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

HRID 1822755Notes

Reaction equation

HRID 1822755 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[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>O1CCCC1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([CH:9]([N+:10]#[C-:11])[C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[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 22170178N-((2,5-Difluorophenyl)(tosyl)methyl)formamide

Product 1

HCID 221701801,4-Difluoro-2-(isocyano(tosyl)methyl)benzeneYield 68.3%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A 5 L three-necked round-bottomed flask, equipped with a mechanical stirrer, an addition funnel and a thermometer, was charged with N-[(2,5-Difluoro-phenyl)-(toluene-4-sulfonyl)-methyl]-formamide (207.0 g, 0.636 moles) and tetrahydrofuran (J. T. Baker, low water, 1.5 L). Phosphorous oxychloride (118.6 ml, 1.27 moles) was quickly poured into the reaction mixture (less than 5 minutes). The mixture was stirred at room temperature for 10 minutes and then cooled to 4° C. using an ice/water bath. 2,6-Lutidine (445 ml, 3.82 moles) was added via the addition funnel over a period of 30 minutes. The cooling bath was then removed and the mixture was stirred at room temperature for 18 hours. The reaction mixture was poured into a stirred and ice-water cooled solution of 1.5 kg of ice and 1.1 L of saturated aqueous sodium bicarbonate (NaHCO3). The mixture was then extracted with ethyl acetate (2 L plus 1.5 L). The combined organic extracts were washed with 1N aqueous hydrochloric acid (3 L), saturated aqueous NaHCO3 (3 L) and brine (3 L); and then dried (MgSO4). After removing all solvents, isopropanol (1.8 L) was added to the residual brownish solid. The resulting slurry was stirred at room temperature for 2 hours. Water (0.9 L) was added and the slurry was stirred for additional 30 minutes at room temperature and then filtered. The cake was washed with 2:1 isopropanol-water (2×500 ml) and dried in a vacuum-oven (30° C.) for 48 hours. The product, [α-(p-Toluenesulfonyl)-2,5-difluorobenzyl]isonitrile (133.4 g, yield 68%,), was obtained as a brownish powder.

Workup

  1. customA 5 L three-necked round-bottomed flask, equipped with a mechanical stirrer, an addition funnel
  2. temperaturecooled to 4° C.
  3. customThe cooling bath was then removed
  4. stirringthe mixture was stirred at room temperature for 18 hours
  5. additionThe reaction mixture was poured into
  6. stirringa stirred
  7. extractionThe mixture was then extracted with ethyl acetate (2 L plus 1.5 L)
  8. washThe combined organic extracts were washed with 1N aqueous hydrochloric acid (3 L), saturated aqueous NaHCO3 (3 L) and brine (3 L)
  9. dry with materialand then dried (MgSO4)
  10. customAfter removing all solvents, isopropanol (1.8 L)
  11. additionwas added to the residual brownish solid
  12. stirringThe resulting slurry was stirred at room temperature for 2 hours
  13. additionWater (0.9 L) was added
  14. stirringthe slurry was stirred for additional 30 minutes at room temperature
  15. filtrationfiltered
  16. washThe cake was washed with 2:1 isopropanol-water (2×500 ml)
  17. customdried in a vacuum-oven (30° C.) for 48 hours

Sources & evidence

ORD record
ord-cb89f7e1ca234627a2a7c72be229b9f5
Source dataset
uspto-grants-2006_05
Patent number
US07037923B2

Reaction notes

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