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Compound c, represented by Formula 3, was synthesized using Compound a and Compound b purified in Example 1-1. Lithium tert-butoxide was reacted in an inexpensive t-BuOH (tert-butyl alcohol) solvent to obtain compound c in a yield of 54percent. As a result of comparing various base conditions such as pyridine, DMAP, Et3N, K2CO3, KOAc, NaOEt, NaH, and Na / MeOH, Compound c was obtained in a yield of 66percent at a room temperature of Na / MeOH and 71percent at 70 ° C. Also, a reaction of 1 g scale was carried out to synthesize compound c in the final 70percent yield. Then, in order to hydrolyze the obtained compound c, hydrolysis optimum reaction conditions were searched under various acid or base conditions.The reaction was detected in the acid hydrolysis conditions of HCl / CH2Cl2 or H2SO4 / H2O, but the yield was not improved, and the hydrolysis reaction was carried out using the base conditions.The reaction was optimized using sodium hydroxide (NaOH) and THF, DMSO, toluene or H2O solvent, and 3N NaOH / THF at 100 was selected. As a result, telmisartan, a compound represented by the following formula (4), was obtained in a yield of 93percent.
63.9%
With trifluoroacetic acid In <i>N</i>-methyl-acetamide
EXAMPLE 9 4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in dimethylformamide. Yield: 63.9percent of theory, Melting point: 261°-263° C.
Reference：
[1] Patent: KR2018/29401, 2018, A, . Location in patent: Paragraph 0111; 0114; 0118
[2] Journal of Chemical Research, 2010, # 2, p. 95 - 97
[3] Patent: US5591762, 1997, A,
[4] Journal of Medicinal Chemistry, 1993, vol. 36, # 25, p. 4040 - 4051
With potassium tert-butylate; In 1-methyl-pyrrolidin-2-one; at 10℃; for 4h;
To a 100 mL flask was added 2-n-propyl-4-methyl-6- (1'-methylbenzimidazol-2-yl) benzimidazole1.0 g (3.3 mmol), N-methylpyrrolidone4 g of potassium tert-butoxide and 0.4 g (3.6 mmol) of potassium tert-And stirring was started with a magnetic stirrer.While cooling to below 10 C.,A solution of 1.2 g (3.5 mmol) of 4'-bromomethylbiphenyl-2-carboxylic acid tert-butyl ester dissolved in 4.1 g of N-methylpyrrolidone was added dropwise over 2 hours. After the dropwise addition, the mixture was stirred at an internal temperature of 0 to 10 C. for 2 hours. As a result of sampling the reaction solution and conducting liquid chromatography analysis, it was found that 2 - n - propyl - 4 - methyl - 6 - (1 '- methylbenzimidazol - 2 - yl) benzimidazole was not detected and 4' - [[4- Methyl-6- (1-methyl-1 H-benzimidazol-2-yl) -2-propyl- 1 H- benzimidazol- 1 - yl] methyl] biphenyl-2-carboxylic acid tert-butyl ester was 86.0% Area percentage) was generated.
71%
With sodium; In methanol; at 70℃;
Compound c, represented by Formula 3, was synthesized using Compound a and Compound b purified in Example 1-1. Lithium tert-butoxide was reacted in an inexpensive t-BuOH (tert-butyl alcohol) solvent to obtain compound c in a yield of 54%. As a result of comparing various base conditions such as pyridine, DMAP, Et3N, K2CO3, KOAc, NaOEt, NaH, and Na / MeOH, Compound c was obtained in a yield of 66% at a room temperature of Na / MeOH and 71% at 70 C. Also, a reaction of 1 g scale was carried out to synthesize compound c in the final 70% yield. Then, in order to hydrolyze the obtained compound c, hydrolysis optimum reaction conditions were searched under various acid or base conditions.The reaction was detected in the acid hydrolysis conditions of HCl / CH2Cl2 or H2SO4 / H2O, but the yield was not improved, and the hydrolysis reaction was carried out using the base conditions.The reaction was optimized using sodium hydroxide (NaOH) and THF, DMSO, toluene or H2O solvent, and 3N NaOH / THF at 100 was selected. As a result, telmisartan, a compound represented by the following formula (4), was obtained in a yield of 93%.
