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

HRID 459961Notes

Reaction equation

HRID 459961 reaction equation
[CH:1]1([NH:6][C:7]2[C:12]([CH2:13][NH:14][C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[C:16]=3[F:25])=[CH:11][N:10]=[C:9]([S:26][CH3:27])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].C1N=CN([C:35](N2C=NC=C2)=[O:36])C=1>C1COCC1>[CH:1]1([N:6]2[C:7]3=[N:8][C:9]([S:26][CH3:27])=[N:10][CH:11]=[C:12]3[CH2:13][N:14]([C:15]3[C:20]([F:21])=[CH:19][CH:18]=[C:17]([O:22][CH2:23][CH3:24])[C:16]=3[F:25])[C:35]2=[O:36])[CH2:2][CH2:3][CH2:4][CH2:5]1

Participants

5

Reactant 3

HCID 24758Sodium hydrideHCID 682631,1'-CarbonyldiimidazoleHCID 18444837Cyclopentyl-{5-[(3-ethoxy-2,6-difluoro-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-amine

Product 1

HCID 184446931-Cyclopentyl-3-(3-ethoxy-2,6-difluoro-phenyl)-7-methylsulfanyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-oneYield 81%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

A solution of 1.00 g (2.53 mmol) of cyclopentyl-{5-[(3-ethoxy-2,6-difluoro-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl }-amine in 20 mL of dry THF was cooled to 0C. To this solution was added 0.25 g (6.33 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 1.24 g (7.60 mmol, 3.0 equivalents) of CDI. After 0.5 hour the reaction was warmed to reflux for 24 hours. 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 crude material was eluted onto a Biotage 90 g silica gel column that had been pre-equilibrated with 3:1 hexane/ethyl acetate using the same solvent mixture. Fractions of pure product were combined and concentrated in vacuo to give 0.86 g (81%) of the title compound as a foam: mp 45° C. dec. MS (APCI) (m+1)/z 421.2 Analysis calculated for C20H22F2N4SO2: C, 57.13; H, 5.27; N, 13.32. Found: C, 57.12; H, 5.08; N, 13.21.

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 hours
  5. concentrationThe reaction was 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. washThe crude material was eluted onto a Biotage 90 g silica gel column that
  11. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-60236d8c3a324587b9d692af1c60794a
Source dataset
uspto-grants-2007_03
Patent number
US07196090B2

Reaction notes

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