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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011mol), THF (54 mL) and water (6 mL) were mixed to dissolve them. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-water (THF : water = 9 : 1) (10 mL). Water (87.5 mL) was added dropwise to the filtrate and washing. After stirring for about 1 hour, the crystals were separated, and washed with THF-water (THF : water = 2 : 3) (20 mL). Drying afforded 4.5 g of Compound (I) (yield 90%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.08% and ethyl ester compound was 0.06% as analogues in the crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 3780 ppm as a residual solvent in the crystals. In addition, other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 4 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-water (THF : water = 9 : 1) (10 mL). Water (87.5 mL) was added dropwise to the combined filtrate and washing. After stirring for about 1 hour, the crystals were separated and washed with THF-water (THF : water = 2 : 3) (20 mL). The resulting wet crystals and water (50 mL) were mixed, and stirred for about 30 minutes. The crystals were separated, and washed with water (20 mL). Drying afforded 4.4 g of Compound (I) (yield 88%). The crystals were analyzed by high performance liquid chromatography (Condition (A)) and as a result, ketone compound was 0.12% and ethyl ester compound was 0.13% as analogues in the crystals. The crystals were analyzed by Atomic Absorption Spectrometry, and as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 8 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-water (THF : water = 9 : 1) (10 mL). Water (87.5 mL) was added dropwise to the combined filtrate and washing over about 10 minutes. After stirring for about 1 hour, the crystals were separated, and washed with THF-water (THF : water = 2 : 3) (20 mL). Drying afforded 4.2 g of Compound (I) (yield 84%). The crystals were analyzed by high performance liquid chromatography (condition(A)), as a result, ketone compound was 0.05% and ethyl ester compound was 0.13% as analogues in the crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 9 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-water (THF : water = 9 : 1) (10 mL). The combined filtrate and washing was added dropwise to water (87.5 mL). After stirring for about 1 hour, the crystals were separated, and washed with THF-water (THF : water = 2 : 3) (20 mL). Drying afforded 4.4 g of Compound (I) (yield 88%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.23% and ethyl ester compound was 0.13% as analogues in the crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 14 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with ethanol (10 mL). Ethanol (98 mL) was added to the combined filtrate and washing, and water (102 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with ethanol-water (ethanol : water = 1 : 1) (20 mL). Drying afforded 3.8 g of Compound (I) (yield 76%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.17% and ethyl ester compound was 0.10% as analogues in the crystals. The crystals were analyzed by ga... |
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Purification / work up; |
2-(Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), DMSO (7 mL) and acetone (63 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with DMSO-acetone (DMSO : acetone = 9 : 1) (10 mL). Water (80 mL) was added dropwise to the combined filtrate and washing. After stirring for about 1 hour, the crystals were separated, and washed with acetone-water (acetone : water = 1 : 1) (20 mL). Drying afforded 4.5 g of Compound (I) (yield 90%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.29% and ethyl ester compound was 0.10% as analogues in the crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 11 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), DMSO (7 mL) and acetone (63 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with DMSO-acetone (DMSO : acetone = 9 : 1) (10 mL). Water (34 mL) was added dropwise to the combined filtrate and washing. After stirring for about 1 hour, the crystals were separated, and washed with acetone-water (acetone : water = 1 : 1) (20 mL). Drying afforded 4.0 g of Compound (I) (yield 80%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.25% and ethyl ester compound was 0.11% as analogues in the crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (63 mL), acetone (63 mL) and water (14 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-acetone (THF : acetone = 1 : 1) (10 mL). Water (70 mL) was added dropwise to the combined filtrate and washing. After stirring for about 1 hour, crystals were separated, and washed with acetone-water (acetone : water = 1 : 1 ) (20 mL). Drying afforded 3.0 g of Compound (I) (yield 60%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.06% and ethyl ester compound was 0.09% as analogues in crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 940 ppm and acetone was 460 ppm as a residual solvent in the crystals. Other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 32 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol) was dissolved in 1N sodium hydroxide (24 mL, 0.024 mol). The solution was ultrafiltered. Methanol (50 mL) was added to the filtrate, and concentrated hydrochloric acid was added thereto under ice-cooling to adjust the pH to about 3. The crystals were collected by filtration, and washed with water (100 mL). THF (54 mL) was added to the crystals, and dissolved them. