Pyrrolidine → 4-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyrrolidin-1-ylethoxy)ethoxy)quinazoline hydrochloride

HRID 1838598Notes

Reaction equation

HRID 1838598 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].[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]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:29]4[CH2:33][CH2:32][CH2:31][CH2:30]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 31268PyrrolidineHCID 187534287-(2-(2-Bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline

Product 1

HCID 224782984-(4-Chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyrrolidin-1-ylethoxy)ethoxy)quinazoline hydrochlorideYield 20%

Conditions

Temperature
80 °C

Procedure

A solution of 7-(2-(2-bromoethoxy)ethoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline (150 mg, 0.32 mmol), (prepared as described for the starting material in Example 63), in pyrrolidine (2 ml) was heated at 80° C. for 5 hours. The mixture was allowed to cool and was partitioned between ethyl acetate and water. The organic layer was 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/triethylamine (80/20/0 followed by 80/20/1). The purified product was dissolved in methylene chloride and 2.9M ethereal hydrogen chloride (1 ml) was added. The volatiles were removed by evaporation, the residue was triturated with ether, collected by filtration and dried under vacuum to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(2-(2-pyrrolidin-1-ylethoxy)ethoxy)quinazoline hydrochloride (35 mg, 20%).

Workup

  1. temperatureto cool
  2. customwas partitioned between ethyl acetate and water
  3. washThe organic layer was washed with water
  4. dry with materialbrine, dried (MgSO4)
  5. customthe solvent removed by evaporation
  6. customThe residue was purified by column chromatography on silica eluting with methylene chloride/methanol/triethylamine (80/20/0 followed by 80/20/1)
  7. dissolutionThe purified product was dissolved in methylene chloride
  8. addition2.9M ethereal hydrogen chloride (1 ml) was added
  9. customThe volatiles were removed by evaporation
  10. customthe residue was triturated with ether
  11. filtrationcollected by filtration
  12. customdried under vacuum

Sources & evidence

ORD record
ord-b1dd45011c8f4113a3f63c3e495e6c6b
Source dataset
uspto-grants-2004_01
Patent number
US06673803B2

Reaction notes

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