Toluene → N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide

HRID 2302088Notes

Reaction equation

HRID 2302088 reaction equation
Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F-:12].[K+].C1(C)C=CC=CC=1.[Li].ClC1C=CSC=1C[C@H]([NH:32][S:33]([C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=1)(=[O:35])=[O:34])CC>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[F:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([NH:32][S:33]([C:36]2[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH:5]=[CH:4][N:3]=1

Participants

7

Reactant 4

HCID 1140TolueneHCID 522689Potassium FluorideHCID 105357732,4-Dichloro-3-nitropyridineHCID 69848256(R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide lithium salt

Product 1

HCID 86758391N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamideYield 60%

Reagents, catalysts & solvents 2

HCID 74236Tetrabutylammonium BromideCatalystHCID 962WaterSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 150.0 g (0.781 mol) of 2,4-dichloro-3-nitropyridine, 226.5.g (3.9 mol) of potassium fluoride (spray dried), 75.0 g (0.233 mol) tetrabutyl-ammonium bromide (TBAB) and 800 ml of toluene is heated to reflux with a Dean-Stark trap attached to the reaction vessel. Approximately 100 ml of toluene is distilled off after which the mixture is cooled to 60° C. and 254.7 g (0.741 mol) (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide lithium salt is added. The mixture is heated at reflux for 4 hours and then cooled to room temperature. 800 ml of water is added and the reaction mixture stirred for 10 minutes. The layers are separated. The organic layer is washed twice with 800 ml of water, insoluble material is removed by filtration and the filtrate is concentrated under reduced pressure. Crystallized solid is slurried with 1 L of methanol for 1 hour at room temperature. The methanol is removed by filtration and the solid is slurried with 1 L of heptane for 1 hour. The heptane is removed by filtration and the solid is slurried with 1 L of methanol for 1 hour. The product is air-dried on the filter, then dried under vacuum at room temperature with a nitrogen bleed for 16 hours to give (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide (225.7 g, 60% yield. 95 A% pure (HPLC). The product contains approximately 2 A% of (R)-N-[1-[3-chlorothien-2-yl)methyl]propyl]-N-(2-chloro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide.

Workup

  1. temperatureis heated
  2. temperatureto reflux with a Dean-Stark trap
  3. distillationApproximately 100 ml of toluene is distilled off after which the mixture
  4. temperatureThe mixture is heated
  5. temperatureat reflux for 4 hours
  6. temperaturecooled to room temperature
  7. customThe layers are separated
  8. washThe organic layer is washed twice with 800 ml of water, insoluble material
  9. customis removed by filtration
  10. concentrationthe filtrate is concentrated under reduced pressure
  11. customCrystallized solid
  12. waitis slurried with 1 L of methanol for 1 hour at room temperature
  13. customThe methanol is removed by filtration
  14. waitthe solid is slurried with 1 L of heptane for 1 hour
  15. customThe heptane is removed by filtration
  16. waitthe solid is slurried with 1 L of methanol for 1 hour
  17. customThe product is air-dried on the filter
  18. customdried under vacuum at room temperature with a nitrogen
  19. waitbleed for 16 hours

Sources & evidence

ORD record
ord-6030e47afe9945beaf60e751a47b65e3
Source dataset
uspto-grants-2002_08
Patent number
US06429315B1

Reaction notes

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