Trifluoroacetic acid → ethyl 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine-3-carboxylate

HRID 510030Notes

Reaction equation

HRID 510030 reaction equation
[NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.CN(C)[CH:22]=[C:23]([F:26])[CH:24]=O.FC(F)(F)C(O)=O>O1CCOCC1>[F:26][C:23]1[CH:22]=[C:3]2[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5][N:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:2]2=[N:1][CH:24]=1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acidHCID 11391384ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylateHCID 54236093(2z)-3-(Dimethylamino)-2-fluoroacrylaldehyde

Product 1

HCID 56849011ethyl 5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine-3-carboxylate

Reagents, catalysts & solvents 1

HCID 312751,4-DioxaneSolvent

Procedure

13.487 g (51.228 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparation described for example 20A in WO 00/06569) were initially charged in 300 ml of dioxane, and 6 g (51.228 mmol) of 3-(dimethylamino)-2-fluoroacrylaldehyde (preparation described in Justus Liebigs Annalen der Chemie 1970; 99-107) were added at RT. Subsequently, 4.736 ml (61.473 mmol) of trifluoroacetic acid were added and the mixture was heated to reflux while stirring for 3 days. After cooling, the mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The phases were separated and the organic phase was washed twice with water. The combined aqueous phases were subsequently extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue (22 g) was subsequently purified by chromatography on silica gel (eluent: dichloromethane). This gave 5.67 g (35% of theory) of the title compound.

Workup

  1. temperaturethe mixture was heated
  2. temperatureto reflux
  3. temperatureAfter cooling
  4. concentrationthe mixture was concentrated under reduced pressure, and water and ethyl acetate
  5. additionwere added to the residue
  6. customThe phases were separated
  7. washthe organic phase was washed twice with water
  8. extractionThe combined aqueous phases were subsequently extracted twice with ethyl acetate
  9. dry with materialThe combined organic phases were dried over sodium sulfate
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe residue (22 g) was subsequently purified by chromatography on silica gel (eluent: dichloromethane)

Sources & evidence

ORD record
ord-8f065c4c5ca14ddd9ce6c051b2f93bf1
Source dataset
uspto-grants-2015_08
Patent number
US09096592B2

Reaction notes

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