Acetone → methyl 3-[3-fluoro-4(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]-2-bromopropionate

HRID 329895Notes

Reaction equation

HRID 329895 reaction equation
N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[C:4]([F:18])[CH:3]=1.CC(C)=O.N([O-])=O.[Na+].[C:27]([O:31][CH3:32])(=[O:30])[CH:28]=[CH2:29].[BrH:33]>O>[F:18][C:4]1[CH:3]=[C:2]([CH2:29][CH:28]([Br:33])[C:27]([O:31][CH3:32])=[O:30])[CH:7]=[CH:6][C:5]=1[N:8]1[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]1

Participants

7

Reactant 5

HCID 180AcetoneHCID 260Hydrogen BromideHCID 7294Methyl AcrylateHCID 148197251-(2-Fluoro-4-aminophenyl)-3-methyl-4-(difluoromethyl)-1H-1,2,4-triazol-5(4H)-oneHCID 23668193Sodium Nitrite

Product 1

HCID 14819726methyl 3-[3-fluoro-4(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]-2-bromopropionate

Reagents, catalysts & solvents 1

HCID 962WaterSolvent2×

Conditions

Temperature
8 °C

Procedure

A mixture of 9.0 g (0.035 mole) of 1-(4-amino-2-fluorophenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one in 25 mL of 48% hydrobromide acid was stirred and 70 mL of acetone was added. The reaction mixture was cooled to 8° C. and a solution of 2.5 g (0.036 mole) of sodium nitrite in 7 mL of water was added below the surface of the reaction mixture. The reaction mixture temperature was kept below 15° C. during the addition. Upon completion of addition 25.0 g (0.30 mole) of methyl acrylate was added. The reaction mixture was then cooled to 0°-5° C. and 0.15 g of cuprous bromide was added slowly. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it was stirred for 1 hour. After this time the reaction mixture was diluted with water and was extracted with diethyl ether. The ether extract was dried with magnesium sulfate and filtered. The filtrate was passed through a pad of silica gel and concentrated under reduced pressure to yield 11.3 g of methyl 3-[3-fluoro-4(4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenyl]-2-bromopropionate as an oil. The nmr spectrum was consistent with the proposed structure.

Workup

  1. additionThe reaction mixture temperature was kept below 15° C. during the addition
  2. additionwas added
  3. temperatureThe reaction mixture was then cooled to 0°-5° C.
  4. additionUpon completion of addition the reaction mixture
  5. temperatureto warm to ambient temperature where it
  6. stirringwas stirred for 1 hour
  7. extractionwas extracted with diethyl ether
  8. extractionThe ether extract
  9. dry with materialwas dried with magnesium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-2995de62c03444b4a837f12d776cf14b
Source dataset
uspto-grants-1990_01
Patent number
US04894084

Reaction notes

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