4-Chloro-2-fluoroaniline → 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride

HRID 279652Notes

Reaction equation

HRID 279652 reaction equation
[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.Cl.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]3[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=3)=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][N:27]([CH3:35])[C:28]4[CH:33]=[C:32]([CH3:34])[N:31]=[CH:30][N:29]=4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[C:4]([F:9])[CH:3]=1

Participants

4

Reactant 2

HCID 938984-Chloro-2-fluoroanilineHCID 226249054-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride

Product 1

HCID 226249404-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochlorideYield 56%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

4-Chloro-2-fluoroaniline (77 mg, 0.53 mmol) was added to a solution of 4-chloro-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride (140 mg, 0.35 mmol) in isopropanol (5 ml) and the mixture heated at reflux for 1 hour. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by flash chromatography eluting with methylene chloride/methanol (95/5). The purified solid was dissolved in methylene chloride/methanol and ethereal hydrogen chloride (1 ml of a 5M solution) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(N-methyl-N-(6-methylpyrimidin-4-yl)amino)ethoxy)quinazoline hydrochloride (75 mg, 39%).

Workup

  1. temperaturethe mixture heated
  2. temperatureat reflux for 1 hour
  3. customThe solvent was removed by evaporation
  4. customthe residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution
  5. customThe organic layer was separated
  6. washwashed with brine
  7. dry with materialdried (MgSO4)
  8. customthe solvent removed by evaporation
  9. customThe residue was purified by flash chromatography
  10. washeluting with methylene chloride/methanol (95/5)
  11. dissolutionThe purified solid was dissolved in methylene chloride/methanol
  12. additionethereal hydrogen chloride (1 ml of a 5M solution) was added
  13. customThe volatiles were removed by evaporation
  14. customthe residue was triturated with ether
  15. filtrationcollected by filtration
  16. washwashed with ether
  17. customdried under vacuum

Sources & evidence

ORD record
ord-8c5f9a293b494cfcaa7a64567ee9c0a6
Source dataset
uspto-grants-2002_03
Patent number
US06362336B1

Reaction notes

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