Ammonia → 4-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-ol

HRID 1948918Notes

Reaction equation

HRID 1948918 reaction equation
C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=O)C.[Cl:18][C:19]1[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].Cl.N>C(#N)C>[Cl:18][C:19]1[C:20]([F:26])=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH:22][C:8]1[C:7]2[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([OH:4])[CH:6]=2)[N:11]=[CH:10][N:9]=1

Participants

6

Reactant 4

HCID 222AmmoniaHCID 313Hydrochloric AcidHCID 750143-Chloro-2-fluoroanilineHCID 220221604-Chloro-7-methoxyquinazolin-6-yl acetate

Product 1

HCID 574768684-((3-Chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-olYield 95.6%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

6-Acetoxy-4-chloro-7-methoxyquinazoline (Example 25-5 in WO01/66099; 10.0 g, 39.6 mmole) was suspended in acetonitrile (400 ml) and 3-chloro-2-fluoroaniline (6.05 g, 41.6 mmole) and hydrogen chloride (4.0M solution in 1,4-dioxane) (10.4 ml, 41.6 mmole) were added. The reaction mixture was refluxed for one hour and then allowed to cool to ambient temperature. The resulting precipitate was filtered off, washed with acetonitrile and diethylether to give a white solid. This solid was added in portions to a stirred 1N methanolic ammonia solution (400 ml). The mixture was stirred for two hours and the precipitate filtered, washed with acetonitrile followed by diethylether and dried under vacuum to give 4-(3-chloro-2-fluoroanilino)-6-hydroxy-7-methoxyquinazoline as a white solid (12.1 g, 95%); 1H NMR Spectrum: (DMSOd6) 3.95 (s, 3H); 7.18 (s, 1H); 7.20-7.25 (m, 1H); 7.39-7.44 (m, 1H); 7.47-7.52 (m, 1H); 7.65 (s, 1H); 8.31 (s, 1H); 9.45 (br.s, 1H); Mass Spectrum: (M+H)+ 320.

Workup

  1. temperatureThe reaction mixture was refluxed for one hour
  2. filtrationThe resulting precipitate was filtered off
  3. washwashed with acetonitrile and diethylether
  4. customto give a white solid
  5. filtrationthe precipitate filtered
  6. washwashed with acetonitrile
  7. customdried under vacuum

Sources & evidence

ORD record
ord-8db0a8be751d4a818ced7a3b015400fe
Source dataset
uspto-grants-2013_03
Patent number
US08399667B2

Reaction notes

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