Potassium Hydroxide → 1-{[3-Fluoro-4-(methyloxy)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-amine

HRID 1808598Notes

Reaction equation

HRID 1808598 reaction equation
[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([NH2:12])=[N:6][NH:7]2.CC(N(CC1C=CC=C(CN2C3C(=C(C(=O)C)C=CC=3)C(NS(C3SC(Cl)=CC=3)(=O)=O)=N2)C=1)C(=O)[O-])(C)C.[OH-].[K+].Br[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[C:57]([F:63])[CH:56]=1>CS(C)=O.C(OCC)(=O)C.ClCCl>[F:63][C:57]1[CH:56]=[C:55]([CH2:54][N:7]2[C:8]3[C:4](=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][CH:9]=3)[C:5]([NH2:12])=[N:6]2)[CH:60]=[CH:59][C:58]=1[O:61][CH3:62]

Participants

8

Reactant 4

HCID 14797Potassium HydroxideHCID 27745534-(Bromomethyl)-2-fluoro-1-methoxybenzeneHCID 185260534-Methoxy-1H-indazol-3-amineHCID 866448151,1-dimethylethyl({3-[(4-acetyl-3-{[(5-chloro-2-thienyl)sulfonyl]amino}-1H-indazol-1-yl)methyl]phenyl}methyl)carbamate

Product 1

HCID 580545111-{[3-Fluoro-4-(methyloxy)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-amineYield 48%

Reagents, catalysts & solvents 3

HCID 679Dimethyl SulfoxideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

4-(Methyloxy)-1H-indazol-3-amine (for a preparation see Intermediate 1) (490 mg, 3 mmol) and potassium hydroxide (185 mg, 3.30 mmol) were dissolved in DMSO (30 mL). The reaction was left to stir for 30 min, before 4-(bromomethyl)-2-fluoro-1-(methyloxy)benzene (657 mg, 3.00 mmol) was added to the reaction mixture and stirred for 1 h at room temperature under nitrogen. The reaction mixture was diluted with ethyl acetate (250 mL) and washed with water (2×250 mL) and brine (250 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered before being evaporated in vacuo to afford a brown oil. The residue was loaded in dichloromethane on a silica 100 g cartridge and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo and the residue re-purified by chromatography on silica 70 g using a 0-50% ethyl acetate-dichloromethane over 40 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (432 mg, 48%) as an off-white solid. LCMS (System A) RT=0.96 min, ES+ve m/z 302 (M+H)+.

Workup

  1. waitThe reaction was left
  2. additionwas added to the reaction mixture
  3. washwashed with water (2×250 mL) and brine (250 mL)
  4. dry with materialThe organic layer was dried over anhydrous magnesium sulphate
  5. filtrationfiltered
  6. custombefore being evaporated in vacuo
  7. customto afford a brown oil
  8. custompurified by chromatography on Flashmaster
  9. customover 40 min
  10. customevaporated in vacuo
  11. customthe residue re-purified by chromatography on silica 70 g
  12. customover 40 min
  13. customevaporated in vacuo

Sources & evidence

ORD record
ord-ad7e9bf254304daf99f936179b1e2960
Source dataset
uspto-grants-2013_01
Patent number
US08357716B2

Reaction notes

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