2-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)benzimidazole

4-Methyl-2-n-propyl-lH-benzimidazole-6-carboxylic acid (50 gms) is suspended in Poly phosphoric acid (300 gms), temperature is raised and maintained for 30 min at 70 - 75Variant 2; Methanesulphonic acid is heated to about 80° C. At a temperature of 75° C. to 85° C., 2-propyl-4-methyl-1H-benzimidazole-6-carboxylic acid is added. Then at 85° C. to 95° C. N-methyl-o-phenylene-diamine is added.The mixture is heated to110° C. to 130° C. and phosphorus pentoxide is metered in until an internal temperature of not more than 160° C. is reached. Then the mixture is stirred for 3 hours at a maximum temperature of 145° C. It is cooled to <100° C. and water is metered into the reaction mixture. 50percent sodium hydroxide solution is added at <100° C. until a pH of less than 3 is obtained.Finally, treatments with charcoal are carried out at <100° C.At a temperature of <80° C. isopropanol is added and the mixture is adjusted with sodium hydroxide solution to a pH between 4.5 and 7. The aqueous phase is separated off. In order to precipitate dimethyl-2'-propyl-2, 5'-bi-1H-benzimidazole water is metered in, the contents of the apparatus are cooled to at least 40° C. for technical reasons and the product is isolated.Yield: 78-90percent of theoryHPLC purity: >99.5percent.The compound 11 (40 g, 0.14 mol) and sodium dithionite (148 g, 0.84 mol) was suspended in a mixture of methanol (320 ml) and water (320 ml), butyl aldehyde (256 ml, 0.28 mol) was added, then the stirred mixture was heated at reflux for 12 h. After cooling, the reaction mixture was poured slowly into water (2400 ml) with stirring. The resultant suspension was filtered and the collected solid washed with water, and crystallized from toluene to give bis-benzimidazole 4 (36.5 g, 85percent) as light yellow solid; mp: 138-139 °C; A mixture of methyl 4-methyl-2-propyl-1H-benzo[d]imidazole-6-carboxylate 2 (10 mmol) and N-methyl-o-phenylenediamine (10 mmol) in PPA (20 ml) were taken in a two necked flask fitted with a condenser and the reaction mixture was refluxed at 150 Example 1:Orthophosphoric acid (210 gms) was taken in round bottomed flask and ΡAdd to a 500 mL four-necked flask (0.1 mol), DMSO (150 mL), stirred and stirred, followed by the addition of potassium carbonate 13.8 (0.1 mol), 18.6 g (0.1 mol) of p-aminobenzyl bromide, and the reaction was carried out at room temperature for 10 h. 1200 mL of toluene and 600 mL of water were added and the mixture was stirred for a while and the layers were separated. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to obtain an oil , 50 mL of n-hexane was added, stirred for a while, solid precipitated, and the solid was collected by filtration and used directly in the next step60% NaH (1.0 g, 0.025 mol) was added to DMF (10 mL) The mixture was stirred under ice-water and the compound of formula I (3.05 g, 0.01 mol) was added, The mixture was stirred at room temperature for 30 minutes. The title compound (II) (2.46 g, 0.01 mol) of was dissolved in DMF (10 mL) and slowly added to the above reaction solution, Stirred at room temperature for 1 hour; heated to 50 C for 4 hours, TLC detection reaction ends. The reaction solution was poured into ice water (100 mL), stirred, With concentrated hydrochloric acid to adjust the pH to solid precipitation; filter, the resulting filter with water once, Dried to give a solid brown telmisartan (4.3 g, yield 84%).The compound of formula I (0.62 g, 1 eq) was added to acetonitrile (10 ml) and stirred well. KOH (0.14 g, 1.1 eq) was added slowly, stirred for about 10 minutes, The title compound of Example 10 was added (II, R = COOCH3) (0.5 g, 1 eq) was slowly added, and after stirring for 3-4 hours, TLC After the reaction was complete, 50% ethanol (30 mL) was added directly, The reaction was refluxed for 6 hours. After the TLC test reaction was complete, the organic solvent was recovered under reduced pressure, The remaining solution was added dropwise with hydrochloric