With potassium tert-butylate; In dimethyl sulfoxide; at 25 - 30℃; for 3.5h;Product distribution / selectivity;
10 g (0.0329 mol) of 2-propyl-4-methyl-6-(r-methylbenzimidazole-2- yl)benzimidazole (1) was dissolved in 60 ml of dimethylsulfoxide (DMSO). 3.7 g (0.0329 mol) of Potassium tert-butoxide was added to the aforementioned solution and stirred at room temperature (25-3O0C) for 30 min. Afterwards, 11.45 g (0.0329 mol) of tert-Butyl-4-bromomethylbiphenyl-2-carboxylate (2) was added and the obtained mixture was stirred at room temperature (25-3O0C) for 3 h. At this stage, the reaction was quenched with water (400 ml) and stirred for 30 min. The reaction mass was filtered. The resulting wet cake was slurried in water (200 ml) and stirred for 30 min. The reaction mass was filtered and the obtained solid was dried under vacuum at 60-650C until constant weight. 18.3 g obtained (93% HPLC).
With sodium hydroxide; In tetrahydrofuran; at 100℃;
Compound c, represented by Formula 3, was synthesized using Compound a and Compound b purified in Example 1-1. Lithium tert-butoxide was reacted in an inexpensive t-BuOH (tert-butyl alcohol) solvent to obtain compound c in a yield of 54%. As a result of comparing various base conditions such as pyridine, DMAP, Et3N, K2CO3, KOAc, NaOEt, NaH, and Na / MeOH, Compound c was obtained in a yield of 66% at a room temperature of Na / MeOH and 71% at 70 C. Also, a reaction of 1 g scale was carried out to synthesize compound c in the final 70% yield. Then, in order to hydrolyze the obtained compound c, hydrolysis optimum reaction conditions were searched under various acid or base conditions.The reaction was detected in the acid hydrolysis conditions of HCl / CH2Cl2 or H2SO4 / H2O, but the yield was not improved, and the hydrolysis reaction was carried out using the base conditions.The reaction was optimized using sodium hydroxide (NaOH) and THF, DMSO, toluene or H2O solvent, and 3N NaOH / THF at 100 was selected. As a result, telmisartan, a compound represented by the following formula (4), was obtained in a yield of 93%.
63.9%
With trifluoroacetic acid; In N-methyl-acetamide;
EXAMPLE 9 4'-[[2-n-Propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in dimethylformamide. Yield: 63.9% of theory, Melting point: 261-263 C.
To the solution of tert-butyl 4'-((6-formyl-4-methyl-2-n- propyl- Jff-benzimidazol- 1 -yl) methyl) biphenyl-2-carboxylate ( 150 mg, 0,32 mmol) in ethanol (9 mL), iV-methyl-o-nitroaniline (48 mg, 0,32 mmol) was added and stirred over -0,5 h. IM aqueous solution of sodium dithionite Na2S2theta4 (1 mL, 3,0 eq., prepared freshly before the use) was added. The mixture was stirred at <n="21"/>temperature 500C for 2 h and kept overnight (ok. 16 h). An additional amount of N- methyl- o-nitroaniline (20 mg) and IM aqueous solution of sodium dithionite Na2S2U4 (0,5 mL) were added and stirred at temperature 500C for 4 h.To the cooled reaction mixture IM HCl (5 mL) and water (20 mL) were added. The mixture was extracted with CH2CI2 (4x 10 mL). The combined organic phases were washed with IM HCl (15 mL) and water (15 mL) and dried over MgSO4. The solution was filtered and concentrated to give 223 mg compounds as an intensively yellow film.The film was purified by chromatography on silica gel, using as eluent CHCI3 with gradually added MeOH (0-3%). There was obtained 117 mg (yield 64,0 %) of telmisartan tert- butyl ester as colorless film.
telmisartan tert-butyl ester DL-tartarate[ No CAS ]
Yield
Reaction Conditions
Operation in experiment
68.64%
In methanol for 5h; Reflux;
6.6
g (0,0087 mol) of telmisartan te/t-butylester, obtained as described in step6.1., was dissolved in methanol (25 ml) and 1,31 g (0,0087 mol) DL-tartaric acid was added. The reaction mass was heated under reflux for 5 h. Afterwards, the solvent was distilled under vacuum. 52 ml of acetone was added to the obtained residue and the suspension was stirred for 10 min. The solvent was distilled under vacuum completely. 30 ml of tert-Butylmethylether was added to the obtained residue and the suspension was heated to reflux for 1 h. Distill out the solvent completely under vacuum. Again, 30 ml of te/t-Butylmethylether was added to the obtained residue and the suspension was heated to reflux for 1 h. Afterwards, the reaction mass was cooled down to 25-30 C, filtered and the resulted solid was dried under vacuum at 5O0C until constant weight.Yield: 4.3 gYield (molar): 68.64%HPLC: 97.72%M.P.: 174°C
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