Hydrochloric Acid → 6-bromo-N4-(3-chloro-4-fluorophenyl)-4,7-quinazolinediamine

HRID 1592951Notes

Reaction equation

HRID 1592951 reaction equation
[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]=[CH:7][NH:6][C:5]2=O.P(Cl)(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:35]=[CH:36][C:37]=1[F:38])[NH2:34].Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.C(O)(C)C.[Cl-].[Na+].O.C(O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:34][C:33]1[CH:35]=[CH:36][C:37]([F:38])=[C:31]([Cl:30])[CH:32]=1

Participants

12

Reactant 6

HCID 313Hydrochloric AcidHCID 97083-Chloro-4-fluoroanilineHCID 14798Sodium HydroxideHCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 135738671HCID 135738671, compound

Product 1

HCID 589981116-bromo-N4-(3-chloro-4-fluorophenyl)-4,7-quinazolinediamine

Reagents, catalysts & solvents 5

HCID 702EthanolSolventHCID 1140TolueneSolventHCID 3776IsopropanolSolventHCID 8058HexaneSolventHCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
80 °C

Procedure

Formamidine acetate (4.51 g, 43.3 mmol) and methoxyethanol (60 mL) were added to 5-bromo-4-nitroanthranyl acid (described in JP-A-2000-169451) (5.65 g, 21.7 mmol) and the mixture was refluxed for 4 hrs. Water was added until the reaction mixture becomes about 200 mL and the precipitate was filtered and washed with water. The precipitate was dried under reduced pressure to give 6-bromo-7-nitro-3H-quinazolin-4-one (5.21 g, 64%). To a solution (20 mL) of 6-bromo-7-nitro-3H-quinazolin-4-one (1.34 g, 5.0 mmol) in toluene were added phosphorous oxychloride (0.70 mL, 7.5 mmol) and diisopropylethylamine (1.29 mL, 7.5 mmol), and the mixture was stirred at 80° C. for 5 hrs. A solution (5 mL) of 3-chloro-4-fluoroaniline (1.09 g, 7.5 mmol) in isopropanol was added at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into hexane (30 mL) and the mixture was stirred at room temperature for 30 min. The product was collected by filtration and dried. To this compound were added reduced iron (1.10 g, 20.0 mmol), 1N hydrochloric acid (10 mL) and ethanol (30 mL) and the mixture was refluxed for 1 hr. 1N Aqueous sodium hydroxide solution (10 mL) was added and the mixture was stirred at 50° C. for 30 min. Saturated brine was added and the mixture was extracted with ethyl acetate. The organic layer was concentrated and the residue was suspension-washed with acetonitrile (10 mL) to give 6-bromo-N4-(3-chloro-4-fluorophenyl)-4,7-quinazolinediamine (5′) (987 mg, 54%).

Workup

  1. stirringthe mixture was stirred overnight
  2. stirringthe mixture was stirred at room temperature for 30 min
  3. filtrationThe product was collected by filtration
  4. customdried
  5. temperaturethe mixture was refluxed for 1 hr
  6. stirringthe mixture was stirred at 50° C. for 30 min
  7. extractionthe mixture was extracted with ethyl acetate
  8. concentrationThe organic layer was concentrated
  9. washthe residue was suspension-washed with acetonitrile (10 mL)

Sources & evidence

ORD record
ord-4bb8835885574d7a9b92ef64fcf3647d
Source dataset
uspto-grants-2007_11
Patent number
US07294629B2

Reaction notes

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