4-Chloro-2-fluoroaniline → 4-(4-Chloro-2-fluoroanilino)-7-(3-morpholinopropoxy)quinazoline hydrochloride

HRID 1596277Notes

Reaction equation

HRID 1596277 reaction equation
Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[C:26]([F:31])[CH:25]=1>C(O)(C)C>[ClH:2].[Cl:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:13][CH2:14][CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)=[CH:10][CH:11]=3)[N:6]=[CH:5][N:4]=2)=[C:26]([F:31])[CH:25]=1

Participants

4

Reactant 2

HCID 938984-Chloro-2-fluoroanilineHCID 217015574-Chloro-7-(3-morpholinopropoxy)quinazoline hydrochloride

Product 1

HCID 217015924-(4-Chloro-2-fluoroanilino)-7-(3-morpholinopropoxy)quinazoline hydrochlorideYield 11.2%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Procedure

A mixture of 4-chloro-7-(3-morpholinopropoxy)quinazoline hydrochloride (238 mg, 0.69 mmol) and 4-chloro-2-fluoroaniline (145 mg, 1 mmol) in isopropanol (5 ml) was heated at reflux for 1 hour. The solvent was removed by evaporation and the residue partitioned between water and ethyl acetate and the aqueous layer adjusted to pH8 with sodium hydrogen carbonate. 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/acetonitrile/methanol (60/30/10 followed by 60/20/20). The resulting semi-purified solid was repurified by chromatography on neutral alumina eluting with methylene chloridelmetlhanol (95/5). The resulting white solid was dissolved in methylene chloride and 4 M ethereal hydrogen chloride (0.5 ml) was added. The volatiles were removed by evaporation, and the residue triturated by the addition of methylene chloride followed by methanol and ether. The precipitated solid was collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-7-(3-morpholinopropoxy)quinazoline hydrochloride (35 mg, 10%).

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 1 hour
  3. customThe solvent was removed by evaporation
  4. customthe residue partitioned between water and ethyl acetate
  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/acetonitrile/methanol (60/30/10 followed by 60/20/20)
  11. customThe resulting semi-purified solid was repurified by chromatography on neutral alumina eluting with methylene chloridelmetlhanol (95/5)
  12. dissolutionThe resulting white solid was dissolved in methylene chloride
  13. addition4 M ethereal hydrogen chloride (0.5 ml) was added
  14. customThe volatiles were removed by evaporation
  15. customthe residue triturated by the addition of methylene chloride
  16. filtrationThe precipitated solid was collected by filtration
  17. customdried under vacuum

Sources & evidence

ORD record
ord-c73eab1bc9634952b30e9ea31bb57db9
Source dataset
uspto-grants-2001_09
Patent number
US06291455B1

Reaction notes

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