Methyl chlorodifluoroacetate → 5-n-Butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one

HRID 1198698Notes

Reaction equation

HRID 1198698 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N:11]1[C:15](=[O:16])[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][C:19]=2[F:38])[C:13]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:12]1.Cl[C:44]([F:50])([F:49])C(OC)=O.[F-:51].[K+].[Br-].[K+]>O.CN(C=O)C>[CH2:39]([C:13]1[N:14]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:36])(=[O:37])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:20][C:19]=2[F:38])[C:15](=[O:16])[N:11]([C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[C:44]([F:50])([F:51])[F:49])[N:12]=1)[CH2:40][CH2:41][CH3:42]

Participants

7

Reactant 4

HCID 73935Methyl chlorodifluoroacetateHCID 253877Potassium BromideHCID 522689Potassium FluorideHCID 103494052-(2-Bromo-5-nitrophenyl)-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one

Product 1

HCID 117648385-n-Butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-oneYield 62%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
120 °C

Procedure

A mixture of 400 mg (0.606 mmol) of 2-(2-bromo-5-nitrophenyl)-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-5-n-butyl-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 31, Step C), 128 μL (175 mg, 1.21 mmol) of methyl chlorodifluoroacetate, 42 mg (0.73 mmol) of potassium fluoride, 116 mg (0.606 mmol) of cuprous iodide, 72 mg (0.606 mmol) of potassium bromide, and 1.2 mL of DMF was stirred under N2 at 120° C. in a sealed tube for 15 hours. The cooled mixture was diluted with water and extracted 3× with ethyl acetate. The combined organic fractions were washed with brine, dried (Na2SO4), and filtered. The filtrate was concentrated, and the residue was flash chromatographed on silica gel (elution with 6:1 hexane-EtOAc) to give 243 mg (62%) of the title compound as a stiff, pale yellow foam, mp 145° -146° C. [Subsequently eluted was 28 mg of the 2-chloro-5-nitrophenyl analog.] The desired product was homogeneous by TLC in 5:1 hexane-EtOAc; mass spectrum (FAB) m/e 656 (M+Li)+.

Workup

  1. extractionextracted 3× with ethyl acetate
  2. washThe combined organic fractions were washed with brine
  3. dry with materialdried (Na2SO4)
  4. filtrationfiltered
  5. concentrationThe filtrate was concentrated
  6. customchromatographed on silica gel (elution with 6:1 hexane-EtOAc)

Sources & evidence

ORD record
ord-c75e802e6c184604b72b4d6bdef15b7e
Source dataset
uspto-grants-1994_01
Patent number
US05281614

Reaction notes

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