2,6-Lutidine → 4-(azidomethyl)-6-bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

HRID 1878014Notes

Reaction equation

HRID 1878014 reaction equation
[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:9](=[O:20])[O:8][C:7]([CH2:25]O)([C:21]([F:24])([F:23])[F:22])[C:6]=2[CH:27]=1.CC1C=CC=C(C)N=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+].[N-:56]=[N+:57]=[N-:58].[Na+]>C(Cl)(Cl)Cl.C(OCC)(=O)C.O>[N:56]([CH2:25][C:7]1([C:21]([F:24])([F:23])[F:22])[C:6]2[CH:27]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=2[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9](=[O:20])[O:8]1)=[N+:57]=[N-:58]

Participants

9

Reactant 5

HCID 79372,6-LutidineHCID 33557Sodium AzideHCID 67749Trifluoromethanesulfonic anhydrideHCID 516892Sodium BicarbonateHCID 445498016-bromo-4-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Product 1

HCID 445498024-(azidomethyl)-6-bromo-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6212ChloroformSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

6-Bromo-4-(hydroxymethyl)-1-(4-methoxybenzyl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one (61.3 g, 0.137 mol) was dissolved in chloroform (400 mL) and 2,6-dimethylpyridine (48.0 mL, 0.412 mol), and while stirring the solution at 0° C., trifluoromethanesulfonic anhydride (46.4 mL, 0.275 mol) was added dropwise thereto. After the reaction solution was stirred for 1 hour under ice-cooling, a saturated aqueous sodium hydrogen carbonate solution was added thereto. Then, the solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed sequentially with a saturated aqueous ammonium chloride 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 resulting residue was dissolved in DMF (270 mL), and sodium azide (26.7 g, 0.411 mol) was added thereto. After the reaction solution was stirred at 80° C. for 3 hours, the temperature of the solution was brought to room temperature and water was added thereto. The solution was diluted with ethyl acetate and the organic layer was separated. The organic layer was washed sequentially with an aqueous citric acid solution, water 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=2/3) and further the resulting yellow solid was washed with hexane, whereby the objective compound (46 g, 71%) was obtained as a white solid.

Workup

  1. temperaturecooling
  2. customthe organic layer was separated
  3. washThe organic layer was washed sequentially with a saturated aqueous ammonium chloride solution and saturated brine
  4. dry with materialdried over magnesium sulfate
  5. customAfter the drying agent was removed by filtration
  6. customthe solvent was evaporated under reduced pressure
  7. dissolutionThe resulting residue was dissolved in DMF (270 mL)
  8. stirringAfter the reaction solution was stirred at 80° C. for 3 hours
  9. customwas brought to room temperature
  10. customthe organic layer was separated
  11. washThe organic layer was washed sequentially with an aqueous citric acid solution, water and saturated brine
  12. dry with materialdried over magnesium sulfate
  13. customAfter the drying agent was removed by filtration
  14. customthe solvent was evaporated under reduced pressure
  15. customThe residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/3)
  16. washfurther the resulting yellow solid was washed with hexane, whereby the objective compound (46 g, 71%)
  17. customwas obtained as a white solid

Sources & evidence

ORD record
ord-c375b745209747219ad9f2de7eb0e640
Source dataset
uspto-grants-2012_11
Patent number
US08314094B2

Reaction notes

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