反应详情

To a suspension of 7-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline (1.36 g, 4.24 mmol), (prepared as described in Example 49), in DMF (70 ml), was added potassium carbonate (2.34 g, 17.0 mmol, 4eq.) followed by (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (1.25 g, 4.66 mmol, 1.1 eq.), (prepared as described for the starting material in Example 317), and the resulting yellow suspension heated at reflux. After 4 hours, some starting material remained, and a further addition of (5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone (0.57 g, 2.12 mmol, 0.5eq.) was made. The reaction was heated at reflux for a further 2 hours resulting in consumption of starting material. The reaction was cooled to ambient temperature, the inorganic residue filtered off and the filtrate evaporated in vacuo to leave a brown oil which was purified by column chromatography (methylene chloride/methanol, (100/0 to 90/10)) to give a light brown oil. Trituration with ether afforded a thick oil, which upon chromatography eluting as above gave a yellow oil. Trituration of this oil with ether gave an initial crop of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline (5 mg) as an off-white solid (ca. 90% pure by nmr). Chromatography of the residues (eluting as above) followed by ether trituration gave further crops of (5R)-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline as a white solid (180 mg, >95% pure by nmr), as an off-white solid (800 mg, ca. 95% pure by nmr).

1. custom(prepared
2. temperatureheated
3. temperatureat reflux
4. temperatureThe reaction was heated
5. temperatureat reflux for a further 2 hours
6. customresulting in consumption of starting material
7. filtrationthe inorganic residue filtered off
8. customthe filtrate evaporated in vacuo
9. customto leave a brown oil which
10. customwas purified by column chromatography (methylene chloride/methanol, (100/0 to 90/10))
11. customto give a light brown oil
12. washeluting as
13. customabove gave a yellow oil