Methyl iodide → 3-[4-(4-Chlorophenylmethoxy)-2-fluorophenyl]-1-methyl-6-trifluoromethyluracil

HRID 1608928Notes

Reaction equation

HRID 1608928 reaction equation
[NH2:1][C:2]([C:9]([F:12])([F:11])[F:10])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].[F:15][C:16]1[CH:21]=[C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH:19]=[CH:18][C:17]=1[N:31]=[C:32]=[O:33].[C:34](=O)([O-])[O-].[K+].[K+].CI>O1CCCC1.CN(C)C=O.O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][O:22][C:20]2[CH:19]=[CH:18][C:17]([N:31]3[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[N:1]([CH3:34])[C:32]3=[O:33])=[C:16]([F:15])[CH:21]=2)=[CH:25][CH:26]=1

Participants

9

Reactant 5

HCID 6328Methyl iodideHCID 11430Potassium CarbonateHCID 24758Sodium hydrideHCID 136209Ethyl 3-amino-4,4,4-trifluoro-2-butenoateHCID 152794002-Fluoro-4-(4-chlorophenylmethoxy)phenyl isocyanate

Product 1

HCID 152794033-[4-(4-Chlorophenylmethoxy)-2-fluorophenyl]-1-methyl-6-trifluoromethyluracil

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
-20 °C

Procedure

A stirred mixture of 3.8 grams (0.02 mole) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate and 0.8 gram (0.02 mole) of sodium hydride in 60 mL of tetrahydrofuran was cooled to -20° C., and a solution of 5.5 grams (0.02 mole) of 2-fluoro-4-(4-chlorophenylmethoxy)phenyl isocyanate in 60 mL of tetrahydrofuran was added slowly. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature. The reaction mixture was then heated to 70° C. where it was stirred for about 18 hours. After this time the reaction mixture was cooled and concentrated under reduced pressure to a solid residue. The residue was slurried in diethyl ether and filtered to collect the solid sodium salt of 3-[4-(4-chlorophenylmethoxy)-2-fluorophenyl]-6-trifluoromethyluracil. The solid sodium salt was then taken up with 2.8 grams (0.2 mole) of potassium carbonate and 5.9 grams (0.04 mole) of methyl iodide in 80 mL of N,N-dimethylformamide, and the stirred mixture was heated at 70° C. for about 7 hours. After this time the reaction mixture was poured into water, and the resultant solid was collected by filtration, yielding, when dried, 4.5 grams of 3-[4-(4-chlorophenylmethoxy)-2-fluorophenyl]-1-methyl-6-trifluoromethyluracil, mp 134°-135° C. The NMR spectrum was consistent with the proposed structure.

Workup

  1. additionUpon completion of addition
  2. temperatureto warm to ambient temperature
  3. temperatureThe reaction mixture was then heated to 70° C. where it
  4. temperatureAfter this time the reaction mixture was cooled
  5. concentrationconcentrated under reduced pressure to a solid residue
  6. filtrationfiltered
  7. customto collect the solid sodium salt of 3-[4-(4-chlorophenylmethoxy)-2-fluorophenyl]-6-trifluoromethyluracil
  8. temperaturethe stirred mixture was heated at 70° C. for about 7 hours
  9. filtrationthe resultant solid was collected by filtration
  10. customyielding
  11. customwhen dried

Sources & evidence

ORD record
ord-2dec55e0561a4120aff38a004563a59b
Source dataset
uspto-grants-1995_03
Patent number
US05399543

Reaction notes

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