Hydrochloric Acid → 5-Fluoro-2-(1H-pyrazolo[3,4-c]pyridin-5-yloxy)-benzonitrile

HRID 1897455Notes

Reaction equation

HRID 1897455 reaction equation
[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[C:15]([CH3:17])[C:14]([N+:18]([O-])=O)=[CH:13][N:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].Cl.[N:22]([O-])=O.[Na+].[N+]([O-])([O-])=O.[Na+].CC([O-])=O.[K+]>CC(O)=O.O.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:16]=[C:15]3[CH:17]=[N:22][NH:18][C:14]3=[CH:13][N:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 24268Sodium NitrateHCID 517044Potassium AcetateHCID 23668193Sodium NitriteHCID 574841175-Fluoro-2-(4-methyl-5-nitro-pyridin-2-yloxy)-benzonitrile

Product 1

HCID 574187565-Fluoro-2-(1H-pyrazolo[3,4-c]pyridin-5-yloxy)-benzonitrileYield 88%

Reagents, catalysts & solvents 2

HCID 8857Ethyl AcetateSolventHCID 21899381Acetic acid--water (1/1)Solvent

Conditions

Temperature
0 °C

Procedure

Intermediate (1u) (0.25 g, 1.03 mmol) and NH4BF4 (0.22 g, 2.06 mmol) were dissolved in 10 mL of mixed solvent of AcOH/water (2:1) and cooled to 0° C., and followed by addition of concentrated HCl (0.43 mL, 5.16 mmol) and NaNO2 (0.078 g, 1.13 mmol) to the solution at 0° C. The color of the solution immediately turned into yellow as sodium nitrate was added. The reaction mixture was then allowed to warm to room temperature. After stirring 2 hours, the solvent was removed under reduced pressure and azeotroped with toluene three times to removed the water, to give a pale yellow crude solid. The solid was dissolved in 10 mL of EtOAc and KOAc was added to the solution. The color of suspension turned into deep orange in 30 minutes and then stirred an additional hour. The white inorganic salt was removed by filtration and washed with EtOAc. The combined filtrate was diluted with EtOAc to 100 mL of total volume and transferred to a separatory funnel, washed with sat. NaHCO3 (10 mL) and brine, dried over MgSO4, filtered and evaporated to obtain a deep orange colored solid. The crude solid was purified on silica gel with EtOAc/hexane (2:3) to afford an orange yellow colored solid (2u) (0.23 g, 88% yield over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.15 (s, 1H), 7.30-7.34 (m, 2H), 7.32-7.22 (m, 2H), 7.12 (dd, J=9.4, 4.7 Hz, 1H) ppm.

Workup

  1. additionwas added
  2. temperatureto warm to room temperature
  3. customthe solvent was removed under reduced pressure
  4. customazeotroped with toluene three times
  5. customto removed the water
  6. customto give a pale yellow crude solid
  7. customdeep orange in 30 minutes
  8. stirringstirred an additional hour
  9. customThe white inorganic salt was removed by filtration
  10. washwashed with EtOAc
  11. additionThe combined filtrate was diluted with EtOAc to 100 mL of total volume
  12. customtransferred to a separatory funnel
  13. washwashed with sat. NaHCO3 (10 mL) and brine
  14. dry with materialdried over MgSO4
  15. filtrationfiltered
  16. customevaporated
  17. customto obtain a deep orange colored solid
  18. customThe crude solid was purified on silica gel with EtOAc/hexane (2:3)

Sources & evidence

ORD record
ord-f0933c282d80490f87fddb5acc4415f4
Source dataset
uspto-grants-2013_08
Patent number
US08518983B2

Reaction notes

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