Diethyl Ether → (5r)-6-Methoxy-4-(2-methyl-1h-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazoline

HRID 454320Notes

Reaction equation

HRID 454320 reaction equation
[OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S([CH2:40][C@@H:41]2[NH:45][C:44](=[O:46])[CH2:43][CH2:42]2)(=O)=O)=CC=1.CCOCC>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:40][C@@H:41]1[NH:45][C:44](=[O:46])[CH2:43][CH2:42]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2

Participants

6

Reactant 4

HCID 3283Diethyl Ether2×HCID 11430Potassium CarbonateHCID 57059127(5R)-5-(p-toluenesulphonylmethyl)-2-pyrrolidinone2×HCID 1357631087-hydroxy-6-methoxy-4-(2-methyl-1H-indol-5-yloxy)quinazoline

Product 1

HCID 53950848(5r)-6-Methoxy-4-(2-methyl-1h-indol-5-yloxy)-7-(2-oxopyrrolidin-5-ylmethoxy)quinazolineYield 0.3%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

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, 4 eq.) 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, 0.5 eq.) 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).

Workup

  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

Sources & evidence

ORD record
ord-839fd55154e94c76a524b14c420db96b
Source dataset
uspto-grants-2013_07
Patent number
US08492560B2

Reaction notes

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