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

HRID 429955Notes

Reaction equation

HRID 429955 reaction equation
[CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]([O:8][CH3:9])=[O:7].[NH2:11][C:12]([NH2:14])=[O:13].[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH:19]=O.B(F)(F)F.CCOCC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C.C(O)(=O)C>[CH3:9][O:8][C:6]([C:5]1[CH:19]([C:18]2[CH:21]=[CH:22][C:23]([F:24])=[C:16]([F:15])[CH:17]=2)[NH:14][C:12](=[O:13])[NH:11][C:4]=1[CH2:3][O:2][CH3:1])=[O:7]

Participants

10

Reactant 5

HCID 311Citric AcidHCID 1176UreaHCID 8000Boron trifluoride etherateHCID 123500Methyl 4-methoxyacetoacetateHCID 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 4

HCID 8895Cupric acetateCatalystHCID 176Acetic AcidSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
20 °C

Procedure

A solution of methyl 4-methoxyacetoacetate (702 g, 4.8 mol), urea (433 g, 7.2 mol), 3,4-difluorobenzaldehyde (670 g, 4.7 mol), boron trifluoride diethyl etherate(1126 g, 7.9 mol), copper(II) acetate (94 g, 0.52 mol), and acetic acid (36 mL) in THF (7.5 L) was heated to reflux for 8 hours. The reaction mixture was cooled to 20° C. Ethyl acetate (8 L) and 10% citric acid aqueous solution (7.5 kg) was added. The two layers were separated and the aqueous layer was extracted with ethyl acetate (4 L). The combined organic layers were washed with 10% aqueous sodium carbonate (2×5 L) and with 5% brine (1×5 L). The organic layer was concentrated under reduced pressure, with toluene being added continuously and the mixture was concentrated until the level of THF and ethyl acetate was <0.5% volume to toluene, to a final volume was about 2.5 L. The toluene slurry was warmed to 80° C. to dissolve the solids. The solution was cooled slowly to 60° C. and seeded. The slurry was aged at 60° C. for 1 hour and cooled slowly to 20° C. over 4 hours. Hexane (700 mL) was added over 30 minutes. The slurry was aged for 1 hour and filtered. The solid was washed with toluene (1.5 L) and dried to afford (+)-2 as a white solid.

Workup

  1. temperatureto reflux for 8 hours
  2. customThe two layers were separated
  3. extractionthe aqueous layer was extracted with ethyl acetate (4 L)
  4. washThe combined organic layers were washed with 10% aqueous sodium carbonate (2×5 L) and with 5% brine (1×5 L)
  5. concentrationThe organic layer was concentrated under reduced pressure, with toluene being
  6. additionadded continuously
  7. concentrationthe mixture was concentrated until the level of THF and ethyl acetate
  8. temperatureThe toluene slurry was warmed to 80° C.
  9. dissolutionto dissolve the solids
  10. temperatureThe solution was cooled slowly to 60° C.
  11. temperaturecooled slowly to 20° C. over 4 hours
  12. additionHexane (700 mL) was added over 30 minutes
  13. waitThe slurry was aged for 1 hour
  14. filtrationfiltered
  15. washThe solid was washed with toluene (1.5 L)
  16. customdried
  17. customto afford (+)-2 as a white solid

Sources & evidence

ORD record
ord-0ad1b0ab78084bd58dfba2fcaa90cac3
Source dataset
uspto-grants-2001_11
Patent number
US06320049B1

Reaction notes

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