Trifluoroacetic acid → HCID 66657212, compound

HRID 660122Notes

Reaction equation

HRID 660122 reaction equation
C([O:5]C([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:9]1)=O)(C)(C)C.Br[C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([Cl:33])[CH:27]=1.F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[C:53]([CH3:56])([O-:55])C.[Na+].F[C:59](F)(F)[C:60]([OH:62])=[O:61]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[C:53]([OH:55])(=[O:5])/[CH:56]=[CH:59]/[C:60]([OH:62])=[O:61].[C:60]([OH:62])(=[O:61])/[CH:59]=[CH:24]/[C:19]([OH:55])=[O:18].[Cl:33][C:28]1[CH:27]=[C:26]([N:13]([CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[CH:31]=[CH:30][C:29]=1[F:32]

Participants

10

Reactant 5

HCID 6422Trifluoroacetic acidHCID 35430654-Bromo-2-chloro-1-fluorobenzeneHCID 23676156Sodium t-butoxideHCID 44558591Tri-t-butylphosphine fluoroborateHCID 66657237HCID 66657237, compound

Product 1

HCID 66657212HCID 66657212, compoundYield 10.6%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 962WaterSolventHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a toluene solution (4 ml) containing 3(S)-[4-(pyridin-2-yloxy)butylamino]pyrrolidine-1-carboxylic acid tert-butyl ester (0.2 g, 0.6 mmol) and 4-bromo-2-chloro-1-fluorobenzene (0.8 ml, 0.65 mmol) were added tri-tert-butylphosphine tetrafluoroborate (14 mg, 0.05 mmol), tris(dibenzylideneacetone)dipalladium (11 mg, 0.012 mmol) and sodium tert-butoxide (110 mg, 1.2 mmol) and heated under reflux under a nitrogen atmosphere for 12 hours. After cooling to room temperature, water was added to the reaction solution, and extraction with ethyl acetate was conducted. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The solvent was distilled off from the purified product under reduced pressure. The residue was dissolved in 0.4 ml dichloromethane, and trifluoroacetic acid (0.06 ml, 0.8 mmol) was added thereto, followed by stirring at room temperature for 3 hours. After concentrating under reduced pressure, the residue was purified by HPLC. After collecting objective fractions, the solvent was distilled off under reduced pressure, and 10% aqueous potassium carbonate solution was added to the residue, followed by extraction with dichloromethane. The extract was dried over magnesium sulfate and concentrated under reduced pressure, and an ethanol solution containing fumaric acid (8.1 mg) was added to the residue (ethanol solution) to thereby obtain a uniform solution. After concentration under reduced pressure, water (3 ml) was added to the residue, followed by freeze-drying to thereby obtain 19 mg of white solid (3-chloro-4-fluorophenyl)-[4-(pyridin-2-yloxy)butyl]-(S)-pyrrolidin-3-ylamine difumarate.

Workup

  1. temperatureheated
  2. temperatureunder reflux under a nitrogen atmosphere for 12 hours
  3. dry with materialThe extract was dried over magnesium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customthe residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1)
  6. distillationThe solvent was distilled off from the purified product under reduced pressure
  7. dissolutionThe residue was dissolved in 0.4 ml dichloromethane
  8. concentrationAfter concentrating under reduced pressure
  9. customthe residue was purified by HPLC
  10. customAfter collecting objective fractions
  11. distillationthe solvent was distilled off under reduced pressure, and 10% aqueous potassium carbonate solution
  12. additionwas added to the residue
  13. extractionfollowed by extraction with dichloromethane
  14. dry with materialThe extract was dried over magnesium sulfate
  15. concentrationconcentrated under reduced pressure
  16. additionan ethanol solution containing fumaric acid (8.1 mg)
  17. additionwas added to the residue (ethanol solution)
  18. customto thereby obtain a uniform solution
  19. concentrationAfter concentration under reduced pressure, water (3 ml)
  20. additionwas added to the residue
  21. customby freeze-drying

Sources & evidence

ORD record
ord-05d4c1e96d324003a065460d2823ca62
Source dataset
uspto-grants-2011_12
Patent number
US08084442B2

Reaction notes

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