Acetic Acid → 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione

HRID 1722972Notes

Reaction equation

HRID 1722972 reaction equation
[NH2:1]/[C:2](/[C:9]([F:12])([F:11])[F:10])=[CH:3]\[C:4]([O:6]CC)=O.[H-].[Na+].[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:20][C:19]([NH:26][C:27](=O)[O:28]CC)=[C:18]([F:32])[CH:17]=1.C(O)(=O)C>CN(C)C=O>[Cl:15][C:16]1[C:21]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:20][C:19]([N:26]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]([F:10])([F:11])[F:12])[NH:1][C:27]2=[O:28])=[C:18]([F:32])[CH:17]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 24758Sodium hydrideHCID 5702529Ethyl 3-amino-4,4,4-trifluorocrotonateHCID 20026143ethyl N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-carbamate

Product 1

HCID 114285773-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
150 °C

Procedure

A solution of 10.5 g of ethyl 3-amino-4,4,4-trifluorocrotonate in 25 ml of absolute dimethylformamide is added dropwise while stirring at 0° C. during 5 minutes to a suspension of 2.5 g of a 55% sodium hydride dispersion in 25 ml of absolute dimethylformamide. The temperature rises to 20° C. and the mixture is subsequently stirred at this temperature for 30 minutes. Thereafter, 14.4 g of ethyl N-(4-chloro-2-fluoro-5-isopropoxyphenyl)-carbamate are added, and the mixture is stirred at room temperature for 30 minutes and heated at 150° C. (bath temperature) for 2.5 hours. The reaction mixture is cooled to 50° C., neutralized with 3.5 ml of concentrated acetic acid and largely concentrated at 60° C. under reduced pressure. The residue is poured into a solution of 200 ml of water and 30 ml of 2N hydrochloric acid and the aqueous mixture is extracted twice with 150 ml of diethyl ether each time, and the organic phases are washed twice with 50 ml of water each time, dried over anhydrous sodium sulphate and evaporated to dryness under reduced pressure. The residue is recrystallized from diethyl ether-n-hexane. There is obtained 3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, m.p. 195°-197° C.

Workup

  1. customrises to 20° C.
  2. stirringthe mixture is stirred at room temperature for 30 minutes
  3. temperatureThe reaction mixture is cooled to 50° C.
  4. concentrationlargely concentrated at 60° C. under reduced pressure
  5. additionThe residue is poured into a solution of 200 ml of water and 30 ml of 2N hydrochloric acid
  6. extractionthe aqueous mixture is extracted twice with 150 ml of diethyl ether each time
  7. washthe organic phases are washed twice with 50 ml of water each time
  8. dry with materialdried over anhydrous sodium sulphate
  9. customevaporated to dryness under reduced pressure
  10. customThe residue is recrystallized from diethyl ether-n-hexane

Sources & evidence

ORD record
ord-eb408fff2d304ee9a1620c81e6c9adb7
Source dataset
uspto-grants-1989_08
Patent number
US04859229

Reaction notes

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