16]3[CH2:17][CH2:18][C@H:14]([NH:13][C:3]4[CH:4]=[C:5]([F:12])[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:7][C:2]=4[F:1])[C:15]3=[O:25])[CH2:20][CH2:21]2)=[N:40][CH:41]=1

Participants

7

Reactant 4

HCID 3283Diethyl EtherHCID 81531DiisopropylethylamineHCID 3362242,5-DichloropyrazineHCID 66800289(S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one2×

Product 1

HCID 86688082(S)-1-(1-(5-chloropyrazin-2-yl)piperidin-4-yl)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-oneYield 42.5%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of (S)-3-(2,5-difluoro-4-(methylsulfonyl)phenylamino)-1-(piperidin-4-yl)pyrrolidin-2-one (Table 2, compound 1; 1.5 g, 4.02 mmol) and DIEA (3.50 mL, 20.1 mmol) in DMF (15 mL) was added 2,5-dichloropyrazine (1.20 g, 8.03 mmol). This mixture was heated to 100° C. for 3 hours under nitrogen. The mixture was poured into brine (150 mL) and extracted into ethyl acetate (3×500 mL). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil. Ether (100 mL) was added and a precipitate formed overnight. The ether was decanted and the solid was triturated using ethanol (100 mL) at reflux with stirring for 5 minutes. The material was purified by column chromatography using 50% to 100% ethyl acetate/hexane. The resulting solid was dried over the weekend under high vacuum to provide the title compound (0.83 g, 39% yield). Mass spectrum (apci) m/z=486.1 (M+H).

Workup

  1. extractionextracted into ethyl acetate (3×500 mL)
  2. dry with materialThe combined organic layers were dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated in vacuo
  5. customto give an oil
  6. customa precipitate formed overnight
  7. customThe ether was decanted
  8. customthe solid was triturated
  9. temperatureat reflux
  10. customThe material was purified by column chromatography
  11. customThe resulting solid was dried over the weekend under high vacuum

Sources & evidence

ORD record
ord-70d50193066f4a868e3bbea0105f3615
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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