Dimethylformamide → 4-Fluoro-N-{[2-oxo-6-(1H-1,2,4-triazol-5-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}benzamide

HRID 1878021Notes

Reaction equation

HRID 1878021 reaction equation
C(OC[N:10]1[CH:14]=[N:13][CH:12]=[N:11]1)C1C=CC=CC=1.C([Li])CCC.Br[C:21]1[CH:22]=[CH:23][C:24]2[N:29](CC3C=CC(OC)=CC=3)[C:28](=[O:39])[O:27][C:26]([CH2:44][NH:45][C:46](=[O:54])[C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][CH:48]=3)([C:40]([F:43])([F:42])[F:41])[C:25]=2[CH:55]=1.CN(C=O)C>C1COCC1.C(OCC)(=O)C.O.[Br-].[Zn+2].[Br-].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:53][C:50]1[CH:51]=[CH:52][C:47]([C:46]([NH:45][CH2:44][C:26]2([C:40]([F:41])([F:42])[F:43])[C:25]3[CH:55]=[C:21]([C:12]4[NH:11][N:10]=[CH:14][N:13]=4)[CH:22]=[CH:23][C:24]=3[NH:29][C:28](=[O:39])[O:27]2)=[O:54])=[CH:48][CH:49]=1

Participants

10

Reactant 4

HCID 6228DimethylformamideHCID 44549804N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamideHCID 684880251-[(benzyloxy)methyl]-1H-1,2,4-triazoleHCID 178418339Butyllithium

Product 1

HCID 445502754-Fluoro-N-{[2-oxo-6-(1H-1,2,4-triazol-5-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}benzamideYield 95.5%

Reagents, catalysts & solvents 5

HCID 10421208Zinc bromideCatalystHCID 178418397HCID 178418397, compoundCatalystHCID 962WaterSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolvent

Procedure

To a stirring and cooling solution of 1-[(benzyloxy)methyl]-1H-1,2,4-triazole (41.7 mg, 0.22 mmol) in THF (0.3 mL) at −78° C., n-butyl lithium (92 μL, 2.4 M hexane solution) was added dropwise thereto. After the reaction solution was stirred at the same temperature for 10 minutes, a solution of zinc bromide (59.5 mg, 0.26 mmol) in THF (0.3 mL) was added thereto at −78° C. The solution was stirred at −78° C. for 20 minutes, and then the temperature of the solution was gradually raised to room temperature. To the reaction solution, tetrakis(triphenylphosphine)palladium (10 mg, 0.009 mmol), N-{[6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide (50 mg, 0.088 mmol) and DMF (0.5 mL) were added, and the solution was stirred overnight at 100° C. The temperature of the solution was brought to room temperature and the solution was diluted with ethyl acetate and water was added thereto. Then, the organic layer was separated. The organic layer was washed sequentially with an aqueous citric acid solution and saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1), and 36.6 mg of a pale yellow liquid was obtained as a crude product.

Workup

  1. customat −78° C
  2. stirringThe solution was stirred at −78° C. for 20 minutes
  3. stirringthe solution was stirred overnight at 100° C
  4. customwas brought to room temperature
  5. additionwas added
  6. customThen, the organic layer was separated
  7. washThe organic layer was washed sequentially with an aqueous citric acid solution and saturated brine
  8. dry with materialdried over magnesium sulfate
  9. customAfter the drying agent was removed by filtration
  10. customthe solvent was evaporated under reduced pressure
  11. customThe residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/1)

Sources & evidence

ORD record
ord-b3f74beeba6549e7bf5fb80c94e17e1c
Source dataset
uspto-grants-2012_11
Patent number
US08314094B2

Reaction notes

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