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

HRID 650563Notes

Reaction equation

HRID 650563 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 well-stirred mixture of methyl 4-methoxyacetoacetate (50 g, 0.351 mol), 3,4-difluorobenzaldehyde (51.39 g, 0.351 mmol), and urea (31.64 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 mL, 0.456 mole). The mixture was stirred and refluxed for 8 h, whereupon TLC (1/1 EtOAc/hexanes) indicated completion of the reaction. It 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 on silica gel using 50% ethyl acetate in hexanes and then ethyl acetate as eluents to give the product as a pale yellow foam, which on trituration with hexane became white powder (103.3 g, 94%). 1H NMR (CDCl3) 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. customcompletion of the reaction
  2. temperatureIt 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 on silica gel using 50% ethyl acetate in hexanes

Sources & evidence

ORD record
ord-fe5b8b7538c64283b9dfbaaf4771f118
Source dataset
uspto-grants-2001_08
Patent number
US06274585B1

Reaction notes

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