Methyl 1-[(2′-cyano[1,1′-biphenyl]-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate

The concentrate of methyl 3-amino-2-N-[(2'-cyanobiphenyl-4-yl)methyl]aminobenzoate [MBA] obtained in Reference Example5, tetraethyl orthocarbonate [TEC] obtained in Reference Example 6 (397 kg) and acetic acid (62 kg) were mixed, and the mixture was heated (78 to 82°C) under reflux for about 1 to 2 hrs.. Hydroxylamine hydrochloride (33.4 g, 0.48 mol), DBU (109.5 g, 0.72 mol) plusTo 190ml dioxane at room temperature for 30min, JoinMethyl 2-ethoxy-1- (2'-cyanobiphenyl-4-yl) methylbenzimidazole-7-carboxylate(32.9 g, 0.08 mol), The reaction was stirred at 80-85 ° C until TLC showed complete reaction (about 11h)After cooling to room temperature N'N-carbonyldiimidazole (13.0 g, 0.08 mol)Stirring 1h, The solvent was evaporated under reduced pressure, water 160ml, Stirring 8percent diluted hydrochloric acid to adjust the pH to 4, Suction filtration, washed with water, washed with dichloromethane, dried to give a white powder 36.4g, a yield of 96.7percent.Hydroxylamine hydrochloride (33.4 g, 0.48 mol), DBU (109.5 g, 0.72 mol) plusTo 190ml dioxane at room temperature for 30min, JoinMethyl 2-ethoxy-1- (2'-cyanobiphenyl-4-yl) methylbenzimidazole-7-carboxylate(32.9 g, 0.08 mol), The reaction was stirred at 80-85 ° C until TLC showed complete reaction (about 11h)After cooling to room temperature N'N-carbonyldiimidazole (13.0 g, 0.08 mol)Stirring 1h, The solvent was evaporated under reduced pressure, water 160ml, Stirring 8percent diluted hydrochloric acid to adjust the pH to 4, Suction filtration, washed with water, washed with dichloromethane, dried to give a white powder 36.4g, a yield of 96.7percent.N, N-dimethylacetamide 2L, Water 16L, added to the reaction bottle, Hydroxylamine hydrochloride (3.37 kg 48.6 mol) was added, Sodium carbonate (5.15 kg 48.6 mol) was added, Dimethyl sulfoxide (75 mL) and hydroxylamine hydrochloride (6 g) were stirred at 20°C to 30°C. Sodium bicarbonate (9 g) was added to the solution and stirred at 45 °C to 50 °C for 1 hour. Methyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate (3 g) was added to the reaction mixture and heated at 80 °C to 85 °C for 20 hours. The reaction mixture was cooled to 20 °C to 30 °C and de-ionized water (75 mL) was added to the reaction mixture. The solid obtained was filtered and washed with water (75 mL). The solid obtained was purified in 2-butanol (15 mL) at 90 °C to 95 °C for 4 hours and further cooled to 20 °C to 30 °C for 4 hours. The solid obtained was filtered, washed with 2-butanol (6 mL), and dried to obtain the title compound. Yield: 2.75 g (85percent) HPLC Purity: 96.89percent60 g of N, N-dimethylformamide was added to the reaction flask.Add 19.5 g of sodium carbonate with stirring and mix well.Add 8.5 g of hydroxylamine hydrochloride and warm to 35 ° C.The reaction was stirred for 30 minutes and 25 g of compound IV-1 was added.Continue to raise the temperature to 60 ° C, stir the reaction for 24 h, after the reaction is over, The crystallized crystals were cooled and filtered to obtain a crude compound III-1. The crude product obtained, DMSO was added to the reaction flask, and the temperature was crystallized for 1 hour, and the temperature was crystallized.Filtration and drying gave Compound III-1 in a yield of 75percent.To a 500 mL four-neck flask, 20 g of Compound 1 was added, and while stirring, 100 mL of dimethyl sulfoxide solution in which 10.14 g (3 eq) of hydroxylamine hydrochloride was added was added, and the mixture was heated to 90 DEG C and 30.95 g (6 eq) was added in portions under stirring. Sodium carbonate, after the completion of the reaction for 9-10 hours, after the completion of the reaction, it is allowed to come to room temperature, and 100 mL of water is added to stir the mixture. The solid precipitates, which is cooled down to 0-5°C. Stirring is continued for about 1 hour, and the mixture is dried by suction to obtain 15.2 g of compound 2. The yield was 70.4percent.Weighed hydroxylamine hydrochloride (60.8mmol), triethylamine (63.2mmol), dimethyl sulfoxide 60mL was added to a 100mL two-neck round bottom flask, stirred at room temperature for 30min, added to the reaction system1-[(2'-Cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester (6.08 mmol) was reacted at 75 ° C for 6 h and the reaction was completed. Thereafter, the mixture was cooled to room temperature, and the product in the reaction mixture was extracted with dichloromethane, distilled under reduced pressure, solvent was removed, and recrystallized to give 1-[(2'-(hydroxyindolyl)[1, 1-biphenyl]- Methyl 4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate, yield 35percent.Example 1Preparation of