Potassium Carbonate → 4-[(4-Fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-(3-[4-(2-propynyl)piperazin-1-yl]propoxy}quinazoline

HRID 916440Notes

Reaction equation

HRID 916440 reaction equation
OC(C(F)(F)F)=O.OC(C(F)(F)F)=O.[CH2:15]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[C:16]#[CH:17].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:44]=[C:43]2[C:38]([C:39]([O:45][C:46]3[C:47]([F:56])=[C:48]4[C:52](=[CH:53][CH:54]=3)[NH:51][C:50]([CH3:55])=[CH:49]4)=[N:40][CH:41]=[N:42]2)=[CH:37][C:36]=1[O:57][CH3:58]>CC(N(C)C)=O>[F:56][C:47]1[C:46]([O:45][C:39]2[C:38]3[C:43](=[CH:44][C:35]([O:34][CH2:33][CH2:32][CH2:31][N:21]4[CH2:22][CH2:23][N:18]([CH2:15][C:16]#[CH:17])[CH2:19][CH2:20]4)=[C:36]([O:57][CH3:58])[CH:37]=3)[N:42]=[CH:41][N:40]=2)=[CH:54][CH:53]=[C:52]2[C:48]=1[CH:49]=[C:50]([CH3:55])[NH:51]2

Participants

5

Reactant 3

HCID 11430Potassium CarbonateHCID 589602427-(3-Bromopropoxy)-4-((4-fluoro-2-methyl-1H-indol-5-yl)oxy)-6-methoxyquinazolineHCID 872383581-Prop-2-ynylpiperazine diTFA salt

Product 1

HCID 101744954-[(4-Fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-(3-[4-(2-propynyl)piperazin-1-yl]propoxy}quinazolineYield 73.7%

Reagents, catalysts & solvents 1

HCID 31374DimethylacetamideSolvent

Conditions

Temperature
85 °C

Procedure

1-Prop-2-ynylpiperazine diTFA salt (329 mg, 0.94 mmol) and potassium carbonate (258 mg, 1.87 mmol) were added to a solution of 7-(3-bromopropoxy)-4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxyquinazoline (144 mg, 0.31 mmol), (prepared as described for the starting material in Example 7), in DMA (3.6 ml). The reaction mixture was stirred at 85° C. overnight before being filtered. The filtrate was concentrated under vacuum and the crude product was purified by column chromatography eluting with increasingly polar mixtures of ammonia/methanol in methylene chloride (1 to 7%). A second purification by column chromatography eluting with a mixture of methanol in methylene chloride (1/9) gave 4-[(4-fluoro-2-methylindol-5-yl)oxy]-6-methoxy-7-(3-[4-(2-propynyl)piperazin-1-yl]propoxy}quinazoline as a white solid (115 mg, 73%).

Workup

  1. custom(prepared
  2. filtrationbefore being filtered
  3. concentrationThe filtrate was concentrated under vacuum
  4. customthe crude product was purified by column chromatography
  5. washeluting
  6. temperaturewith increasingly polar mixtures of ammonia/methanol in methylene chloride (1 to 7%)
  7. customA second purification by column chromatography
  8. washeluting with a mixture of methanol in methylene chloride (1/9)

Sources & evidence

ORD record
ord-880e3c6e4dd94a8f9d16c337768b200b
Source dataset
uspto-grants-2007_09
Patent number
US07268230B2

Reaction notes

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