Lithium Hydroxide → N-{5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2,6-difluorobenzamide

HRID 1159961Notes

Reaction equation

HRID 1159961 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:30])=[C:21]([NH:23][C:24](=[O:29])C(F)(F)F)[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[Li+].[OH-].[F:33][C:34]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[C:35]=1C(Cl)=O.C(O)C(N)(CO)CO>CN(C=O)C.O.C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[CH:19][C:20]([F:30])=[C:21]([NH:23][C:24](=[O:29])[C:35]4[C:34]([F:33])=[CH:42][CH:41]=[CH:40][C:39]=4[F:43])[CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1

Participants

8

Reactant 4

HCID 3939Lithium HydroxideHCID 6503Tris(hydroxymethyl)aminomethaneHCID 874382,6-Difluorobenzoyl chlorideHCID 59511417N-{5-[3-(2-Chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2,2,2-trifluoroacetamide

Product 1

HCID 59513873N-{5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2,6-difluorobenzamideYield 49%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Procedure

A solution of N-{5-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]-2-fluorophenyl}-2,2,2-trifluoroacetamide (300 mg, 0.69 mmol) and 1M LiOH (4.13 ml, 4.13 mmol) in 10:1 THF:H2O (15 mL) was heated at 50° C. overnight. The reaction was washed with brine (25 mL) and the aqueous layer was extracted with EtOAc (25 mL). The organic layers were combined, filtered through a cotton plug, and solvent removed by rotary evaporation. After high vacuum removal of residual solvent, the crude mixture was dissolved in DCM (10 mL) and to this was added 2,6-difluorobenzoyl chloride (519 mg, 2.94 mmol). After stirring 3 h at ambient temperature, DMF (25 mL) was added to dissolve any suspended solids followed by the addition of excess polymer-bound trisamine resin. Upon overnight stirring, the amine resin was removed by vacuum filtration, rinsed with MeOH (50 mL), and filtrate concentrated under reduced pressure to afford the desired amide (162 mg, 49%) as an off-white solid. ESIMS (M+H)+=480.

Workup

  1. washThe reaction was washed with brine (25 mL)
  2. extractionthe aqueous layer was extracted with EtOAc (25 mL)
  3. filtrationfiltered through a cotton plug, and solvent
  4. customremoved by rotary evaporation
  5. customAfter high vacuum removal of residual solvent
  6. dissolutionthe crude mixture was dissolved in DCM (10 mL)
  7. dissolutionto dissolve any suspended solids
  8. stirringUpon overnight stirring
  9. customthe amine resin was removed by vacuum filtration
  10. washrinsed with MeOH (50 mL), and filtrate
  11. concentrationconcentrated under reduced pressure

Sources & evidence

ORD record
ord-c443e1f8202344ed9ef452ef5548a201
Source dataset
uspto-grants-2010_10
Patent number
US07812022B2

Reaction notes

Loading…