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

HRID 2085374Notes

Reaction equation

HRID 2085374 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

To a stirring mixture of methyl 4-methoxyacetoacetate (50.0 g, 0.342 mol), 3,4-difluorobenz-aldehyde (51.4 g, 0.362 mol), and urea (31.6 g, 0.527 mole) in THF (300 mL) at room Temperature were added copper(I) oxide (5.06 g, 0.035 mole) and acetic acid (2.05 mL), sequentially, followed by dropwise addition of boron trifluoride diethyl etherate (56.0 mL, 0.442 mole). The mixture was stirred and refluxed for 8 h, whereupon TLC (1/1 EtOAc/hexanes) analysis 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 evaporated. The crude product was purified by flash column (ethyl acetate/hexanes, 1/1; then ethyl acetate), giving the product as pale yellow foam, which on trituration with hexane became white powder (103 g, 97%). 1H NMR d 3.48 (s, 3H), 3.65 (s, 3H), 4.65 (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. customcompletion of the reaction
  2. temperatureThe reaction mixture was cooled
  3. filtrationthe resulting mixture was filtered through Celite
  4. washThe Celite pad was washed with dichloromethane (400 mL)
  5. customThe organic layer was separated from the filtrate
  6. extractionthe aqueous layer was extracted with more dichloromethane (3×300 mL)
  7. dry with materialThe combined organic extracts were dried (sodium sulfate)
  8. customthe solvent evaporated
  9. customThe crude product was purified by flash column (ethyl acetate/hexanes, 1/1

Sources & evidence

ORD record
ord-91447fa4a566424d94a737b6ef2720fb
Source dataset
uspto-grants-2004_04
Patent number
US06720324B2

Reaction notes

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