5-Chloro-2,4-difluorobenzenesulphonyl chloride → 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-2-yl)benzenesulfonamide

HRID 509120Notes

Reaction equation

HRID 509120 reaction equation
[CH3:1][O:2][C:3]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:4]=1[CH2:5][NH:6][C:7]1[N:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C[Si](C)(C)N[Si](C)(C)C.[Li].[Cl:29][C:30]1[CH:31]=[C:32]([S:38](Cl)(=[O:40])=[O:39])[C:33]([F:37])=[CH:34][C:35]=1[F:36]>O1CCCC1>[Cl:29][C:30]1[C:35]([F:36])=[CH:34][C:33]([F:37])=[C:32]([S:38]([N:6]([CH2:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:3]=2[O:2][CH3:1])[C:7]2[N:8]=[CH:9][CH:10]=[CH:11][N:12]=2)(=[O:40])=[O:39])[CH:31]=1

Participants

5

Reactant 3

HCID 27735275-Chloro-2,4-difluorobenzenesulphonyl chlorideHCID 55026262N-[(2,4-dimethoxyphenyl)methyl]pyrimidin-2-amineHCID 57426343Lithium bis(trimethylsilyl)amide

Product 1

HCID 580422645-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(pyrimidin-2-yl)benzenesulfonamideYield 19%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution of (2,4-dimethoxybenzyl)-pyrimidin-2-yl-amine (Preparation 38, 736 mg, 3 mmol) in anhydrous tetrahydrofuran (20 mL) was cooled to −78° C. before the addition of lithium(hexamethyldisilazane) (1M solution in tetrahydrofuran, 3.30 mL, 3.30 mmol). The reaction was allowed to warm to 0° C. for 30 minutes before cooling again to −78° C. The resulting solution was added to a solution of 3-chloro-4,6-difluorobenzenesulfonyl chloride (890 mg, 3.6 mmol) in tetrahydrofuran (10 mL) at −78° C. After 30 minutes at this temperature the reaction was warmed to room temperature and stirred for 24 hours. The reaction was quenched by the addition of saturated aqueous ammonium chloride solution and extracted into ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified using silica gel column chromatography (50-100% dichloromethane in heptane gradient elution) to afford the title compound as a white solid (260 mg, 19%).

Workup

  1. temperaturebefore cooling again to −78° C
  2. temperatureAfter 30 minutes at this temperature the reaction was warmed to room temperature
  3. customThe reaction was quenched by the addition of saturated aqueous ammonium chloride solution
  4. extractionextracted into ethyl acetate
  5. washThe organic layer was washed with brine
  6. dry with materialdried over magnesium sulfate
  7. concentrationconcentrated in vacuo
  8. customThe residue was purified
  9. washsilica gel column chromatography (50-100% dichloromethane in heptane gradient elution)

Sources & evidence

ORD record
ord-8bc57f50556741e795a7db7e50eb3ea3
Source dataset
uspto-grants-2015_08
Patent number
US09096558B2

Reaction notes

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