Water → 3-{[3-Amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile

HRID 1808547Notes

Reaction equation

HRID 1808547 reaction equation
[OH-].[K+].[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([NH2:14])=[N:8][NH:9]2.Cl[CH2:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21].O>CS(C)=O.C1CCCCC1.C(OCC)(=O)C>[NH2:14][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH3:3])[N:9]([CH2:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=2)[C:20]#[N:21])[N:8]=1

Participants

8

Reactant 4

HCID 962WaterHCID 14797Potassium HydroxideHCID 5221263-(Chloromethyl)benzonitrileHCID 185260534-Methoxy-1H-indazol-3-amine

Product 1

HCID 580544253-{[3-Amino-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrileYield 59%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 8078CyclohexaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of ground potassium hydroxide (6.75 g, 120 mmol) in DMSO (300 mL) at room temperature under nitrogen was added 4-(methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (7.85 g, 48.1 mmol), and this gave a deep red solution. After 5 minutes 3-(chloromethyl)benzonitrile (8.84 g, 58.3 mmol) was added in one portion. The reaction mixture was stirred for 20 minutes and then poured into water (500 mL), forming an emulsion. This was extracted using chloroform (3×500 mL). The combined organic solutions were washed with water (400 mL) and passed through a hydrophobic frit. The solvent was removed in vacuo, the residue was applied to a 340 g silica cartridge, and eluted with a gradient of 0-100% ethyl acetate in cyclohexane over 8 CV. This gave an orange solid which was treated with ethyl acetate (10 mL) and cyclohexane (90 mL). The solid was collected by filtration and washed with cyclohexane (50 mL). The solid was dried in vacuo to give the title compound (7.89 g, 59%) as a pale orange solid. LCMS (System A) RT=0.93 min, ES+ve m/z 279 (M+H)+.

Workup

  1. customthis gave a deep red solution
  2. customforming an emulsion
  3. extractionThis was extracted
  4. washThe combined organic solutions were washed with water (400 mL)
  5. customThe solvent was removed in vacuo
  6. washeluted with a gradient of 0-100% ethyl acetate in cyclohexane over 8 CV
  7. customThis gave an orange solid which
  8. filtrationThe solid was collected by filtration
  9. washwashed with cyclohexane (50 mL)
  10. customThe solid was dried in vacuo

Sources & evidence

ORD record
ord-ba959fee657e48e1973a3e8d658ebbf5
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

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