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

HRID 459959Notes

Reaction equation

HRID 459959 reaction equation
[CH:1]1([NH:4][C:5]2[C:10]([CH2:11][NH:12][C:13]3[C:18]([F:19])=[C:17]([O:20][CH3:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=3[F:24])=[CH:9][N:8]=[C:7]([S:25][CH3:26])[N:6]=2)[CH2:3][CH2:2]1.[H-].[Na+].C1N=CN([C:34](N2C=NC=C2)=[O:35])C=1>C1COCC1>[CH:1]1([N:4]2[C:5]3=[N:6][C:7]([S:25][CH3:26])=[N:8][CH:9]=[C:10]3[CH2:11][N:12]([C:13]3[C:18]([F:19])=[C:17]([O:20][CH3:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=3[F:24])[C:34]2=[O:35])[CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 682631,1'-CarbonyldiimidazoleHCID 18444839Cyclopropyl-(5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-amine

Product 1

HCID 184446951-Cyclopropyl-3-(2,6-difluoro-3,5-dimethoxy-phenyl)-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-oneYield 94.6%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 7.66 g (20.0 mmol) of cyclopropyl-(5-[(2,6-difluoro-3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl)-amine in 150 mL of dry THF was cooled to 0° C. To this solution was added 2.00 g (50.1 mmol, 2.5 equivalents) of NaH as a 60% oil suspension. The reaction was stirred for 0.5 hour, the ice bath was removed, and the reaction was stirred for another 0.5 hour. To the reaction was added 9.74 g (60.1 mmol, 3.0 equivalents) of CDI. After 0.5 hour the reaction was warmed to reflux for 24 hous.r The reaction was concentrated in vacuo and the residue was partitioned between dichloromethane and a saturated solution of ammonium chloride. The dichloromethane layer was washed again with ammonium chloride and then once with a saturated solution of NaCl, dried, and concentrated in vacuo. The residue was stirred with diethyl ether and the suspension filtered to give 7.73 g (93%) of the title compound as a solid: mp 173° C.–176° C. MS (APCI) (m+1)/z 409.1 Analysis calculated for C18H18F2N4SO3: C, 52.93; H, 4.44; N, 13.72. Found: C, 52.74; H, 4.34; N, 13.80.

Workup

  1. customthe ice bath was removed
  2. stirringthe reaction was stirred for another 0.5 hour
  3. temperatureAfter 0.5 hour the reaction was warmed
  4. temperatureto reflux for 24 hous.r The reaction
  5. concentrationwas concentrated in vacuo
  6. customthe residue was partitioned between dichloromethane
  7. washThe dichloromethane layer was washed again with ammonium chloride
  8. dry with materialonce with a saturated solution of NaCl, dried
  9. concentrationconcentrated in vacuo
  10. stirringThe residue was stirred with diethyl ether
  11. filtrationthe suspension filtered

Sources & evidence

ORD record
ord-62cdf6d341544042a15fc156fcacca2c
Source dataset
uspto-grants-2007_03
Patent number
US07196090B2

Reaction notes

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