Potassium Iodide → 4-(2-Fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride

HRID 279549Notes

Reaction equation

HRID 279549 reaction equation
Cl.[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([O:24]C(OC)=O)=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.Cl.[Cl:30][CH2:31][C:32]1[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:30].[F:2][C:3]1[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[CH:19][C:4]=1[NH:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH2:31][C:32]3[N:33]([CH3:37])[CH:34]=[CH:35][N:36]=3)=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1

Participants

6

Reactant 4

HCID 4875Potassium IodideHCID 11430Potassium CarbonateHCID 27954062-(chloromethyl)-1-methyl-1H-imidazole hydrochlorideHCID 1356711794-(2-Fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride

Product 1

HCID 226249034-(2-Fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline hydrochlorideYield 22.4%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (470 mg, 1 mmol), (prepared as described for the starting material in Example 22), 2-chloromethyl-1-methylimidazole hydrochloride (335 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) and potassium iodide (20 mg) in DMF (15 ml) was heated at 60° C. for 2 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was separated, washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The crude product was dissolved in methanol (20 ml), 2M sodium hydroxide (1 ml) was added and the mixture stirred for 15 minutes. Concentrated hydrochloric acid (0.5 ml) was added and the solvent was removed by evaporation. The crude product was purified by reverse phase chromatography eluting with methanol/water (1/1). Concentrated hydrochloric acid (0.3 ml) was added to the combined fractions containing the pure product and the solvent was removed by evaporation to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((1-methylimidazol-2-yl)methoxy)quinazoline hydrochloride (100 mg, 21%).

Workup

  1. custom(prepared
  2. temperatureto cool
  3. custompartitioned between ethyl acetate and water
  4. customThe organic layer was separated
  5. washwashed with water and brine
  6. dry with materialdried (MgSO4)
  7. customthe solvent removed by evaporation
  8. dissolutionThe crude product was dissolved in methanol (20 ml)
  9. addition2M sodium hydroxide (1 ml) was added
  10. additionConcentrated hydrochloric acid (0.5 ml) was added
  11. customthe solvent was removed by evaporation
  12. customThe crude product was purified by reverse phase chromatography
  13. washeluting with methanol/water (1/1)
  14. additionConcentrated hydrochloric acid (0.3 ml) was added to the combined fractions
  15. additioncontaining the pure product
  16. customthe solvent was removed by evaporation

Sources & evidence

ORD record
ord-0396871c058146c98b494445ac149bb4
Source dataset
uspto-grants-2002_03
Patent number
US06362336B1

Reaction notes

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