反应详情

A solution of diethyl azodicarboxylate (209 mg, 1.2 mmol) in methylene chloride (1 ml) and then (S)-1-3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0.56 mmol) was added dropwise to a suspension of 4-(4-bromo-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (146 mg, 0.4 mmol), (prepared as described for the starting material in Example 48), and triphenylphosphine (314 mg, 1.2 mmol) in methylene chloride (4 ml) under nitrogen. The mixture was stirred for 1 hour at ambient temperature and further triphenylphosphine (109 mg, 0.4 mmol) and (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (40 mg, 0.23 mmol) were added followed by the dropwise addition of diethyl azodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred for 30 minutes at ambient temperature and further (S)-1-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (34 mg, 0.2 mmol) was added. The mixture was then stirred for 2 hours at ambient temperature and the mixture was purified by pouring directly onto a column of silica and eluting with methylene chloride/ethyl acetate/methanol (60/35/5). The purified product was triturated with ether, collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride and 3M hydrogen chloride in ethyl acetate (0.4 ml) was added. The resulting precipitate was collected by filtration, washed with ethyl acetate and dried under vacuum to give (S)-4-(4-bromo-2-fluoroanilino)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)-6-methoxyquinazoline hydrochloride (110 mg, 47%).

1. custom(prepared
2. stirringThe mixture was stirred for 30 minutes at ambient temperature
3. stirringThe mixture was then stirred for 2 hours at ambient temperature
4. customthe mixture was purified
5. additionby pouring directly onto a column of silica
6. washeluting with methylene chloride/ethyl acetate/methanol (60/35/5)
7. customThe purified product was triturated with ether
8. filtrationcollected by filtration
9. washwashed with ether
10. customdried under vacuum
11. dissolutionThe solid was dissolved in methylene chloride
12. addition3M hydrogen chloride in ethyl acetate (0.4 ml) was added
13. filtrationThe resulting precipitate was collected by filtration
14. washwashed with ethyl acetate
15. customdried under vacuum