Fumaric Acid → (3-fluorophenyl)-(S)-pyrrolidin-3-yl-(4-trifluoromethylphenyl)amine difumarate

HRID 1966038Notes

Reaction equation

HRID 1966038 reaction equation
C([N:8]1[CH2:12][CH2:11][C@H:10]([N:13]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[CH:25]=2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>ClCCl>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[F:30][C:26]1[CH:25]=[C:24]([N:13]([C@H:10]2[CH2:11][CH2:12][NH:8][CH2:9]2)[C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][CH:15]=2)[CH:29]=[CH:28][CH:27]=1

Participants

5

Reactant 3

HCID 444972Fumaric AcidHCID 5213051-Chloroethyl chloroformateHCID 66657156((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine

Product 1

HCID 66657271(3-fluorophenyl)-(S)-pyrrolidin-3-yl-(4-trifluoromethylphenyl)amine difumarateYield 78.4%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Procedure

To a 1,2-dichloromethane solution (1 ml) containing ((S)-1-benzylpyrrolidin-3-yl)-(3-fluorophenyl)-(4-trifluoromethylphenyl)amine (0.48 g, 1.1 mmol) was added 1-chloroethyl chloroformate (0.82 g, 5.8 mmol). The mixture was stirred at room temperature for 15 hours and heated under reflux for 3 hours. The solvent was distilled off under reduced pressure, and 5 ml methanol was then added to the residue and heated under reflux for 3 hours. After distilling the solvent off under reduced pressure, the residue was then dissolved in dichloromethane and washed with an aqueous saturated sodium hydrogencarbonate solution. After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was dissolved in ethanol, fumaric acid (128 mg, 1.1 mmol) was then added thereto, giving a uniform solution. The solvent was distilled off under reduced pressure, and the crystals produced by adding dichloromethane to the residue were separated by filtration and dried, giving 0.24 g of light brown powdery (3-fluorophenyl)-(S)-pyrrolidin-3-yl-(4-trifluoromethylphenyl)amine difumarate.

Workup

  1. temperatureheated
  2. temperatureunder reflux for 3 hours
  3. distillationThe solvent was distilled off under reduced pressure, and 5 ml methanol
  4. additionwas then added to the residue
  5. temperatureheated
  6. temperatureunder reflux for 3 hours
  7. distillationAfter distilling the solvent off under reduced pressure
  8. dissolutionthe residue was then dissolved in dichloromethane
  9. washwashed with an aqueous saturated sodium hydrogencarbonate solution
  10. dry with materialAfter drying over magnesium sulfate
  11. distillationthe solvent was distilled off under reduced pressure
  12. dissolutionThe residue was dissolved in ethanol
  13. customgiving a uniform solution
  14. distillationThe solvent was distilled off under reduced pressure
  15. customthe crystals produced
  16. customwere separated by filtration
  17. customdried

Sources & evidence

ORD record
ord-404b82c6abbd45729acfd8fb0e1812bb
Source dataset
uspto-grants-2013_04
Patent number
US08420623B2

Reaction notes

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