Potassium Carbonate → HCID 21186979, compound

HRID 1384632Notes

Reaction equation

HRID 1384632 reaction equation
S(Cl)(Cl)=O.[OH:5][CH2:6][CH2:7][CH2:8][S:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1.[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][S:9][C:10]4[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=4)=[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 22624964HCID 22624964, compoundHCID 1355137204-(4-Chloro-2-fluorophenylamino)-7-hydroxy-6-methoxyquinazoline

Product 1

HCID 21186979HCID 21186979, compoundYield 6.1%

Reagents, catalysts & solvents 3

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

Conditions

Temperature
5 °C

Procedure

Thionyl chloride (0.80 ml, 11 mmol) was added to a solution of 2-(3-hydroxypropylthio)-1-methylimidazole (1.25 g, 7.3 mmol) in trichloromethane (25 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 2-(3-chloropropylthio)-1-methylimidazole hydrochloride (1.0 g) which was used directly. Part of this product (226 mg, 1.0 mmol) was 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 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 washed with water, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography eluting with methylene chloride/methanol (100/0 increasing to 95/5) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-(1-methylimidazol-2-ylthio)propoxy)quinazoline (29 mg, 6%). m.p. 199-201° C. 1H NMR Spectrum: (DMSOd6) 2.22(m, 2H); 3.44(s, 3H); 3.94(s, 3H); 4.10(m, 4H); 7.10(d, 2H); 7.30(dd, 1H); 7.50-7.60(m, 2H); 7.79(s, 1H); 8.34(s, 1H); 9.50(s, 1H) MS-ESI: 474 [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 2-(3-chloropropylthio)-1-methylimidazole hydrochloride (1.0 g) which
  6. custom(prepared
  7. temperatureto cool
  8. extractionextracted with ethyl acetate
  9. washThe combined extracts were washed with water
  10. dry with materialdried (MgSO4)
  11. customthe solvent removed by evaporation
  12. customThe residue was purified by column chromatography
  13. washeluting with methylene chloride/methanol (100/0 increasing to 95/5)

Sources & evidence

ORD record
ord-c1a6dc21543042078fc6153ded878137
Source dataset
uspto-grants-2001_07
Patent number
US06258951B1

Reaction notes

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