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N,N-Dimethylaniline → 7-((2-Chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride

HRID 1384609
Notes
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Reaction equation

HRID 1384609 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14](=O)[NH:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:21][CH3:22])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[F:37][C:38]1[CH:44]=[C:43]([CH3:45])[C:42]([OH:46])=[CH:41][C:39]=1[NH2:40]>C1(C)C=CC=CC=1.C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[CH:19]=[C:18]3[C:13]([C:14]([NH:40][C:39]4[CH:41]=[C:42]([OH:46])[C:43]([CH3:45])=[CH:44][C:38]=4[F:37])=[N:15][CH:16]=[N:17]3)=[CH:12][C:11]=2[O:21][CH3:22])[CH:5]=[CH:4][N:3]=1
ParticipantsProcedureWorkupSources & evidenceReaction notes

Participants

7

Reactant 4

HCID 949N,N-DimethylanilineHCID 24813Phosphorus oxychlorideHCID 101540985-Amino-4-fluoro-2-methylphenolHCID 135671182HCID 135671182, compound

Product 1

HCID 226248987-((2-Chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochlorideYield 62.4%

Reagents, catalysts & solvents

2
HCID 1140TolueneSolventHCID 3776IsopropanolSolvent

Procedure

A mixture of 7-((2-chloro-4-pyridyl)methoxy)-6-methoxy-3,4-dihydroquinazolin-4-one (150 mg, 0.47 mmol), phosphoryl chloride (0.2 ml) and N,N-dimethylaniline (0.2 ml) in toluene (5 ml) was heated at reflux for 1 hour. The volatiles were removed by evaporation and the residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The organic layer was separated, dried (MgSO4) and the solvent removed by evaporation. A solution of 2-fluoro-5-hydroxy-4-methylaniline (67 mg, 0.47 mmol), (prepared as described for the starting material in Example 13), in isopropanol (10 ml) was added to the solid residue and the mixture was heated at reflux for 2 hours. The mixture was allowed to cool and the precipitated product collected by filtration, washed with acetone and dried to give 7-((2-chloro-4-pyridyl)methoxy)-4-(2-fluoro-5-hydroxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (70 mg, 30%). m.p. 245-250° C. 1H NMR Spectrum: (DMSOd6) 2.30(s, 3H); 4.10(s, 3H); 5.45(s, 2H); 6.90(d, 1H); 7.10(d, 1H); 7.35(s, 1H); 7.50(d, 1H); 7.65(s, 1H); 8.25(s, 1H); 8.45(d, 1H); 8.75(s, 1H); 9.60(br s, 1H); 11.30(s, 1H) MS-ESI: 441 [MH]+

Workup

  1. temperaturewas heated
  2. temperatureat reflux for 1 hour
  3. customThe volatiles were removed by evaporation
  4. customthe residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution
  5. customThe organic layer was separated
  6. dry with materialdried (MgSO4)
  7. customthe solvent removed by evaporation
  8. additionwas added to the solid residue
  9. temperaturethe mixture was heated
  10. temperatureat reflux for 2 hours
  11. temperatureto cool
  12. filtrationthe precipitated product collected by filtration
  13. washwashed with acetone
  14. customdried

Sources & evidence

ORD record
ord-463da39fc1a84b8b878373dcd8207e41
Source dataset
uspto-grants-2001_07
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US06258951B1

Reaction notes

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On this pageParticipantsProcedureWorkupSources & evidenceReaction notes