Sodium hydride → 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one

HRID 459958Notes

Reaction equation

HRID 459958 reaction equation
[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][CH2:24][CH3:25])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.[H-].[Na+].[C:28](N1C=CN=C1)(N1C=CN=C1)=[O:29]>O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([CH2:24][CH3:25])[C:28]1=[O:29]

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 682631,1'-CarbonyldiimidazoleHCID 18444814(5-[(2,6-Difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-ethyl-amine

Product 1

HCID 184447933-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-oneYield 92.1%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of 4.92 g (11.58 mmol) of (5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-ethyl-amine in 85 mL of anhydrous tetrahydrofuran was cooled to 0° C. using an ice/acetone bath. The reaction mixture was treated with 1.16 g (28.95 mmol) of sodium hydride and continued stirring at 0° C. for 30 minutes. After 30 minutes, 5.63 g (34.74 mmol) of 1,1′-carbonyldiimidazole was added and continued to stir at 0° C. for an additional 30 minutes. After 1 hour, the ice bath was removed and the reaction mixture was allowed to warm up to room temperature. The reaction mixture heated at reflux overnight under nitrogen atmosphere. Evaporated the tetrahydrofuran and partitioned the residue between dichloromethane and water. The aqueous layer was extracted one time with 250 mL dichloromethane. The dichloromethane extracts were combined, dried over sodium sulfate, filtered and evaporated. The crude product was purified using medium-pressure chromatography eluting with 2:1 hexanes/ethyl acetate to give 4.23 g (92%) of the title compound: mp 165° C.–168° C. MS (APCI) (m+1)/z 397.1.

Workup

  1. waitAfter 30 minutes
  2. stirringto stir at 0° C. for an additional 30 minutes
  3. waitAfter 1 hour
  4. customthe ice bath was removed
  5. temperatureto warm up to room temperature
  6. temperatureThe reaction mixture heated
  7. temperatureat reflux overnight under nitrogen atmosphere
  8. customEvaporated the tetrahydrofuran
  9. custompartitioned the residue between dichloromethane and water
  10. extractionThe aqueous layer was extracted one time with 250 mL dichloromethane
  11. dry with materialdried over sodium sulfate
  12. filtrationfiltered
  13. customevaporated
  14. customThe crude product was purified
  15. washeluting with 2:1 hexanes/ethyl acetate

Sources & evidence

ORD record
ord-4dacbd5af003409491d766cc6df5b5e0
Source dataset
uspto-grants-2007_03
Patent number
US07196090B2

Reaction notes

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