Methyl iodide → 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

HRID 2261253Notes

Reaction equation

HRID 2261253 reaction equation
[Br:1][C:2]1[C:7](=[O:8])[NH:6][C:5]2[N:9]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[F:19])[N:10]=[CH:11][C:4]=2[CH:3]=1.[H-].[Na+].[Br-].[Li+].[CH3:24]I>COCCOC.CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:24])[C:5]2[N:9]([C:12]3[C:13]([F:19])=[CH:14][CH:15]=[CH:16][C:17]=3[F:18])[N:10]=[CH:11][C:4]=2[CH:3]=1

Participants

7

Reactant 4

HCID 6328Methyl iodideHCID 24758Sodium hydrideHCID 82050Lithium BromideHCID 1359231755-Bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one

Product 1

HCID 461976915-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-oneYield 44.7%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 80711,2-DimethoxyethaneSolvent

Conditions

Temperature
0 °C

Procedure

5-Bromo-1-(2,6-difluorophenyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (11.3 g, 34.7 mmol) in DME (78 mL) and DMF (7.7 mL) was cooled to 0° C. under argon. NaH (1.24 g of 95% wt., 49 mmol) was then added in small portions and the solution was allowed to stir at 0° C. for 10 min. Finely ground lithium bromide (8.83 g, 102 mmol) was then added and the solution stirred at RT for 20 min at which point MeI (4.37 ml, 68.9 mmol) was added. The suspension was heated at 40° C. for 16 h then cooled to RT. The reaction mixture was quenched with water and extracted with EtOAc (3×100 mL). The combined organic solution was washed with 2×50 mL brine, dried over MgSO4, filtered and concentrated. The resulting crude solid was then suspended in 300 mL of 1:1 solution of EtOAc:Hexanes with stirring over 30 min. The solution was then allowed to precipitate in the freezer for 2 h. The resulting solid was then collected by filtration washing with MTBE affording 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (5.27 g) in >95% purity as a beige solid. The mother liquor was then concentrated to ca. 15 ml in vacuo (rotary evaporator) and treated with 50 mL of MTBE and again chilled in the freezer overnight. The resulting solid was collected by filtration and washing with MTBE to afford a second crop of 5-bromo-1-(2,6-difluorophenyl)-7-methyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (1.54 g) in ca. 95% purity. MS (ESI, pos.ion) m/z: 340.0/342.0 (M+1). For a related reference, see: Liu, H.; Ko, S.-B.; Josien, H.; Curran, D. P. Tetrahedron Lett. 1995, 36, 8917-8920.

Workup

  1. additionwas added
  2. temperatureThe suspension was heated at 40° C. for 16 h
  3. temperaturethen cooled to RT
  4. customThe reaction mixture was quenched with water
  5. extractionextracted with EtOAc (3×100 mL)
  6. washThe combined organic solution was washed with 2×50 mL brine
  7. dry with materialdried over MgSO4
  8. filtrationfiltered
  9. concentrationconcentrated
  10. stirringHexanes with stirring over 30 min
  11. customto precipitate in the freezer for 2 h
  12. filtrationThe resulting solid was then collected by filtration
  13. washwashing with MTBE

Sources & evidence

ORD record
ord-3c1ae18008c142cc847ff8f7317cd484
Source dataset
uspto-grants-2010_12
Patent number
US07846944B2

Reaction notes

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