反应详情

Triphenylphosphine (410 mg, 1.5 mmol) and 1-methyl-3-pyrrolidinol (0.128 ml, 1.5 mmol) were added to a solution of 4-(chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (250 mg, 0.78 mmol), (prepared as described for the starting material in Example 2), in methylene chloride (4 ml). Diethyl azodicarboxylate (0.246 ml, 1.5 mmol) was added dropwise and the reaction mixture was stirred for 1 hour at ambient temperature. Additional triphenylphosphine (61 mg, 0.23 mmol) followed by diethyl azodicarboxylate (37 μl, 0.23 mmol) was added and the mixture was stirred for 15 minutes at ambient temperature. The solvent was removed by evaporation and the residue was purified by column chromatography eluting with methylene chloride/methanol (80/20) followed by methylene chloride/methanol/triethylamine (80/20/0.5). The purified product was dissolved in methylene chloride/methanol and the insolubles were removed by filtration. A solution of hydrogen chloride in 2-propanol (0.5 ml of a 5M solution) was added to the filtrate and the volatiles were removed by evaporation. The residue was triturated with 2-propanol and ether, collected by filtration and dried to give 4-(4-chloro-2-fluoranilino)-6-methoxy-7-(1-methylpyrrolidin-3-yloxy)quinazoline hydrochloride hydrate (149 mg, 40%).

1. custom(prepared
2. additionwas added
3. stirringthe mixture was stirred for 15 minutes at ambient temperature
4. customThe solvent was removed by evaporation
5. customthe residue was purified by column chromatography
6. washeluting with methylene chloride/methanol (80/20)
7. dissolutionThe purified product was dissolved in methylene chloride/methanol
8. customthe insolubles were removed by filtration
9. additionA solution of hydrogen chloride in 2-propanol (0.5 ml of a 5M solution) was added to the filtrate
10. customthe volatiles were removed by evaporation
11. customThe residue was triturated with 2-propanol and ether
12. filtrationcollected by filtration
13. customdried