Diisopropylethylamine → (3S)-1-(1-(5-chloropyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one

HRID 408026Notes

Reaction equation

HRID 408026 reaction equation
[CH3:1][C:2]1([CH3:26])[CH:7]([N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][C:15]=3[F:24])[C:9]2=[O:25])[CH2:6][CH2:5][NH:4][CH2:3]1.[Cl:27][C:28]1[CH:33]=[N:32][C:31](Cl)=[CH:30][N:29]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C.[Cl-].[Na+].O>[Cl:27][C:28]1[N:29]=[CH:30][C:31]([N:4]2[CH2:5][CH2:6][CH:7]([N:8]3[CH2:12][CH2:11][C@H:10]([NH:13][C:14]4[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:21])=[O:22])=[CH:16][C:15]=4[F:24])[C:9]3=[O:25])[C:2]([CH3:26])([CH3:1])[CH2:3]2)=[N:32][CH:33]=1

Participants

6

Reactant 3

HCID 81531DiisopropylethylamineHCID 3362242,5-DichloropyrazineHCID 67469736(3S)-1-(3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one

Product 1

HCID 86688123(3S)-1-(1-(5-chloropyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-oneYield 18%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
100 °C

Procedure

To a solution of (3S)-1-(3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.010 g, 0.026 mmol) in DMF (1 mL) was added 2,5-dichloropyrazine (0.0078 g, 0.052 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.018 mL, 0.10 mmol) and the reaction was stirred for 3 hours at 100° C. The reaction was cooled, poured into brine and extracted into EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under vacuum. Reverse phase HPLC purification of the crude material gave (3S)-1-(1-(5-chloropyrazin-2-yl)-3,3-dimethylpiperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.0023 g, 0.0046 mmol, 18% yield) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 1.02 (s, 3H), 1.03 (s, 3H), 1.81-1.91 (m 1H), 2.12-2.21 (m, 1H), 2.71-2.81 (m, 2H), 2.95-3.05 (m, 2H), 3.03 (m, 3H), 3.52 (dd, 2H), 3.97 (d, 1H), 4.15-4.23 (m, 2H), 4.47-4.51 (m, 1H), 5.12 (bs, 1H), 6.80 (t, 1H), 7.55 (d, 1H), 7.61 (d, 1H), 7.90 (s, 1H), 8.05 (s, 1H).

Workup

  1. temperatureThe reaction was cooled
  2. extractionextracted into EtOAc
  3. washThe organic layer was washed with water and brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated under vacuum
  7. customReverse phase HPLC purification of the crude material

Sources & evidence

ORD record
ord-73881cf22605466f8edf3c2336723f1f
Source dataset
uspto-grants-2014_06
Patent number
US08754226B2

Reaction notes

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