反应详情

Diethyl azodicarboxylate (325 μl, 2 mmol) was added dropwise to a mixture of (E)-4-morpholinobut-2-en-1-ol (151 mg, 0.96 mmol), (J. Med. Chem. 1972, 15, 110-112), 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (220 mg, 0.688 mol), (prepared as described for the starting material in Example 2), and triphenylphosphine (541 mg, 2 mmol) in methylene chloride (4 ml). The mixture was stirred for 30 minutes at ambient temperature, and further (E)-4-morpholinobut-2-en-1-ol (10 mg, 0.06 mmol), triphenylphosphine (36 mg, 0.137 mol) and diethyl azodicarboxylate (22 μl, 0.14 mmol) were added. The mixture was stirred for 20 minutes and the volatiles were removed by evaporation. The residue was purified by column chromatography on silica eluting with methylene chloride/methanol (92/8). The purified solid was dissolved in methylene chloride and 2M ethereal hydrogen chloride (3 ml) was added. The volatiles were removed by evaporation and the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give (E)-4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(4-morpholinobut-2-en-1-yloxy)quinazoline hydrochloride (165 mg, 45%).

1. custom(prepared
2. stirringThe mixture was stirred for 20 minutes
3. customthe volatiles were removed by evaporation
4. customThe residue was purified by column chromatography on silica eluting with methylene chloride/methanol (92/8)
5. dissolutionThe purified solid was dissolved in methylene chloride
6. addition2M ethereal hydrogen chloride (3 ml) was added
7. customThe volatiles were removed by evaporation
8. customthe solid was triturated with ether
9. filtrationcollected by filtration
10. washwashed with ether
11. customdried under vacuum