Potassium Carbonate → 4-(4-Fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline

HRID 454321Notes

Reaction equation

HRID 454321 reaction equation
Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[C:33]([OH:34])=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:24][C:25]1[C:33]([O:34][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:32][CH:31]=[C:30]2[C:26]=1[CH:27]=[C:28]([CH3:35])[NH:29]2

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 103520364-fluoro-2-methyl-1H-indol-5-olHCID 11088974HCID 11088974, compound

Product 1

HCID 101832934-(4-Fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazolineYield 62.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
95 °C

Procedure

A solution of 4-chloro-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.22 g, 3.65 mmol), (prepared as described for the starting material in Example 241), 4-fluoro-5-hydroxy-2-methylindole (723 mg, 4.38 mmol), (prepared as described for the starting material in Example 237), in DMF (20 ml) containing potassium carbonate (756 mg, 5.48 mmol) was stirred at 95° C. for 3 hours. After cooling, the mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography eluting with methylene chloride/methanol (9/1) followed by methylene chloride/methanol/methanol saturated with ammonia (90/5/5). The fractions containing the expected product were combined and evaporated. The residue was triturated with ether, filtered, washed with ether and dried under vacuum. The solid was dissolved in methylene chloride/ethyl acetate and the minimum of methanol, filtered and the volatiles were removed under vacuum. The solid was triturated with ether, filtered, washed with ether and dried under vacuum at 50° C. to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(2-(1-methylpiperidin-4-yl)ethoxy)quinazoline (1.06 g, 62%).

Workup

  1. custom(prepared
  2. temperatureAfter cooling
  3. filtrationthe mixture was filtered
  4. customthe filtrate was evaporated
  5. customThe residue was purified by column chromatography
  6. washeluting with methylene chloride/methanol (9/1)
  7. additionThe fractions containing the expected product
  8. customevaporated
  9. customThe residue was triturated with ether
  10. filtrationfiltered
  11. washwashed with ether
  12. customdried under vacuum
  13. dissolutionThe solid was dissolved in methylene chloride/ethyl acetate
  14. filtrationthe minimum of methanol, filtered
  15. customthe volatiles were removed under vacuum
  16. customThe solid was triturated with ether
  17. filtrationfiltered
  18. washwashed with ether
  19. customdried under vacuum at 50° C.

Sources & evidence

ORD record
ord-64771a064fa5420db102b1bacf465965
Source dataset
uspto-grants-2013_07
Patent number
US08492560B2

Reaction notes

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