Dimethyl Sulfoxide → 3-{[[2-(Cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile

HRID 604088Notes

Reaction equation

HRID 604088 reaction equation
Br[C:2]1[CH:3]=[N:4][C:5]([N:8]([CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[C:32]#[N:33])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[N:20]([CH2:24][CH:25]2[CH2:27][CH2:26]2)[CH2:21][CH2:22][CH3:23])=[N:6][CH:7]=1.CS(C)=[O:43]>>[CH:25]1([CH2:24][N:20]([CH2:21][CH2:22][CH3:23])[C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][C:10]=2[CH2:9][N:8]([CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[C:32]#[N:33])[C:5]2[N:4]=[CH:3][C:2]([OH:43])=[CH:7][N:6]=2)[CH2:27][CH2:26]1

Participants

3

Reactant 2

HCID 679Dimethyl SulfoxideHCID 866268403-({(5-Bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-methyl)-5-trifluoromethyl-benzonitrile

Product 1

HCID 866268413-{[[2-(Cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile

Conditions

Temperature
80 °C

Procedure

3-({(5-Bromo-pyrimidin-2-yl)-[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-amino}-methyl)-5-trifluoromethyl-benzonitrile (2.81 g) is dissolved in dimethylsulfoxide (12.6 ml) and the mixture is degassed under reduced pressure and flushed with nitrogen gas. Thereto are added potassium acetate (1.32 g), bis(pinacolato)diboron (2.88 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (732 mg) and the mixture is heated at 80° C. under nitrogen atmosphere and stirred for 1 hour and 40 minutes. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (26 ml) and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (15.7 ml) under ice-cooling. Two hours thereafter, thereto is added a saturated aqueous sodium thiosulfate under ice-cooling to consume the excess hydrogen peroxide, and thereto are added water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give 3-{[[2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzyl]-(5-hydroxy-pyrimidin-2-yl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (1.94 g). MS (m/z): 564 [M+H]+.

Workup

  1. customthe mixture is degassed under reduced pressure
  2. customflushed with nitrogen gas
  3. additionThereto are added potassium acetate (1.32 g), bis(pinacolato)diboron (2.88 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium methylene chloride complex (732 mg)
  4. temperatureThe reaction solution is cooled to room temperature
  5. additionare added water and ethyl acetate
  6. customthe mixture is separated
  7. washthe organic layer is washed with a saturated brine
  8. dry with materialdried over sodium sulfate
  9. concentrationconcentrated under reduced pressure
  10. dissolutionThe resulting residue is dissolved in tetrahydrofuran (26 ml)
  11. additionis added dropwise a 30% aqueous hydrogen peroxide solution (15.7 ml) under ice-
  12. temperaturecooling
  13. additionTwo hours thereafter, thereto is added a saturated aqueous sodium thiosulfate under ice-
  14. temperaturecooling
  15. customto consume the excess hydrogen peroxide
  16. additionare added water and ethyl acetate
  17. customthe mixture is separated
  18. washThe organic layer is washed with a saturated brine
  19. dry with materialdried over sodium sulfate
  20. concentrationconcentrated under reduced pressure
  21. customThe resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1)

Sources & evidence

ORD record
ord-e0ca6e20165149b9b499e0643461a6d6
Source dataset
uspto-grants-2011_03
Patent number
US07906517B2

Reaction notes

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