Sulfuric Acid → 1-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one

HRID 1090980Notes

Reaction equation

HRID 1090980 reaction equation
N[C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[C:8]([Cl:24])=[CH:9][C:10]([F:23])=[C:11]([N:13]3[C:17](=[O:18])[N:16]([CH:19]([F:21])[F:20])[C:15]([CH3:22])=[N:14]3)[CH:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:28].N([O-])=O.[Na+].C1(C)C(C)=CC=CC=1>O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:24][C:8]1[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([OH:28])=[CH:26][CH:25]=2)=[CH:12][C:11]([N:13]2[C:17](=[O:18])[N:16]([CH:19]([F:20])[F:21])[C:15]([CH3:22])=[N:14]2)=[C:10]([F:23])[CH:9]=1

Participants

7

Reactant 4

HCID 1118Sulfuric AcidHCID 7237O-XyleneHCID 199122101-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-oneHCID 23668193Sodium Nitrite

Product 1

HCID 199122251-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one

Reagents, catalysts & solvents 2

HCID 24463Copper sulfate pentahydrateCatalystHCID 962WaterSolvent2×

Conditions

Temperature
20 °C

Procedure

While maintaining a temperature of 20° to 25° C., 4.4 g (0.011 mole) of 1-[5-(4-aminophenoxy)-4-chloro-2-fluorophenyl]-4-difluoromethyl-4,5-dihydro -3-methyl-1,2,4-triazol-5(1H)-one was added to 4.0 mL of stirred, concentrated sulfuric acid. To this was added a solution of 0.89 g (0.13 mole) of sodium nitrite dissolved in 6.0 mL of water, while continuing to maintain a temperature of about 20° C. After complete addition, the mixture was stirred at 20° C. for 30 minutes. This mixture was added through a glass tube to the bottom of a stirred, refluxing mixture of 32.0 g (0.13 mole) of copper (II) sulfate pentahydrate, 80 mL of water and 30 mL of xylene. After complete addition the mixture was refluxed for one hour. The mixture was cooled, and the organic phase was separated from the aqueous phase. The organic phase was extracted with an aqueous, sodium hydroxide solution (6.0 g of sodium hydroxide pellets dissolved in 250 mL of water). The basic extract was neutralized with concentrated hydrochloric acid, causing a precipitate to form. The solid was collected by filtration to yield 2.3 g of 1-[4-chloro-2-fluoro-5-(4-hydroxyphenoxy)phenyl]-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5-(1H)-one, m.p. 162°-162° C., Compound 2 of Table 1.

Workup

  1. additionwas added to 4.0 mL
  2. additionAfter complete addition
  3. stirringthe mixture was stirred at 20° C. for 30 minutes
  4. additionThis mixture was added through a glass tube to the bottom of a stirred
  5. temperaturerefluxing
  6. additionAfter complete addition the mixture
  7. temperaturewas refluxed for one hour
  8. temperatureThe mixture was cooled
  9. customthe organic phase was separated from the aqueous phase
  10. extractionThe organic phase was extracted with an aqueous, sodium hydroxide solution (6.0 g of sodium hydroxide pellets dissolved in 250 mL of water)
  11. extractionThe basic extract
  12. customto form
  13. filtrationThe solid was collected by filtration

Sources & evidence

ORD record
ord-04912b974481496dbc566e9ab52c0993
Source dataset
uspto-grants-1992_01
Patent number
US05084085

Reaction notes

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