4-Methyl-6-(1-methylbenzimidazol-2-yl)-2-propyl-1H-benzimidazole

Uses 2-n-propyl-4-methyl-6-(1'-methylbenzimidazole-2-yl)benzimidazole (telmisartan EP impurity A; USP telmisartan related compound A) is an impurity found in telmisartan (T017000). Uses Used as an intermediate in the drug telmisartan. General steps for the synthesis of 1,7'-dimethyl-2'-propyl-1H,1'H-2,5'-dibenzimidazole from N-methyl-2-phenylenediamine hydrochloride and 2-n-propyl-4-methyl-6-carboxybenzimidazole: 4-methyl-2-n-propyl-1H-benzimidazole-6-carboxylic acid (50 g) is suspended in polyphosphoric acid (300 g) and heated to 70-75°C for 30 minutes. Subsequently, N-methyl-2-phenylenediamine dihydrochloride (45 g) is added in portions over 2 hours, and the reaction is continued at 70-75°C for 1 hour. Next, the reaction mixture was heated to 130-135°C and maintained for 10 hours. After the reaction was complete, the mixture was cooled to 70°C, and water (600 mL) was slowly added while maintaining the temperature at 60-90°C. Cooling was continued to 30°C, and the pH was adjusted to 8.0-8.5 with an ammonia solution. Subsequently, the reaction mixture was heated to 50-55°C and maintained for 1 hour. The solid was collected by filtration and the wet filter cake was washed with hot water (200 mL). The wet filter cake was suspended in water (900 mL), heated to 50-55°C, stirred for 1 hour, filtered, and washed again with hot water (100 mL). The wet filter cake was dried to constant weight at 70-75°C. The dried product was suspended in methanol (260 mL), heated to 45-50°C, and activated carbon (6.5 g) was added. The mixture was stirred for 30 minutes. Insoluble matter was removed by filtration through a Hyflo bed. The bed was washed with hot methanol (60 mL), the filtrates were combined, and cooled to 25°C. Water (160 mL) was slowly added to the filtrate at 25-35 °C, and the mixture was heated to reflux temperature and maintained for 1 hour. The reaction mixture was cooled to 0-5 °C and maintained for 2 hours. The resulting solid was filtered, washed with methanol (60 mL), and the wet filter cake was dried at 70-75 °C to constant weight to give 54 g of 4-methyl-6-(1-methylbenzimidazol-2-yl)-2-n-propyl-1H-benzimidazole (yield 77.4%). The water content was determined by KF analysis to be 5.85%.