Ethanol → 4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoic acid ethyl ester

HRID 1485981Notes

Reaction equation

HRID 1485981 reaction equation
[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[NH:11][C:12]([NH2:14])=[O:13].[F:15][C:16]([F:24])([F:23])[C:17](=O)[CH2:18][C:19](=O)[CH3:20].[CH2:25](O)[CH3:26]>>[CH2:25]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([N:11]2[C:19]([CH3:20])=[CH:18][C:17]([C:16]([F:24])([F:23])[F:15])=[N:14][C:12]2=[O:13])[CH:4]=1)[CH3:26]

Participants

4

Reactant 3

HCID 702EthanolHCID 739431,1,1-Trifluoro-2,4-pentanedioneHCID 246890454-Chloro-3-ureido-benzoic acid

Product 1

HCID 686031224-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoic acid ethyl esterYield 9%

Conditions

Temperature
85 °C

Procedure

To a stirred suspension of 4-chloro-3-ureido-benzoic acid (26 g, 121 mmol) in ethanol (375 mL) was added 1,1,1-trifluoro-2,4-pentanedione (28 g, 182 mmol) and concentrated (95%) sulfuric acid (50 mL). The reaction mixture was heated at 85° C. for 6 h. After cooling to room temperature, the mixture was partitioned between water (500 mL) and DCM (1 L) and to this was added 6N aq. NaOH, until pH 9-10 attained. The DCM layer was separated and dried over MgSO4 and filtered. Concentration in vacuo gave an orange oil which was purified via silica gel flash chromatography (eluting with a gradient of 10% to 25% EtOAc in hexanes). The resulting orange solid was further triturated with diethyl ether to give 4-chloro-3-(6-methyl-2-oxo-4-trifluoromethyl-2H-pyrimidin-1-yl)-benzoic acid ethyl ester (3.77 g, 9%) as a colorless solid. MS (M+H)+: 360.8, tR=2.670 min (method 1); 1H NMR (CDCl3) δ 8.16 (1H, dd, J=8.4, 2.1 Hz), 8.00 (1H, d, J=1.8 Hz), 7.70 (1H, d, J=8.4 Hz), 6.63 (1H, s), 4.39 (2H, q, J=6.9 Hz), 2.15 (3H, s), 1.39 (3H, t, J=6.9 Hz).

Workup

  1. concentrationconcentrated (95%) sulfuric acid (50 mL)
  2. temperatureAfter cooling to room temperature
  3. customthe mixture was partitioned between water (500 mL) and DCM (1 L)
  4. additionto this was added 6N aq. NaOH
  5. customThe DCM layer was separated
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationConcentration in vacuo
  9. customgave an orange oil which
  10. customwas purified via silica gel flash chromatography (
  11. washeluting with a gradient of 10% to 25% EtOAc in hexanes)
  12. customThe resulting orange solid was further triturated with diethyl ether

Sources & evidence

ORD record
ord-854b26f2e3e5435bac242e860f1a48e0
Source dataset
uspto-grants-2016_08
Patent number
US09422310B2

Reaction notes

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