Potassium Iodide → 4-(3-Hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylpropoxy)quinazoline hydrochloride

HRID 1384522Notes

Reaction equation

HRID 1384522 reaction equation
Cl.C([O:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([OH:22])=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1)(=O)C.[Cl:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[C:33](Cl)[CH:32]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C=O)C>[ClH:27].[OH:5][C:6]1[CH:7]=[C:8]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)=[C:17]([O:20][CH3:21])[CH:18]=2)[N:13]=[CH:12][N:11]=1

Participants

6

Reactant 4

HCID 4875Potassium IodideHCID 11430Potassium CarbonateHCID 865846804-(3-Chloropropyl)pyridyl hydrochlorideHCID 1356711804-(3-Acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride

Product 1

HCID 701703484-(3-Hydroxy-4-methylanilino)-6-methoxy-7-(4-pyridylpropoxy)quinazoline hydrochlorideYield 63.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
60 °C

Procedure

A solution of 4-(3-acetoxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (400 mg, 1.06 mmol), (prepared as described for the starting material in Example 1), 4-(3-chloropropyl)pyridyl hydrochloride 410 mg, 2.1 mmol), potassium carbonate (438 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 (20 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 (1 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-(3-hydroxy4-methylanilino)-6-methoxy-7-(4-pyridylpropoxy)quinazoline hydrochloride (305 mg, 59%). m.p. 278-282° C. 1H NMR Spectrum: (DMSO-d6) 2.15(s, 3H); 2.3(m, 2H); 3.1(m, 2H); 3.96(s, 3H); 4.24(t, 2H); 6.98(dd, 1H); 7.15(m,2H); 7.44(s, 1H); 7.96(d, 2H); 8.31(s, 1H); 8.77(s, 1H); 8.81(d, 2H); 9.7(br s, 1H); 11.34(s, 1H) MS−ESI: 417 [MH]+

Workup

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

Sources & evidence

ORD record
ord-1f08e79c6ea24682a2cbf97a661f9146
Source dataset
uspto-grants-2001_07
Patent number
US06258951B1

Reaction notes

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