methyl 2-ethoxy [[2'-(hydroxyamidino) biphenyl-4-yl] methyI]-lH- benzimidazole-7-carboxylateTo a solution of hydroxylamine hydrochloride (122 g) and dimethylsulfoxide (1000 ml), Sodium bicarbonate (204 g) was added at 25-30°C, which was further heated to 45-50°C. To the resulting solution l-[(2'cyanobiphenyl-4-yl)methyl]-2-ethoxy benzimidazole-7-carboxylate (40 g) was added and the resulting solution was heated to 85-90°C followed by stirring at the same temperature for about 18 h. Reaction mass was cooled to 15-20°C. Water was added and the solution was stirred for 15-20 min at 15- 20°C. The product was filtered, washed and dried to obtain title compound. (Yield: 38 g; 88percent; (Purity: 87percent with amide impurity 3.86percent.Methanol (400 mL) and sodium hydroxide (56.44 g) were added under a nitrogen atmosphere and stirred at 20° C. to 30° C. to get a clear solution. Dimethylacetamide (750 mL) and hydroxylamine hydrochloride (101.45 g) were added under a nitrogen atmosphere and stirred at 20° C. to 30° C. to get clear solution. Methanolic sodium hydroxide solution was added to the solution of hydroxylamine hydrochloride in dimethylacetamide at 25° C. to 30° C. The reaction mixture was stirred for 30 minutes. Methyl-1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate (100 g) was added to the reaction mixture at 25° C. to 30° C. and heated to 70° C. to 75° C. for 16 hours to 20 hours. The reaction mixture was cooled to 10° C. to 15° C. The reaction mixture was added to deionized water (1000 mL) at 10° C. to 25° C. The pH of the reaction mixture was adjusted to 0.8 to 1.2 using concentrated hydrochloric acid (150 mL). The reaction mixture was stirred for 30 minutes at 20° C. to 30° C. The reaction mixture was filtered through celite and washed with deionized water (100 mL). The aqueous layer was washed with toluene (500 mL) at 25° C. to 30° C. and the pH of the aqueous layer was adjusted to 8.8 to 9.2 using 30percent solution of sodium carbonate (500 mL) at 20° C. to 30° C. The reaction mixture was stirred for 3 hours to 4 hours at 25° C. to 30° C. The reaction mixture was filtered and washed with deionized water (100 mL) at 20° C. to 30° C. Isobutanol (500 mL) was added to the reaction mixture at 20° C. to 30° C. and the reaction mixture was heated to 90° C. to 95° C. The reaction mixture was stirred for 2 hours at 90° C. to 95° C., cooled to 25° C. to 30° C., and stirred for 4 to 6 hours at 25° C. to 30° C. The reaction mixture was filtered and washed with isobutanol (100 mL) at 20° C. to 30° C. The reaction mixture was dried under vacuum for 30 minutes at 20° C. to 30° C. and then at 45° C. to 50° C. to obtain the title compound. Yield: 55 gTaking anhydrous sodium sulfite 122.5 g (0.972 mol)Sodium bicarbonate 408.4 g (4.861 mol)Was added to 2.4 L of DMSO, stirred, A mixture of hydroxylamine hydrochloride (270.2 g, 3.889 mol)Temperature control 50 ~ 55 stirring reaction 2h, Was added 1 - [(2 - cyanobiphenyl-4-yl) methyl] -2-ethoxy-benzimidazole-7-carboxylate (200g, 0.486mol), Temperature control 80 ~ 85 stirring reaction 10h, Rapid dropwise addition of 2.4L water stirring crystallization, Temperature control 20 ~ 25 stirring for 1h, Filtration to give compound II191.3g.HPLC was used to detect compound II 99.07percent and amide impurity 0.32percent.Add 1000g to the 20L reaction bottleMethyl 2-ethoxy-1-((2'-cyanobiphenyl-4-yl)methyl)-1H-benzimidazole-7-carboxylate (II), 1473 mL of 50percent aqueous hydroxylamine solution, 340 mL of triethylamine, 1 g of sodium hexametaphosphate, 0.5 g of tetrabutylammonium chloride and 8 L of industrial ethanol (95percent ethanol). The reaction solution was heated to reflux for 30 h, slightly cooled, and filtered while hot. After cooling and crystallization for 8 h, the solid obtained by suction filtration was dried at 45 ° C for 8 h to obtain white solid intermediate III 910 g, yield: 91.5percent, purity 91.7percent.The hydroxylamine sulphate 196.8g (1.2mol), adding 420ml90percent in ethanol, stirring, 0-20°C, adding anhydrous sodium sulfate for 50g, slowly adding potassium hydroxide 60.5g (1.08mol), stop the exothermic the reaction system, adding the filtrate 125g compound of formula (II) (0.3mol), 87.6g diethylamine (1.2mol), 600 ml ethanol, 75-80 °C reflux 16 hours, cooling to room temperature, filter, intermediate (I) the system results in the type 79.0 g. Detection by HPLC: formula (I) intermediate 85.741percent, amide 7.518percent.

Molecular Weight:411.5
XLogP3:4.9
Hydrogen Bond Acceptor Count:5
Rotatable Bond Count:7
Exact Mass:411.15829154
Monoisotopic Mass:411.15829154
Topological Polar Surface Area:77.1
Heavy Atom Count:31
Complexity:654
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes