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

HRID 279539Notes

Reaction equation

HRID 279539 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]=[C:34]([CH3:37])[S:35][CH: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]=[C:34]([CH3:37])[S:35][CH: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 27342034-(Chloromethyl)-2-methyl-1,3-thiazole--hydrogen chloride (1/1)HCID 1356711794-(2-Fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride

Product 1

HCID 226249794-(2-Fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline hydrochlorideYield 48.6%

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), 4-chloromethyl-2-methylthiazole hydrochloride (368 mg, 2 mmol), potassium carbonate (414 mg, 3 mmol) and potassium iodide (40 mg) in DMF (15 ml) was heated at 60° C. for 24 hours. The mixture was allowed to cool and partitioned between ethyl acetate and water. The organic layer was washed with water and brine, dried (MgSO4) and the solvent removed by evaporation. The residue was dissolved in methanol (15 ml) and 1M sodium hydroxide (2 ml) was added and the mixture stirred for 30 minutes. Concentrated hydrochloric acid (0.5 ml) was added. The solvent was removed by evaporation. The residue was purified by reverse phase HPLC eluting with a gradient (0-70%) of methanol in water. Concentrated hydrochloric acid (0.3 ml) was added to the combined fractions of pure product and the solvent was removed by evaporation. The residue was triturated with acetone, collected by filtration, washed with acetone and dried under vacuum at 55° C. to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-((2-methylthiazol-4-yl)methoxy)quinazoline hydrochloride (225 mg, 48%).

Workup

  1. temperatureto cool
  2. custompartitioned between ethyl acetate and water
  3. washThe organic layer was washed with water and brine
  4. dry with materialdried (MgSO4)
  5. customthe solvent removed by evaporation
  6. dissolutionThe residue was dissolved in methanol (15 ml)
  7. addition1M sodium hydroxide (2 ml) was added
  8. additionConcentrated hydrochloric acid (0.5 ml) was added
  9. customThe solvent was removed by evaporation
  10. customThe residue was purified by reverse phase HPLC
  11. washeluting with a gradient (0-70%) of methanol in water
  12. additionConcentrated hydrochloric acid (0.3 ml) was added to the combined fractions of pure product
  13. customthe solvent was removed by evaporation
  14. customThe residue was triturated with acetone
  15. filtrationcollected by filtration
  16. washwashed with acetone
  17. customdried under vacuum at 55° C.

Sources & evidence

ORD record
ord-f7eab806b3154af388b83342cf7a3c5c
Source dataset
uspto-grants-2002_03
Patent number
US06362336B1

Reaction notes

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