反应详情

Diethyl azodicarboxylate (209 mg, 1.2 mmol) was added dropwise to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinoline (128 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), triphenylphosphine (314 mg, 1.2 mmol) and (S)-(3-hydroxypropyl)-pyrrolidine-2-carboxamide (97 mg, 0.56 mmol), (prepared as described for the starting material in Example 50), in methylene chloride (4 ml). The mixture was stirred for 2 hours at ambient temperature, and further triphenylphosphine (105 mg, 0.4 mmol) and (S)-1-(3-hydroxypropyl)pyrrolidine-2-carboxamide (49 mg, 0.28 mmol) were added followed by the dropwise addition of diethyl azodicarboxylate (70 mg, 0.4 mmol). The mixture was stirred for 1 hour at ambient temperature, and was purified by pouring directly onto a silica column eluting with methylene chloride/acetonitrile/methanol (6/3/1 followed by 60/25/15). The purified oil was triturated with ether, collected by filtration, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride and 2M ethereal hydrogen chloride (0.5 ml) was added. The mixture was diluted with ether and the resulting precipitate was collected by filtration, washed with ether and dried under vacuum to give (S)-7-(3-(2-carbamoylpyrrolidin-1-yl)propoxy)4-(4-chloro-2-fluoroanilino)-6-methoxyquinazoline hydrochloride (70 mg, 32%).

1. custom(prepared
2. custom(prepared
3. stirringThe mixture was stirred for 1 hour at ambient temperature
4. customwas purified
5. additionby pouring directly onto a silica column
6. washeluting with methylene chloride/acetonitrile/methanol (6/3/1 followed by 60/25/15)
7. customThe purified oil 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. addition2M ethereal hydrogen chloride (0.5 ml) was added
13. additionThe mixture was diluted with ether
14. filtrationthe resulting precipitate was collected by filtration
15. washwashed with ether
16. customdried under vacuum