Potassium Carbonate → 7-((2-Acetamidothiazol-4-yl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride

HRID 1384656Notes

Reaction equation

HRID 1384656 reaction equation
[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([NH:6][C:7]2[C:16]3[C:11](=[CH:12][C:13]([OH:19])=[C:14]([O:17][CH3:18])[CH:15]=3)[N:10]=[CH:9][N:8]=2)=[C:4]([F:22])[CH:3]=1.[C:23]([NH:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32]Cl)[N:31]=1)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[C:23]([NH:26][C:27]1[S:28][CH:29]=[C:30]([CH2:32][O:19][C:13]2[CH:12]=[C:11]3[C:16]([C:7]([NH:6][C:5]4[CH:20]=[CH:21][C:2]([Cl:1])=[CH:3][C:4]=4[F:22])=[N:8][CH:9]=[N:10]3)=[CH:15][C:14]=2[O:17][CH3:18])[N:31]=1)(=[O:25])[CH3:24]

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 819632-Acetamido-4-chloromethylthiazoleHCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 226250527-((2-Acetamidothiazol-4-yl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochlorideYield 48.2%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
40 °C

Procedure

A mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 24), 2-acetamido-4-chloromethylthiazole (164 mg, 0.86 mmol) and potassium carbonate (216 mg, 1.5 mmol) in DMF (5 ml)was stirred at 40° C. for 7 hours. The mixture was partitioned between ethyl acetate and water and the aqueous layer was adjusted to pH7 with 2M hydrochloric acid. The organic phase was washed with water, brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified solid was dissolved in a mixture of methylene chloride and methanol and a 5M solution of hydrogen chloride in isopropanol (1.0 ml) was added. The volatiles were removed by evaporation to give a solid, which was triturated with ether, collected by filtration and dried under vacuum to give 7-((2-acetamidothiazol-4-yl)methoxy)-4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (96 mg, 24%). m.p. 194-202° C. 1H NMR Spectrum: (DMSOd6) 2.14(s, 3H); 4.0(s, 3H); 5.31(s, 2H); 7.34(s, 1H); 7.45(dd, 1H); 7.52(s, 1H); 7.60(t, 1H); 7.68(dd, 1H); 8.30(s, 1H); 8.81(s, 1H) MS-ESI: 474 [MH]+

Workup

  1. custom(prepared
  2. customThe mixture was partitioned between ethyl acetate and water
  3. washThe organic phase was washed with water, brine
  4. dry with materialdried (MgSO4)
  5. customthe solvent removed by evaporation
  6. customThe residue was purified by column chromatography
  7. washeluting with methylene chloride/methanol (95/5)
  8. dissolutionThe purified solid was dissolved in a mixture of methylene chloride and methanol
  9. additiona 5M solution of hydrogen chloride in isopropanol (1.0 ml) was added
  10. customThe volatiles were removed by evaporation
  11. customto give a solid, which
  12. customwas triturated with ether
  13. filtrationcollected by filtration
  14. customdried under vacuum

Sources & evidence

ORD record
ord-3ea59a873af54388b6d892ef78d3525a
Source dataset
uspto-grants-2001_07
Patent number
US06258951B1

Reaction notes

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