(S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one → (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-yl]-amide

HRID 1691808Notes

Reaction equation

HRID 1691808 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][C:12](=[O:14])[CH:11]=[CH:10][NH:9]2)=[CH:4][CH:3]=1.[Li]CCCC.[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[N:30]=[C:31]=[O:32])[N:26]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[N:25]=[C:24]2[CH3:43]>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][C:31]([N:9]1[CH:10]=[CH:11][C:12](=[O:14])[CH2:13][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:32])[N:26]([S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])[N:25]=[C:24]2[CH3:43]

Participants

5

Reactant 3

HCID 59377679(S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-oneHCID 593777255-bromo-6-isocyanato-3-methyl-1-(toluene-4-sulfonyl)-1H-indazoleHCID 178418339Butyllithium

Product 1

HCID 59377758(S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-yl]-amideYield 78.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

(S)-2-(4-Fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (58 mg, 0.30 mmol) was dissolved in 10 ml of THF and cooled to −40° C. n-BuLi (1.1 eq, 0.16 ml of a 2.5M soln) was added dropwise, forming a purple suspension. This mixture was allowed to stir for 30 minutes until the purple color changed to white. 5-Bromo-6-isocyanato-3-methyl-1-(toluene-4-sulfonyl)-1H-indazole (1 eq, 146 mg) was added and the mixture was allowed to stir for 1 hour at −40° C., then warmed to warm to room temperature and stirred for 2 hours. The reaction was then quenched with saturated aqueous ammonium chloride solution. The mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (gradient 9:1 to 1:1 hexanes/ethyl acetate) to give (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid [5-bromo-3-methyl-1-(toluene-4-sulfonyl)-1H-indazol-6-yl]-amide (140 mg, 65.1%) as a yellow foam.

Workup

  1. additionwas added dropwise
  2. customforming a purple suspension
  3. stirringto stir for 1 hour at −40° C.
  4. temperaturewarmed
  5. stirringstirred for 2 hours
  6. customThe reaction was then quenched with saturated aqueous ammonium chloride solution
  7. additionThe mixture was diluted with water
  8. extractionextracted with ethyl acetate
  9. washThe combined organic extracts were washed with brine
  10. dry with materialdried over anhydrous sodium sulfate
  11. filtrationfiltered
  12. concentrationconcentrated in vacuo
  13. customThe residue was purified by flash chromatography (gradient 9:1 to 1:1 hexanes/ethyl acetate)

Sources & evidence

ORD record
ord-087998bd2c074924873d83458d3c2166
Source dataset
uspto-grants-2012_04
Patent number
US08153809B2

Reaction notes

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