Reaction #1343718

Reaction equation

2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole

1-methylpiperazine

1-methylpiperazine

1,4-dioxane

→

2-(difluoromethyl)-4-methoxy-1-[4-(4-{[2-(4-methyl-1-piperazinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole

Yield 65.1%

Solvents

THF

Conditions

Workup

1. 1
   Temperaturewas refluxed for 5 hrs
2. 2
   Temperaturethe reaction mixture was refluxed for 20 hrs
3. 3
   TemperatureThe mixture was cooled to room temperature
4. 4
   Otherthe solvents were removed under vacuum
5. 5
   OtherThe residue was partitioned between CH2Cl2 and H2O
6. 6
   OtherThe layers were separated
7. 7
   Extractionthe aqueous layer was extracted with CH2Cl2 (1×)
8. 8
   DryingThe combined organic extracts were dried (Na2SO4)
9. 9
   Otherthe solvent was removed under vacuum
10. 10
    OtherChromatography on silica eluting with CH2Cl2/MeOH (100:0 to 95:5) followed by recrystallization from CH2Cl2/hexanes

Procedure

A mixture of 2-(difluoromethyl)-4-methoxy-1-{4-(4-morpholinyl)-6-[4-(vinylsulfonyl)-1-piperazinyl]-1,3,5-triazin-2-yl}-1H-benzimidazole (Example 3) (150 mg, 0.280 mmol) and 1-methylpiperazine (0.16 mL, 1.44 mmol) in THF (20 mL) was refluxed for 5 hrs and then stirred at room temperature for 3 days. Additional 1-methylpiperazine (0.16 mL, 1.44 mmol) and 1,4-dioxane (20 mL) were added and the reaction mixture was refluxed for 20 hrs. The mixture was cooled to room temperature and the solvents were removed under vacuum. The residue was partitioned between CH2Cl2 and H2O. The layers were separated and the aqueous layer was extracted with CH2Cl2 (1×). The combined organic extracts were dried (Na2SO4) and the solvent was removed under vacuum. Chromatography on silica eluting with CH2Cl2/MeOH (100:0 to 95:5) followed by recrystallization from CH2Cl2/hexanes gave 2-(difluoromethyl)-4-methoxy-1-[4-(4-{[2-(4-methyl-1-piperazinyl)ethyl]sulfonyl}-1-piperazinyl)-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole (116 mg, 65%).

Source