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with acetone (20 mL). Acetone (100 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, heptane (100 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with acetone-heptane (acetone : heptane = 1 : 1) (20 mL). Drying afforded 4.0 g of Compound (I) (yield 80%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.07% and ethyl ester compound was 0.04% as analogues in the crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 170 ppm, acetone was 320 ppm and heptane was below quantitation limit as a residual solvent in the crystals. Other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Endotoxin in the crystals was investigated, and it was found that endotoxin was not present. |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (63 mL), acetone (63 mL) and water (14 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-acetone (THF : acetone = 1 : 1) (10 mL). Water (70 mL) was added dropwise to the combined filtrate and washing. After stirring for about 1 hour, crystals were separated, and washed with acetone-water (acetone : water = 1 : 1 ) (20 mL). Drying afforded 3.0 g of Compound (I) (yield 60%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.06% and ethyl ester compound was 0.09% as analogues in crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 940 ppm and acetone was 460 ppm as a residual solvent in the crystals. Other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). |
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Purification / work up; |
Methyl 2-ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-bemzimidazole-7-carboxylate (3 kg, 6.60 mol), acetone (67 L) and purified water (6.7 L) were mixed. Acetone-water (acetone : water = 10 : 1) were added until they were dissolved at 55 to 60C. Activated charcoal (150g) was added, and the mixture was stirred at the same temperature for about 10 minutes. Activated charcoal was removed by filtration, and washed with acetone-purified water (acetone : purified water = 10:1) (3 L). The solution was gradually cooled to about 10C, and stirred for about 2 hours. The crystals were separated, and washed with acetone-purified water (acetone : purified water = 10 : 1) (6 L). The resulting wet crystals, acetone (37 L) and purified water (3.7 L) were mixed. Acetone-purified water (acetone : purified water = 10 : 1) were added until they were dissolved at 55 to 60C. The solution was gradually cooled to about 10C, and stirred for about 2 hours. The crystals were separated, and washed with acetone-purified water (acetone : purified water = 10 : 1) (10 L). After drying, the resulting crystals were added to a solution obtained by mixing sodium hydroxide (540 g) and purified water (6750 mL). The reaction was allowed to proceed at 65 to 75C for about 2 hours. Methanol (1350 mL) was added at 20 to 30C. Concentrated hydrochloric acid was added dropwise at 0 to 10C to adjust the pH to about 7.5. Activated charcoal (94.5 g) was added, and the mixture was stirred at the same temperature for about 30 minutes. Activated charcoal was removed by filtration, followed by washing with methanol-purified water (methanol : purified water = 2:1) (2025 mL). Concentrated hydrochloric acid was added dropwise at 0 to 10C to adjust the pH to about 3.5. Purified water (11.5 L) was added, and the solution was stirred at 0 to 10C for about 45 minutes. The crystals were separated, and washed with purified water (1350 mL). The resulting wet crystals were added to a solution obtained by mixing sodium hydroxide (263.3 g) and purified water (3375 mL). After dissolution, purified water (3375 mL) was added. The solution was ultrafiltered, and the ultrafilter membrane was washed with purified water (1350 mL). Methanol (20.3 L) was added to the combined filtrate and washing. Concentrated hydrochloric acid was added dropwise at 0 to 10C to adjust a pH to about 3.5. Distilled water (10.1 L) was added, and the solution was stirred at 0 to 10C for about 45 minutes. The crystals were separated, and washed with distilled water (20.3 L). Drying afforded 1215 g of Compound (I) (yield 41.9%). The crystals were analyzed by high performance liquid chromatography (Condition (A)) and, as a result, ketone compound was 0.22% and ethyl ester compound was 0.06% as analogues in the crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (90 mL), ethanol (90 mL) and water (20 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-ethanol-(THF : ethanol = 1 : 1) (10 mL). Water (100 mL) was added dropwise to the combined filtrate and washing. After stirring for about 1 hour, the crystals were separated, and washed with ethanol-water (ethanol : water = 1 : 1) (20 mL). Drying afforded 3.3 g of Compound (I) (yield 66%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.04% and ethyl ester compound was 0.07% as analogues in the crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 1000 ppm and ethanol was 570 ppm as a residual solvent in the crystals. Other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol) and DMSO (20 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with acetone-THF (acetone : THF = 5 : 1) (10 mL). Acetone-THF (acetone : THF = 5 : 1) (60 mL) were added to the combined filtrate and washing, and water (60 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with acetone-water (acetone : water = 1 : 1) (20 mL). Drying afforded 