Dimethyl Sulfoxide → 3-{[3-Amino-5-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrile

HRID 1808588Notes

Reaction equation

HRID 1808588 reaction equation
[OH-].[K+].CS(C)=O.[F:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][N:12]=[C:11]2[NH2:17].Cl[CH2:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[C:25]#[N:26]>O>[NH2:17][C:11]1[C:10]2[C:14](=[CH:15][CH:16]=[C:8]([F:7])[C:9]=2[O:18][CH3:19])[N:13]([CH2:21][C:22]2[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=2)[C:25]#[N:26])[N:12]=1

Participants

6

Reactant 4

HCID 679Dimethyl SulfoxideHCID 14797Potassium HydroxideHCID 5221263-(Chloromethyl)benzonitrileHCID 580545685-Fluoro-4-methoxy-1H-indazol-3-amine

Product 1

HCID 580544013-{[3-Amino-5-fluoro-4-(methyloxy)-1H-indazol-1-yl]methyl}benzonitrileYield 48%

Reagents, catalysts & solvents 1

HCID 962WaterSolvent

Procedure

Finely ground potassium hydroxide (6.59 g, 118 mmol, 2.5 equiv.) was treated with DMSO (100 mL). To this was added 5-fluoro-4-(methyloxy)-1H-indazol-3-amine (for a preparations see Intermediate 56) (8.5 g, 47 mmol) and the mixture stirred at room temperature for 50 minutes. To the red coloured mixture was added 3-chloromethyl benzonitrile (8.9 g, 59 mmol, 1.25 equiv.) in one portion. A small exotherm of −5° C. was observed. The mixture was allowed to stir at room temperature for 25 minutes before pouring into water (600 mL) and extracting with chloroform (400 mL). The aqueous was re-extracted with chloroform (2×400 mL). The organic extracts were combined, washed with water (3×500 mL), dried over MgSO4, filtered and evaporated to give the crude product. This was dry loaded onto silica and chromatographed eluting with 20% petrol up to 70% EtOAc-petrol. The material came off impure so was re-chromatographed on a suction column. The impure material was loaded in DCM and eluted with DCM up to 30% EtOAc-DCM to give the title compound (8.25 g, 48%) as an off-white solid. LCMS (System A) RT=0.96 min, ES+ve m/z 297 (M+H)+.

Workup

  1. customA small exotherm of −5° C.
  2. stirringto stir at room temperature for 25 minutes
  3. extractionextracting with chloroform (400 mL)
  4. extractionThe aqueous was re-extracted with chloroform (2×400 mL)
  5. washwashed with water (3×500 mL)
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. customevaporated
  9. customto give the crude product
  10. customThis was dry
  11. customchromatographed
  12. washeluting with 20% petrol up to 70% EtOAc-petrol
  13. customso was re-chromatographed on a suction column
  14. washeluted with DCM up to 30% EtOAc-DCM

Sources & evidence

ORD record
ord-f1029047b0454e33b65789fe9281f917
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

Loading…