Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)- → Cyclopentyl-{5-[(3-ethoxy-2,6-difluoro-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-amine

HRID 459953Notes

Reaction equation

HRID 459953 reaction equation
[CH:1]1([NH:6][C:7]2[C:12]([CH:13]=O)=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]1[C:21]([F:28])=[C:22]([NH2:27])[C:23]([F:26])=[CH:24][CH:25]=1)[CH3:18].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C1(C)C=CC=CC=1>[CH:1]1([NH:6][C:7]2[C:12]([CH:13]=[N:27][C:22]3[C:23]([F:26])=[CH:24][CH:25]=[C:20]([O:19][CH2:17][CH3:18])[C:21]=3[F:28])=[CH:11][N:10]=[C:9]([S:15][CH3:16])[N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

5

Reactant 3

HCID 18462Bicyclo[2.2.1]heptane-1-methanesulfonic acid, 7,7-dimethyl-2-oxo-, (1S)-HCID 107998964-(Cyclopentylamino)-2-(methylthio)pyrimidine-5-carbaldehydeHCID 184447123-Ethoxy-2,6-difluoroaniline

Product 1

HCID 18444838Cyclopentyl-{5-[(3-ethoxy-2,6-difluoro-phenylimino)-methyl]-2-methylsulfanyl-pyrimidin-4-yl}-amineYield 82%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Procedure

To a solution of the 8.22 g (34.7 mmol) of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde in 170 mL of toluene was added 6.00 g 34.7 mmol, 1 equivalent) of 3-ethoxy-2,6-difluoro-phenylamine and 2.01 g (8.66 mmol, 0.25 equivalents) of camphorsulfonic acid. The reaction was warmed to reflux and the formed water was removed with the aid of a Dean-Stark trap. After reacting for 48 hours, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane and neutralized with a saturated aqueous solution of sodium bicarbonate. The resulting emulsion was filtered through fiberglass filter paper. The methylene chloride layer was isolated from the filtrate, then washed first with a saturated aqueous solution of sodium bicarbonate, followed by a saturated aqueous solution of sodium chloride. The methylene chloride layer was dried with magnesium sulfate and concentrated in vacuo. The residue was dissolved in dichloromethane, stirred with silica gel, and concentrated in vacuo. The residue was placed in the sample injection module of a Biotage FLASH 75 chromatographic apparatus. Chromatography of the crude material on a Biotage 500 g silica gel column with 4:1 hexane/ethyl acetate gave 11.1 g (82%) of the title compound as a solid: mp 136° C.–141° C. MS (APCI) (m+1)/z 393.2 Analysis calculated for C19H22F2N4SO: C, 58.15; H, 5.65; N, 14.28. Found: C, 58.22; H, 5.68; N, 14.26.

Workup

  1. temperatureThe reaction was warmed
  2. temperatureto reflux
  3. customthe formed water was removed with the aid of a Dean-Stark trap
  4. concentrationthe reaction was concentrated in vacuo
  5. dissolutionThe residue was dissolved in dichloromethane
  6. filtrationThe resulting emulsion was filtered through fiberglass
  7. filtrationfilter paper
  8. customThe methylene chloride layer was isolated from the filtrate
  9. washwashed first with a saturated aqueous solution of sodium bicarbonate
  10. dry with materialThe methylene chloride layer was dried with magnesium sulfate
  11. concentrationconcentrated in vacuo
  12. dissolutionThe residue was dissolved in dichloromethane
  13. concentrationconcentrated in vacuo

Sources & evidence

ORD record
ord-0d647939240c450db7897ecbc721944c
Source dataset
uspto-grants-2007_03
Patent number
US07196090B2

Reaction notes

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