4.4 g of Compound (I) (yield 88%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.16% and an ethyl ester compound was 0.15% as analogues in the crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 16 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol) and DMSO (20 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with ethanol-THF (ethanol : THF = 5 : 1)(10 mL). Ethanol-THF (ethanol : THF = 5 : 1) (60 mL) was added to the combined filtrate and washing, and water (60 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with ethanol-water (ethanol : water = 1 : 1) (20 mL). Drying afforded 4.4 g of Compound (I) (yield 88%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.19% and ethyl ester compound was 0.11% as analogues in crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with acetone (10 mL). Acetone (98 mL) was added dropwise to the combined filtrate and washing. After stirring for about 3 hours, the crystals were separated, and washed with acetone (20 mL). Drying afforded 1.7 g of Compound (I) (yield 34%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.05% and ethyl ester compound was 0.06% as analogues in the crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 160 ppm and acetone was 110 ppm as residual solvent in the crystals. Other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 18 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with acetone (10 mL). Acetone (98 mL) was added dropwise to the combined filtrate and washing. After stirring for about 20 hours, the solution was stirred at -15 to -20C for about 3 hours. The crystals were separated, and washed with acetone (20 mL). Drying afforded 2.5 g of Compound (I) (yield 50%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.08% and ethyl ester compound was 0.06% as analogues in the crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 220 ppm and acetone was 230 ppm as residual solvent in the crystals. Other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limitation (0.6 ppm). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with acetone (20 mL). Acetone (100 mL) was added to the combined filtrate and washing. After stirring for about 2 hours, tert-butyl methyl ether (100 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with acetone-tert-butyl methyl ether (acetone : tert-butyl methyl ether = 1:1) (20 mL). Drying afforded 2.9 g of Compound (I) (yield 58%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.10% and ethyl ester compound was 0.05% as analogues in the crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 590 ppm, acetone was 440 ppm and tert-butyl methyl ether was 180 ppm as a residual solvent in the crystals. Other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 21 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with acetone (20 mL). Acetone (100 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, tert-butyl methyl ether (100 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with acetone-tert-butyl methyl ether (acetone : tert-butyl methyl ether = 1 : 1) (20 mL). Drying afforded 2.9 g of Compound (I) (yield 58%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.06% and ethyl ester compound was 0.06% as analogues in the crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 120 ppm, acetone was 200 ppm and tert-butyl methyl ether was below quantitation limit as a residual solvent in the crystals. Other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 22 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with tert-butyl methyl ether (20 mL). tert-Butyl methyl ether (100 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, the crystals were separated, and washed with tert-butyl methyl ether (20 mL). Drying afforded 4.1 g of Compound (I) (yield 82%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.08% and ethyl ester compound was 0.10% as analogues in the crystals. The crystals were analyzed by gas chromatography, as a result, THF was 2340 ppm and tert-butyl methyl ether was 990 ppm as a residual solvent in the crystals. Other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 23 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011mol,), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with tert-butyl methyl ether (20 mL). tert-Butyl methyl ether (20 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, tert-butyl methyl ether (80 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with tert-butyl methyl ether (20 mL). Drying afforded 3.6 g of Compound (I) (72%). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with heptane (20 mL). Heptane (20 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, heptane (80 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with heptane (20 mL). Drying afforded 4.0 g of Compound (I) (80%). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with methanol (20 mL). Methanol (40 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, the crystals were separated, and washed with methanol (20 mL). Drying afforded 3.8 g of Compound (I) (76%). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with ethyl acetate (20 mL). Ethyl acetate (40 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, the crystals were separated, and washed with ethyl acetate (20 mL). Drying afforded 3.2 g of Compound (I) (64% ).Example 30 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with ethyl acetate (20 mL). Ethyl acetate (40 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, heptane (60 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with ethyl acetate-heptane (ethyl acetate : heptane = 1 : 1 (20 mL). Drying afforded 4.0 g of Compound (I) (80%). |
