Methanol → 7-(4-Cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride

HRID 279559Notes

Reaction equation

HRID 279559 reaction equation
[ClH:1].[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.Br[CH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+].CO>CN(C=O)C>[ClH:1].[C:35]([C:34]1[CH:37]=[CH:38][C:31]([CH2:30][O:18][C:12]2[CH:11]=[C:10]3[C:15]([C:6]([NH:5][C:4]4[CH:19]=[C:20]([OH:24])[C:21]([CH3:23])=[CH:22][C:3]=4[F:2])=[N:7][CH:8]=[N:9]3)=[CH:14][C:13]=2[O:16][CH3:17])=[CH:32][CH:33]=1)#[N:36]

Participants

6

Reactant 4

HCID 887MethanolHCID 11430Potassium Carbonate2×HCID 869964-(Bromomethyl)benzonitrileHCID 1356711794-(2-Fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride

Product 1

HCID 226248817-(4-Cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochlorideYield 25%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
50 °C

Procedure

A mixture of 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-hydroxy-6-methoxyquinazoline hydrochloride (187 mg, 0.75 mmol), (prepared as described for the starting material in Example 22), 4-bromomethylbenzonitrile (147 mg, 0.75 mmol) and potassium carbonate (173 mg, 1.25 mmol) in DMF (5 ml) was heated at 50° C. for 1 hour. Methanol (5 ml) and potassium carbonate (138 mg, 1 mmol) were added and the mixture stirred at 65° C. for 2 hours. The solvent was removed by evaporation, water was added to the residue and the mixture adjusted to pH7 with 2M hydrochloric acid. The resulting precipitate was collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified product was triturated with ether, collected by filtration and dried. The solid was dissolved in methylene chloride/isopropanol and a 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added. The mixture was concentrated by evaporation and the resulting precipitate collected by filtration, washed with methylene chloride and dried under vacuum to give 7-(4-cyanobenzyloxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (60 mg, 25%).

Workup

  1. custom(prepared
  2. customThe solvent was removed by evaporation, water
  3. additionwas added to the residue
  4. filtrationThe resulting precipitate was collected by filtration
  5. washwashed with water
  6. customdried under vacuum
  7. customThe solid was purified by column chromatography
  8. washeluting with methylene chloride/methanol (95/5)
  9. customThe purified product was triturated with ether
  10. filtrationcollected by filtration
  11. customdried
  12. dissolutionThe solid was dissolved in methylene chloride/isopropanol
  13. additiona 5M solution of hydrogen chloride in isopropanol (0.5 ml) was added
  14. concentrationThe mixture was concentrated by evaporation
  15. filtrationthe resulting precipitate collected by filtration
  16. washwashed with methylene chloride
  17. customdried under vacuum

Sources & evidence

ORD record
ord-f378272ebb0f4c7e995d0c53293c19ef
Source dataset
uspto-grants-2002_03
Patent number
US06362336B1

Reaction notes

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