Hydrochloric Acid → 6-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine

HRID 1778800Notes

Reaction equation

HRID 1778800 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[N:16]=[CH:15][C:14]3[C:17]([C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)=[N:18][N:19](C4CCCCO4)[C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.S(Cl)([Cl:35])(=O)=O.[ClH:37].C(Cl)(=O)C>C(Cl)Cl.CO.C(#N)C>[Cl:37][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([O:9][CH3:10])=[C:6]([Cl:35])[C:5]=1[C:11]1[N:16]=[CH:15][C:14]2[C:17]([C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)=[N:18][NH:19][C:13]=2[CH:12]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 6367Acetyl chlorideHCID 24648Sulfuryl chloride2×HCID 867228776-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine

Product 1

HCID 762851116-(2,6-dichloro-3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridine

Reagents, catalysts & solvents 3

HCID 887MethanolSolvent2×HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent2×

Procedure

At 0° C. to a stirring solution of 6-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine (80 mg, 0.2 mmol) in methylene chloride (3 mL) was added dropwise a solution of sulfuryl chloride (31 μL, 0.38 mmol)(Acros Organics, Cat. #: 37815) in methylene chloride (1 mL). The mixture was stirred at r.t. overnight. To the mixture was added acetonitrile (2 mL) and it was stirred at r.t. for 1 h. Then, to the mixture was added another 31 μL of sulfuryl chloride and it was stirred at r.t. for 4 h. The solvent was removed under reduced pressure and the residue was treated with methylene chloride and sat'd NaHCO3 solution. After separation the aq. layer was extracted with methylene chloride. The combined organic layers were dried over Na2SO4. After filtration the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%) to afford an intermediate which was dissolved in methanol (3 mL), and cooled to 0° C. To the solution was added a pre-cooled HCl solution prepared from acetyl chloride (700 μL, 10 mmol) and methanol (1 mL). The mixture was stirred at r.t. for 4 h and then the solvents were removed. The residue was dissolved in methanol, and purified by RP-HPLC (pH=2) to afford the desired product (4.8 mg) as a TFA salt. LCMS (M+H)+=404.1.

Workup

  1. stirringwas stirred at r.t. for 1 h
  2. stirringwas stirred at r.t. for 4 h
  3. customThe solvent was removed under reduced pressure
  4. additionthe residue was treated with methylene chloride and sat'd NaHCO3 solution
  5. customAfter separation the aq. layer
  6. extractionwas extracted with methylene chloride
  7. dry with materialThe combined organic layers were dried over Na2SO4
  8. filtrationAfter filtration the filtrate
  9. concentrationwas concentrated under reduced pressure
  10. customThe residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-50%)
  11. customto afford an intermediate which
  12. temperaturecooled to 0° C
  13. stirringThe mixture was stirred at r.t. for 4 h
  14. customthe solvents were removed
  15. dissolutionThe residue was dissolved in methanol
  16. custompurified by RP-HPLC (pH=2)

Sources & evidence

ORD record
ord-e81f0b5696944fd5baa0b50240d27dbe
Source dataset
uspto-grants-2016_02
Patent number
US09266892B2

Reaction notes

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