1-Methylpiperazine → 4-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-[4-methylpiperazin-1-yl]ethoxy)ethoxy)quinazoline hydrochloride

HRID 2227969Notes

Reaction equation

HRID 2227969 reaction equation
Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[F:26])=[N:13][CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[ClH:25].[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:12]2[C:11]3[C:16](=[CH:17][C:8]([O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[C:9]([O:27][CH3:28])[CH:10]=3)[N:15]=[CH:14][N:13]=2)=[C:20]([F:26])[CH:21]=1

Participants

3

Reactant 2

HCID 531671-MethylpiperazineHCID 187534287-(2-(2-Bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline

Product 1

HCID 187534454-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-[4-methylpiperazin-1-yl]ethoxy)ethoxy)quinazoline hydrochlorideYield 28%

Conditions

Temperature
100 °C

Procedure

A mixture of 7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (150 mg, 0.32 mmol) in 1-methylpiperazine (2 ml) was heated at 100° C. for 1 hour. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was separated and washed with water and then brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (85/15 followed by 80/20). The purified solid product was dissolved in methylene chloride/methanol (1/1) and 2.9M ethereal hydrogen chloride was added. The volatiles were removed by evaporation and the solid 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-(2-[4-methylpiperazin-1-yl]ethoxy)ethoxy)quinazoline hydrochloride (54 mg, 28%).

Workup

  1. temperatureto cool
  2. customwas partitioned between ethyl acetate and water
  3. customThe organic layer was separated
  4. washwashed with water
  5. dry with materialbrine, dried (MgSO4)
  6. customthe solvent removed by evaporation
  7. customThe residue was purified by column chromatography on silica eluting with methylene chloride/methanol (85/15 followed by 80/20)
  8. dissolutionThe purified solid product was dissolved in methylene chloride/methanol (1/1)
  9. addition2.9M ethereal hydrogen chloride was added
  10. customThe volatiles were removed by evaporation
  11. customthe solid was triturated with ether
  12. filtrationcollected by filtration
  13. washwashed with ether
  14. customdried under vacuum

Sources & evidence

ORD record
ord-ea95aa6ea6594ee6b5d8e9985229a874
Source dataset
uspto-grants-2002_07
Patent number
US06414148B1

Reaction notes

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