acid (1: 1) to pH neutral. There are solid precipitation, filtration, washing, extraction of telmisartan crude, Recrystallization of telmisartan (yield 75.1%), liquid purity greater than 98%.The compound of formula I (0.62 g, 1 eq) was added to acetonitrile (7 ml) and stirred well. KOH (0.14 g, 1.1 eq) was added slowly, stirred for about 10 minutes, The title compound of Example 10 (II, R = COOCH3) (0.5 g, 1 eq) Slowly add, stir 3-4 hours later, TLC detection reaction is complete, The temperature was lowered to -5 to 5 C and stirred for 4-5 hours. The solid was filtered, Filter cake with a small amount of acetonitrile leaching, washing, drying (50-60 ), To obtain the compound (III, R = COOCH3) (0.93 g, yield 92%), Liquid purity is greater than 98%.The compound of formula I (10 g, 1 eq) was added to DMF (50 ml) and stirred to dissolve, And then cooled to 0-5 C, 55% NaH (3.4 g, 2.5 eq) was added slowly, After the addition, the mixture was stirred at the same temperature for about 1 hour, The temperature of the reaction solution is controlled to 10 degrees or less, The title compound of Example 6 (9.5 g) was dissolved in DMF (10 ml) Slowly dripping, stirring at this temperature for 1-2 hours, TLC or HPLC detection of raw materials after the basic reaction is complete, The temperature maintained at 10 degrees below the addition of dilute hydrochloric acid to adjust the pH value of the solid precipitation, Stirring, the resulting solid filtration, washing, After drying, telmisartan (15.2 g) was obtained in a yield of 95%.The double-benzimidazole heterocyclic compound (500 mg, 1 . 64mmol) soluble in 20mLN, in N - dimethyl formamide, adding sodium hydrogen (79 mg, 3 . 3mmol) at room temperature under stirring 30min, slow the instillment contains N - O-cyano phenyl -4 - bromo methyl indole (560 mg, 1 . 8mmol) of N, N - dimethyl formamide solution (10 ml) in. The mixed liquid continuing stirring at room temperature instead on invitation 2h, TLC monitoring to the reaction is complete. Filtering, the filter cake is dichloromethane (10 ml × 3) washing three times. In the filtrate by adding 200 ml of methylene chloride and 200 ml water, takes organically. After the dichloromethane (150 ml × 3) extracting the aqueous phase three times, the combined organic phase. For saturated salt water (300 ml × 4) washing the organic phase four. For drying the organic phase with anhydrous magnesium sulfate, filter, evaporate the solvent under reduced pressure, to obtain amber solid. The solid weight crystallized to obtain gray solid about 600 mg (yield is about 68.3%).The bisbenzimidazole heterocyclic compound(500 mg, 1.64 mmol) was dissolved in 20 mL of N, N-dimethylformamide, Sodium hydride (79 mg, 3.3 mmol) was added, Stirred at room temperature for 30 min, A solution of N, N-dimethylformamide (10 mL) containing N-o-methoxycarbonylphenyl-4-bromomethylindole (617 mg, 1.8 mmol) was slowly added dropwise.After dripping, The mixture was stirred at room temperature for about 2 h, TLC was monitored until the reaction was complete.Add 2M sodium hydroxide solution 2mL, Stir at room temperature for about 2 h.TLC monitoring to the reaction is complete, The pH was adjusted to 5-6 with 2M hydrochloric acid, 200 mL of dichloromethane and 200 mL of 7 K were added to the reaction solution, Take the organic phase, The aqueous phase was extracted three times with dichloromethane (150 mL X3)Combine the organic phase.The organic phase was washed four times with saturated brine (300 mL X4)Dried over anhydrous magnesium sulfate, filter, The solvent was distilled off under reduced pressure, To give a tan solid.The solid was recrystallized to give about 600 mg (yield: about 66.0%) of the off-white solid product.

Molecular Weight:304.4
XLogP3:4.2
Hydrogen Bond Donor Count:1
Hydrogen Bond Acceptor Count:2
Rotatable Bond Count:3
Exact Mass:304.16879665
Monoisotopic Mass:304.16879665
Topological Polar Surface Area:46.5
Heavy Atom Count:23
Complexity:414
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes