Potassium Carbonate → HCID 21186978, compound

HRID 1384630Notes

Reaction equation

HRID 1384630 reaction equation
S(Cl)(Cl)=O.[OH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=[O:15].[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](O)=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>ClC(Cl)Cl.CN1C(=O)CCC1.O>[Cl:16][C:17]1[CH:36]=[CH:35][C:20]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:5][CH2:6][CH2:7][CH2:8][N:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]4=[O:15])=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)=[C:19]([F:37])[CH:18]=1

Participants

8

Reactant 4

HCID 11430Potassium CarbonateHCID 24386Thionyl ChlorideHCID 2351098825514-24-3HCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 21186978HCID 21186978, compoundYield 50%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6212ChloroformSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
5 °C

Procedure

Thionyl chloride (0.55 ml, 7.5 mmol) was added to a solution of 1-(3-hydroxypropyl)-1,2dihydro-2- pyridone (770 mg, 5 mmol) in trichloromethane (15 ml) at 5° C. The mixture was stirred at 5° C. for 1 hour and then at ambient temperature for 2 hours. The volatiles were removed by evaporation, the residue azeotroped with toluene and dried under vacuum to give crude 1-(3-chloropropyl)-1,2-dihydro-2-pyridone (500 mg) which was used directly. Part of this product (206 mg, 1.2 mmol) was then added to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (350 mg, 1.0 mmol), (prepared as described for the starting material in Example 24), and potassium carbonate (303 mg, 2.2 mmol) in NMP (20 ml) and the reaction mixture was heated at 90° C. for 2 hours. The mixture was allowed to cool, diluted with water and extracted with ethyl acetate. The combined extracts were wash ed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(2-oxo-1,2-dihydro-1-pyridyl)propoxy)quinazoline (194 mg, 50%). m.p. 216-218° C. 1H NMR Spectrum: (DMSOd6) 2.18(m, 2H); 3.90(s, 3H); 4.06(t, 2H); 4.15(t, 2H); 6.18(t, 1H); 6.38(d, 1H); 7.15(s, 1H); 7.30-7.42(m, 2H); 7.50-7.64(m, 3H); 7.79(s, 1H); 8.34(s, 1H); 9.50(s, 1H) MS-ESI: 455 [MH]+

Workup

  1. waitat ambient temperature for 2 hours
  2. customThe volatiles were removed by evaporation
  3. customthe residue azeotroped with toluene
  4. customdried under vacuum
  5. customto give crude 1-(3-chloropropyl)-1,2-dihydro-2-pyridone (500 mg) which
  6. custom(prepared
  7. temperaturethe reaction mixture was heated at 90° C. for 2 hours
  8. temperatureto cool
  9. extractionextracted with ethyl acetate
  10. washThe combined extracts were wash
  11. dry with materialdried (MgSO4)
  12. customthe solvent removed by evaporation
  13. customThe residue was purified by column chromatography
  14. washeluting with methylene chloride/methanol mixtures (100/0 increasing to 95/5)

Sources & evidence

ORD record
ord-6d6c345ce58540c6ad3edce988b16714
Source dataset
uspto-grants-2001_07
Patent number
US06258951B1

Reaction notes

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