Urea → 4-(3,4-Difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester

HRID 2085434Notes

Reaction equation

HRID 2085434 reaction equation
[CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O.[NH2:21][C:22]([NH2:24])=[O:23].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C1COCC1.[Cu-]=O.C(O)(=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:15]([C:14]2[CH:17]=[CH:18][C:19]([F:20])=[C:12]([F:11])[CH:13]=2)[NH:24][C:22](=[O:23])[NH:21][C:4]=1[CH2:3][O:2][CH3:1])=[O:7]

Participants

9

Reactant 5

HCID 1176UreaHCID 8000Boron trifluoride etherateHCID 123500Methyl 4-methoxyacetoacetateHCID 516892Sodium BicarbonateHCID 5880883,4-Difluorobenzaldehyde

Product 1

HCID 108050354-(3,4-Difluoro-phenyl)-6-methoxymethyl-2-oxo-1,2,3,4-tetrahydro-pyrimidine-5-carboxylic acid methyl ester

Reagents, catalysts & solvents 3

HCID 178419072HCID 178419072, compoundCatalystHCID 176Acetic AcidSolventHCID 8028TetrahydrofuranSolvent

Procedure

Copper(I) oxide (5.06 g, 0.035 mole) and acetic acid (2.05 mL) were added sequentially to a stirring solution of methyl 4-methoxyacetoacetate (50.0 g, 0.351 mol), 3,4-difluorobenzaldehyde (51.4 g, 0.351 mmol), and urea (31.6 g, 0.527 mole) in THF (300 mL) at room temperature, followed by dropwise addition of boron trifluoride diethyl etherate (56.0 mL, 0.456 mole). The mixture was stirred at reflux temperature for 8 h, whereupon TLC (1/1 EtOAc/hexanes) indicated completion of the reaction. The reaction mixture was cooled and poured into a mixture of ice and sodium bicarbonate (100 g) and the resulting mixture was filtered through Celite. The Celite pad was washed with dichloromethane (400 mL). The organic layer was separated from the filtrate and the aqueous layer was extracted with more dichloromethane (3×300 mL). The combined organic extracts were dried (sodium sulfate) and the solvent was evaporated. The crude product was purified by flash chromatography (ethyl acetate/hexanes, 1/1;then ethyl acetate), giving the desired product as a pale yellow foam. The foam was triturated with hexanes, giving a white powder (103.3 g, 94%). 1H NMR δ 3.476 (s, 3H), 3.651 (s, 3H), 4.653 (s, 2H), 5.39 (s, 1H), 6.60 (br s, 1H, NH), 7.00-7.20 (m, 3H), 7.72 (br s, 1H, NH).

Workup

  1. temperatureat reflux temperature for 8 h
  2. customcompletion of the reaction
  3. temperatureThe reaction mixture was cooled
  4. filtrationthe resulting mixture was filtered through Celite
  5. washThe Celite pad was washed with dichloromethane (400 mL)
  6. customThe organic layer was separated from the filtrate
  7. extractionthe aqueous layer was extracted with more dichloromethane (3×300 mL)
  8. dry with materialThe combined organic extracts were dried (sodium sulfate)
  9. customthe solvent was evaporated
  10. customThe crude product was purified by flash chromatography (ethyl acetate/hexanes, 1/1;then ethyl acetate)

Sources & evidence

ORD record
ord-8c420198958f4a2db1f4ba901ec28904
Source dataset
uspto-grants-2004_04
Patent number
US06720324B2

Reaction notes

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