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

HRID 1737472Notes

Reaction equation

HRID 1737472 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:29][CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][N:36]=[C:35](Cl)[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:29].[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][CH2:30][CH2:31][CH2:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=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 865846804-(3-Chloropropyl)pyridyl hydrochlorideHCID 1356711794-(2-Fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride

Product 1

HCID 700972524-(2-Fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylpropoxy)quinazoline hydrochlorideYield 51.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

A solution of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (410 mg, 1.00 mmol), 4-(3-chloropropyl)pyridyl hydrochloride (480 mg, 2.5 mmol), potassium carbonate (480 mg) and potassium iodide (40 mg) in DMF (15 ml) was heated at 60° C. for 15 hours. After cooling to ambient temperature the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4) and evaporated. The residue was diluted with methanol (10 ml) and 2M sodium hydroxide (2 ml) was added. After stirring for 1 hour, the reaction mixture was diluted with water (20 ml) and concentrated hydrochloric acid (0.5 ml) was added. The resulting solid was filtered off and was purified by preparative C18 HPLC using a gradient of methanol/water (0% to 80%) as eluant. After evaporation of the methanol, concentrated hydrochloric acid (0.3 ml) was added and the solution was evaporated to dryness. After trituration with acetone, the solid was filtered off and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylpropoxy)quinazoline hydrochloride (243 mg, 48%).

Workup

  1. customwas partitioned between ethyl acetate and water
  2. washThe organic layer was washed with brine
  3. dry with materialdried (MgSO4)
  4. customevaporated
  5. additionThe residue was diluted with methanol (10 ml) and 2M sodium hydroxide (2 ml)
  6. additionwas added
  7. additionthe reaction mixture was diluted with water (20 ml) and concentrated hydrochloric acid (0.5 ml)
  8. additionwas added
  9. filtrationThe resulting solid was filtered off
  10. customwas purified by preparative C18
  11. customAfter evaporation of the methanol, concentrated hydrochloric acid (0.3 ml)
  12. additionwas added
  13. customthe solution was evaporated to dryness
  14. filtrationAfter trituration with acetone, the solid was filtered off
  15. customdried under vacuum

Sources & evidence

ORD record
ord-34167b930861461690f4c28d652cd683
Source dataset
uspto-grants-1999_10
Patent number
US05962458

Reaction notes

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