Preparation method of 2-methyl-1-phenyl-1H-1,3-benzodiazole_Kain Industrial Additive

Background and overview^[1]

Benzimidazoles play an important role in drug development and can be considered an advantageous structure in pharmaceutical research. This benzimidazole scaffold modulates interactions with multiple biological targets is well documented by multiple reports of the observed biological activity and by the fact that several benzimidazole- or azabenzimidazole-based compounds are being developed or marketed as pharmaceuticals. The ability to act is an important factor that makes this type of heterocycle a valuable active pharmaceutical ingredient. 2-Methyl-1-phenyl-1H-1,3-benzodiazole can be used as a pharmaceutical synthesis intermediate.

Preparation^[1]

2-Methyl-1-phenyl-1H-1,3-benzodiazole was prepared as follows: 2-iodonitrobenzene (125 mg, 0.5 mmol) in anhydrous toluene (3 mL), N -The reaction tubes of phenylacetamide (81 mg, 0.6 mmol), CuI (4.8 mg, 0.025 mmol), N-methylethylenediamine (4.4 μL, 0.05 mmol), and potassium phosphate (212 mg, 1 mmol) were blown with dry argon. Scan for 3 minutes. The mixture was then heated at 100 °C for 18 h. After cooling, the reaction was hydrolyzed with 3 mL of water and filtered through Variancartridge ChemElut 12198007, washed with ethyl acetate. The crude mixture was dissolved in 10 mL of glacial acetic acid and refluxed in the presence of iron powder (279 mg, 5 mmol) for 30 min. The acid was removed under reduced pressure, the residue was suspended in saturated sodium bicarbonate solution and extracted with ethyl acetate. The crude product obtained was purified by preparative HPLC to obtain the title compound as a yellow solid (82 mg, 73% yield). mp46-48℃.1HNMRδ2.63 (m, 3H), 7.32 (d, J=Hz, 1H), 7.47 (t, J=Hz, 1H), 7.53 (t, J=Hz, 1H), 7.66-7.72 (m, 5H), 7.88 (d, J=7.2Hz, 2H); 13CNMRδ12.6, 111.8, 115.1, 125.3, 127.1, 130.2, 130.3, 132.9, 133.8, 152.2, 158.3.HRMS (FAB): C14H13N2[M +H+], calculated value: 209.1079; measured value: 209.1072. The same reaction was also carried out on a 25 mmol scale, and the final product 2-methyl-1-phenyl-1H-1,3-benzodiazole (3.9 g) was obtained in a yield of 75%. From 2-bromonitrobenzene (101 mg, 0.5 mmol), the same product 2-methyl-1-phenyl-1H-1,3-benzodiazole (83 mg) was obtained in 80% yield.

Main reference materials

[1] (CN101687815) Regioselective copper-catalyzed synthesis of benzimidazole and azabenzimidazole