1-Bromo-2-isocyanato-4,5-dimethoxybenzene → (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (2-bromo-4,5-dimethoxy-phenyl)-amide

HRID 1691802Notes

Reaction equation

HRID 1691802 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:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>C1COCC1>[Br:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[C:24]([O:29][CH3:30])=[CH:23][C:22]=1[NH:31][C:32]([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:33]

Participants

5

Reactant 3

HCID 582002611-Bromo-2-isocyanato-4,5-dimethoxybenzeneHCID 59377679(S)-2-(4-fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-oneHCID 178418339Butyllithium

Product 1

HCID 46831211(S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (2-bromo-4,5-dimethoxy-phenyl)-amideYield 61.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

(S)-2-(4-Fluoro-phenyl)-2,3-dihydro-1H-pyridin-4-one (57 mg, 0.30 mmol) from Preparation 3 was dissolved in 10 ml of THF and cooled to −40° C. n-BuLi (1.1 eq, 0.12 ml of a 2.5 M soln) was added dropwise, forming a purple suspension. This mixture was allowed to stir for 30 minutes until the purple color changed to white. 1-Bromo-2-isocyanato-4,5-dimethoxy-benzene (1 eq, 77 mg) was added. The mixture was allowed to stir for 15 minutes at −40° C. then allowed to warm to room temperature and stir for 2 hours. The reaction was then quenched with saturated 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 (hexanes/ethyl acetate 7:3) to obtain (S)-2-(4-fluoro-phenyl)-4-oxo-3,4-dihydro-2H-pyridine-1-carboxylic acid (2-bromo-4,5-dimethoxy-phenyl)-amide (82 mg, 61%) as a brown oil. MS (ES+) m/z 449 (M+H).

Workup

  1. additionwas added dropwise
  2. customforming a purple suspension
  3. stirringto stir for 15 minutes at −40° C.
  4. stirringstir for 2 hours
  5. customThe reaction was then quenched with saturated ammonium chloride solution
  6. additionThe mixture was diluted with water
  7. extractionextracted with ethyl acetate
  8. washThe combined organic extracts were washed with brine
  9. dry with materialdried over anhydrous sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated in vacuo
  12. customThe residue was purified by flash chromatography (hexanes/ethyl acetate 7:3)

Sources & evidence

ORD record
ord-eb9446416668422fb0b83e7011027486
Source dataset
uspto-grants-2012_04
Patent number
US08153809B2

Reaction notes

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