Ammonium formate → ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinate

HRID 2376150Notes

Reaction equation

HRID 2376150 reaction equation
[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:16](Cl)[N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[C:24]([F:25])=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][N:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1

Participants

5

Reactant 2

HCID 2723923Ammonium formateHCID 86603759ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-chloro-5-fluoronicotinate

Product 1

HCID 68963376ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-5-fluoronicotinateYield 66.5%

Reagents, catalysts & solvents 2

HCID 23938PalladiumCatalystHCID 702EthanolSolvent

Procedure

To a solution of ethyl 6-{[(3R)-1-benzyl-3-pyrrolidinyl]amino}-2-chloro-5-fluoronicotinate (500 mg) in ethanol (20 mL) were added ammonium formate (584 mg) and 10% Pd/C (300 mg) at 25° C. and the mixture was heated to reflux with stirring for 1 hour. After cooling, the catalyst in the reaction mixture was removed by filtration. The filtrate was evaporated in vacuo. To the residue were added CH2Cl2 (30 ml), ethanol (7 mL), and benzaldehyde (140 mg) at 25° C. After stirring for 5 minutes, sodium triacetoxyborohydride (280 mg) was added to the mixture. The reaction mixture was stirred at 25° C. for 3 hours, and then poured into a mixture of CH2Cl2 and aqueous NaHCO3. The organic layer was separated, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (11 g) using a mixed solvent of dichloromethane and MeOH (100:1 to 40:1). The fractions containing the objective compound were collected and evaporated under reduced pressure. Title compound (302 mg, 66%) was obtained as colorless syrup.

Workup

  1. temperaturethe mixture was heated
  2. temperatureto reflux
  3. temperatureAfter cooling
  4. customthe catalyst in the reaction mixture was removed by filtration
  5. customThe filtrate was evaporated in vacuo
  6. additionTo the residue were added CH2Cl2 (30 ml), ethanol (7 mL), and benzaldehyde (140 mg) at 25° C
  7. stirringAfter stirring for 5 minutes
  8. additionsodium triacetoxyborohydride (280 mg) was added to the mixture
  9. stirringThe reaction mixture was stirred at 25° C. for 3 hours
  10. additionpoured into a mixture of CH2Cl2 and aqueous NaHCO3
  11. customThe organic layer was separated
  12. dry with materialdried over sodium sulfate
  13. concentrationconcentrated in vacuo
  14. customThe residue was purified by column chromatography on silica gel (11 g)
  15. additionThe fractions containing the objective compound
  16. customwere collected
  17. customevaporated under reduced pressure

Sources & evidence

ORD record
ord-fefdbc58606f4f9f91fea5104aeb1ea1
Source dataset
uspto-grants-2008_12
Patent number
US07465731B2

Reaction notes

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