Sodium hydride → 1-{2-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethyl}-1H-pyridin-4-one Hydrochloride

HRID 1869096Notes

Reaction equation

HRID 1869096 reaction equation
[H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6](=[O:9])[CH2:5][CH:4]=1.Cl.[Cl:11][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[C:23]2[C:18]([C:19]([NH:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]#[CH:33])[CH:27]=3)=[N:20][CH:21]=[N:22]2)=[CH:17][C:16]=1[O:34][CH2:35][CH2:36][O:37][CH3:38]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[ClH:11].[C:32]([C:28]1[CH:27]=[C:26]([NH:25][C:19]2[C:18]3[C:23](=[CH:24][C:15]([O:14][CH2:13][CH2:12][N:3]4[CH:4]=[CH:5][C:6](=[O:9])[CH:7]=[CH:8]4)=[C:16]([O:34][CH2:35][CH2:36][O:37][CH3:38])[CH:17]=3)[N:22]=[CH:21][N:20]=2)[CH:31]=[CH:30][CH:29]=1)#[CH:33]

Participants

6

Reactant 3

HCID 24758Sodium hydride2×HCID 17984897Piridin-4-one2×HCID 18925049[7-(2-Chloro-ethoxy)-6-(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)-amine Hydrochloride

Product 1

HCID 189250871-{2-[4-(3-Ethynyl-phenylamino)-6-(2-methoxy-ethoxy)-quinazolin-7-yloxy]-ethyl}-1H-pyridin-4-one HydrochlorideYield 47.1%

Reagents, catalysts & solvents 2

HCID 67553Tetrabutylammonium IodideCatalystHCID 6228DimethylformamideSolvent2×

Conditions

Temperature
22 °C

Procedure

NaH (30 mg of 60% in mineral oil, 0.77 mmol) was added to anhydrous DMF (2.0 mL) followed by pyrid-4-one (79 mg, 0.83 mmol). The mixture was stirred 40 minutes at 22° C. until all solids dissolved and the evolution of H2 ceased. The title product of Example 34 (120 mg, 0.28 mmol) and tetrabutylammonium iodide (15 mg) were added and the reaction mixture was stirred at 22° C. for 7 days under N2. Additional pyrid-4-one (79 mg) and NaH (30 mg of 60%) were dissolved in DMF (2 mL) and the solution was added to the reaction mixture. After another 4 days stirring the mixture was partitioned between CHCl3 and brine. The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica utilizing 10% methanol/CH2Cl2 to afford 65 mg of the free base of the title product which was converted to the mono-hydrochloride salt according to the procedure described for Example 28 (66 mg; M.P. 240°-248° C. (dec); LC-MS: 457 (MH+); anal. RP-HPLC RT: 3.23 min)

Workup

  1. dissolutiondissolved
  2. stirringthe reaction mixture was stirred at 22° C. for 7 days under N2
  3. additionthe solution was added to the reaction mixture
  4. stirringAfter another 4 days stirring the mixture
  5. customwas partitioned between CHCl3 and brine
  6. dry with materialThe organic extracts were dried over Na2SO4
  7. filtrationfiltered
  8. concentrationconcentrated in vacuo
  9. customThe crude product was purified by flash chromatography on silica utilizing 10% methanol/CH2Cl2

Sources & evidence

ORD record
ord-e36ecee2a96c402ebcac4c3322e8b145
Source dataset
uspto-grants-2009_12
Patent number
USRE041065E1

Reaction notes

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