Water → 4-(2-chlorophenyl)-6-[(2-methylpiperazin-1-yl)methyl]-2,4-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile;dihydrochloride

HRID 489432Notes

Reaction equation

HRID 489432 reaction equation
[H-].[Na+].[CH3:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[C:22]([C:23]#[N:24])=[C:21](CBr)[NH:20][C:19]2=[N:27][NH:28][CH:29]=[C:18]12.O.[CH3:31]N(C=O)C>>[ClH:10].[ClH:10].[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]1[C:22]([C:23]#[N:24])=[C:21]([CH2:3][N:4]2[CH2:9][CH2:8][NH:7][CH2:6][CH:5]2[CH3:31])[NH:20][C:19]2=[N:27][NH:28][CH:29]=[C:18]12

Participants

6

Reactant 5

HCID 962WaterHCID 6228Dimethylformamide2×HCID 24758Sodium hydrideHCID 531671-MethylpiperazineHCID 178509439HCID 178509439, compound

Product 1

HCID 1784305344-(2-chlorophenyl)-6-[(2-methylpiperazin-1-yl)methyl]-2,4-dihydro-1H-pyrazolo[3,4-b]pyridine-5-carbonitrile;dihydrochloride

Procedure

4-(2-Chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)-methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine was prepared from ethyl t-butyldimethylsilyloxyacetate, 2-chlorobenzaldehyde and 3-aminopyrazole in the same manner as in Example 94. To a solution of 4-(2-chlorophenyl)-5-cyano-6-(t-butyldimethylsilyloxy)methyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (10 g) in tetrahydrofuran (100 ml) was added a THF solution (24.9 ml) of 1.0 M tetrabutylammonium fluoride and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added ethyl acetate (200 ml), and the resulting mixture was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was crystallized from ethyl acetate to give 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (5.46 g) as a white solid. To a solution of 4-(2-chlorophenyl)-5-cyano-6-hydroxymethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (1.0 g) and carbon tetrabromide (1.27 g) in methylene chloride (35 ml) was added triphenylphosphine (1.0 g) under ice-cooling and the mixture was stirred under ice-cooling for 4 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)) to give 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (0.45 g) as a pale-yellow solid. To a suspension of sodium hydride (25 mg) in DMF (3 ml) was added 1-methylpiperazine (69 μl) and the mixture was stirred at room temperature for 30 minutes. To this reaction mixture was added a solution of 4-(2-chlorophenyl)-5-cyano-6-bromomethyl-4,7-dihydro-2H-pyrazolo[3,4-b]pyridine (200 mg) in DMF (3 ml) under ice-cooling and the mixture was stirred under ice-cooling for 1 hour. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (4:1)). The obtained oil was treated with hydrogen chloride-methanol to give the title compound (87 mg) as white crystals.

Workup

  1. temperaturecooling
  2. stirringthe mixture was stirred under ice-
  3. temperaturecooling for 1 hour
  4. extractionthe mixture was extracted with ethyl acetate
  5. washThe extract was washed with a saturated aqueous sodium chloride solution
  6. dry with materialdried over anhydrous magnesium sulfate
  7. customThe solvent was evaporated
  8. customthe obtained residue was purified by silica gel column chromatography (eluent:ethyl acetate-methanol (4:1))
  9. additionThe obtained oil was treated with hydrogen chloride-methanol

Sources & evidence

ORD record
ord-24d00199c56b4bee8cad092644771559
Source dataset
uspto-grants-2005_12
Patent number
US06977262B2

Reaction notes

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