Trifluoroacetic acid → 4-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline

HRID 454166Notes

Reaction equation

HRID 454166 reaction equation
FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:26])=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:36][N:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:39][CH2:38]1>CN(C=O)C.O>[Cl:8][C:9]1[CH:28]=[CH:27][C:12]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:45][CH2:44][CH2:43][N:40]4[CH2:41][CH2:42][N:37]([CH3:36])[CH2:38][CH2:39]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[C:11]([F:29])[CH:10]=1

Participants

7

Reactant 4

HCID 6422Trifluoroacetic acidHCID 11430Potassium CarbonateHCID 218748183-(4-Methyl-piperazin-1-yl)propyl-4-toluene sulphonateHCID 1356162044-(4-Chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 218748154-(4-Chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazolineYield 48.1%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

A mixture of the trifluoroacetic acid salt of 4-(4-chloro-2-fluorophenoxy)-7-hydroxy-6-methoxyquinazoline (3.2 g, 7.4 mmol), potassium carbonate (6.1 g, 44.2 mmol) and 3-(4-methyl-1-piperazinyl)propyl-4-toluene sulphonate (3.0 g, 9.6 mmol) in DMF (60 ml) was stirred at 90° C. for 5 hours and allowed to cool to ambient temperature. The reaction mixture was poured into water (700 ml) and extracted 5 times with ethyl acetate. The combined extracts were washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine. The ethyl acetate solution was dried over magnesium sulphate, filtered and the solvent removed under vacuum to give a residue which was purified by silica column chromatography, eluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1). The relevant fractions were combined and evaporated under vacuum to give a residue which was triturated with ether, filtered and dried to give 4-(4-chloro-2-fluorophenoxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (1.64 g, 48%).

Workup

  1. temperatureto cool to ambient temperature
  2. extractionextracted 5 times with ethyl acetate
  3. washThe combined extracts were washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine
  4. dry with materialThe ethyl acetate solution was dried over magnesium sulphate
  5. filtrationfiltered
  6. customthe solvent removed under vacuum
  7. customto give a residue which
  8. customwas purified by silica column chromatography
  9. washeluting with dichloromethane/methanol/0.880 aqueous ammonia (100/8/1)
  10. customevaporated under vacuum
  11. customto give a residue which
  12. customwas triturated with ether
  13. filtrationfiltered
  14. customdried

Sources & evidence

ORD record
ord-99950eff4e344ea5a73779f6f7b20fae
Source dataset
uspto-grants-2013_07
Patent number
US08492560B2

Reaction notes

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