2,6-Lutidine → 2,4-Difluoro-1-(isocyano(tosyl)methyl)benzene

HRID 854434Notes

Reaction equation

HRID 854434 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O.N1C(C)=CC=CC=1C>C1COCC1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([CH:9]([N+:10]#[C-:11])[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])(=[O:15])=[O:14])=[CH:21][CH:20]=1

Participants

5

Reactant 3

HCID 79372,6-LutidineHCID 24813Phosphorus oxychlorideHCID 22236872N-((2,4-Difluorophenyl)(tosyl)methyl)formamide

Product 1

HCID 222368732,4-Difluoro-1-(isocyano(tosyl)methyl)benzene

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of N-[(2,4-Difluoro-phenyl)-(toluene-4-sulfonyl)-methyl]-formamide (2.07 g, 6.36 mmol) and THF (15 mL) is added phosphorous oxychloride (POCl3)(1.19 mL, 12.7 mmol) over a period of 5 minutes, and the resulting mixture stirred at room temperature for 10 minutes. The reaction is then cooled to 4° C. using an ice/water bath and 2,6-lutidine (4.45 mL, 38.2 mmol) is added over 30 minutes, maintaining the temperature less than 12° C. The cooling bath is removed and the mixture stirred at room temperature for 18 hours. The reaction mixture is poured into a stirred, ice water cooled, solution of ice and saturated aqueous NaHCO3. The mixture is extracted with ethyl acetate (2×). The combined organic extracts are washed with 1N aqueous hydrochloric acid, saturated aqueous NaHCO3, brine and dried (MgSO4). The solvents are removed in vacuo, and isopropanol (18.0 mL) added to the residual brownish solid. The resulting slurry is stirred at room temperature for 2 hours, then water (9.0 mL) is added and the slurry stirred for an additional 30 minutes at room temperature. The slurry is filtered, the cake washed with 2:1 isopropanol-water (2×) and dried in a vacuum-oven (30° C.) for 48 hours. The title compound may be obtained as a tan solid (1.33 g, 68%).

Workup

  1. temperatureThe reaction is then cooled to 4° C.
  2. temperaturemaintaining the temperature less than 12° C
  3. customThe cooling bath is removed
  4. stirringthe mixture stirred at room temperature for 18 hours
  5. additionThe reaction mixture is poured into a stirred, ice water
  6. temperaturecooled
  7. extractionThe mixture is extracted with ethyl acetate (2×)
  8. washThe combined organic extracts are washed with 1N aqueous hydrochloric acid, saturated aqueous NaHCO3, brine
  9. dry with materialdried (MgSO4)
  10. customThe solvents are removed in vacuo, and isopropanol (18.0 mL)
  11. additionadded to the residual brownish solid
  12. stirringThe resulting slurry is stirred at room temperature for 2 hours
  13. additionwater (9.0 mL) is added
  14. stirringthe slurry stirred for an additional 30 minutes at room temperature
  15. filtrationThe slurry is filtered
  16. washthe cake washed with 2:1 isopropanol-water (2×)
  17. customdried in a vacuum-oven (30° C.) for 48 hours

Sources & evidence

ORD record
ord-7a4584b1f8f3446fa418f909d3737086
Source dataset
uspto-grants-2007_08
Patent number
US07259171B2

Reaction notes

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