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Purification / work up; |
2-(Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with ethyl acetate (20 mL). The combined filtrate and washing was passed through Posidyne filter. The Posidyne filter was washed with ethyl acetate (20 mL). Ethyl acetate (20 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, the crystals were separated, and washed with ethyl acetate (20 mL). Drying afforded 3.6 g of Compound (I) (72%). Example 31 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g)(0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with ethyl acetate (20 mL). The combined filtrate and washing was passed through Posidyne filter. The Posidyne filter was washed with ethyl acetate (20 mL). Ethyl acetate (20 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, heptane (60 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with ethyl acetate-heptane (ethyl acetate : heptane = 1 : 1)(20 mL). Drying afforded 4.0 g of Compound (I) (80%). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with 1-propanol (20 mL). 1-Propanol (100 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, the crystals were separated and washed with 1-propanol (20 mL). Drying afforded 3.8 g of Compound (I) (76%). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with 2-propanol (20 mL). 2-Propanol (40 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, the crystals were separated, and washed with 2-propanol (20 mL). Drying afforded 3.2 g of Compound (I) (64%). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve them. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with acetone (20 mL). Acetone (100 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, heptane (100 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated and washed with acetone-heptane (acetone : heptane = 1 : 1) (20 mL). Drying afforded 3.9 g of Compound (I) (yield 78%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.09% and ethyl ester compound was 0.05% as analogues in the crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 190 ppm, acetone was 340 ppm and heptane was below quantitation limit as a residual solvent in the crystals. In addition, other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 19 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with acetone (20 mL). Acetone (100 mL) was added to the combined filtrate and washing. After stirring for about 2 hours, heptane (100 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with acetone-heptane (acetone : heptane = 1 : 1) (20 mL). Drying afforded 3.8 g of Compound (I) (yield 76%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.24% and ethyl ester compound was 0.05% as analogues in crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with acetone (20 mL). The combined filtrate and washing was passed through Posidyne filter. The Posidyne filter was washed with acetone (20 mL). Acetone (80 mL) was added to the combined filtrate and washing. After stirring for about 20 hours, heptane (100 mL) was added dropwise. After stirring for about 1 hour, the crystals were separated, and washed with acetone-heptane (acetone : heptane = 1:1) (20 mL). Drying afforded 3.9 g of Compound (I) (yield 78%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.08% and ethyl ester compound was 0.05% as analogues in the crystals. The crystals were analyzed by gas chromatography and, as a result, THF was 150 ppm, acetone was 300 ppm and heptane was below quantitation limit as a residual solvent in the crystals. In addition, other residual solvents were not detected. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Endotoxin and bacteria in the crystals were investigated, and it was found that endotoxinand bacteria were not present. |
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Purification / work up; |
2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-water (THF : water = 9 : 1) (10 mL). Water (87.5 mL) was added dropwise to the combined filtrate and washing. After stirring for about 1 hour, the crystals were separated, and washed with THF-water (THF : water = 2 : 3) (20 mL). The resulting wet crystals and ethanol (50 mL) were mixed, and stirred for about 30 minutes. The crystals were separated, and washed with ethanol (20 mL). Drying afforded 4.0 g of Compound (I) (yield 80%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.12% and ethyl ester compound was 0.11% as analogues in the crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in crystals was below quantitation limit (0.6 ppm). Example 6 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-water (THF : water = 9 : 1) (10 mL). Water (87.5 mL) was added dropwise to the combined filtrate and washing. After stirring for about 1 hour, the crystals were separated, and washed with THF-water (THF : water = 2:3) (20 mL). The resulting wet crystals and acetone (50 mL) were mixed, and stirred for about 30 minutes. The crystals were separated, and washed with acetone (20mL). Drying afforded 4.0 g of Compound (I) (yield 80%). The crystals were analyzed by high performance liquid chromatography (Condition (A)) and, as a result, ketone compound was 0.11% and ethyl ester compound was 0.12% as analogues in crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). Example 7 2-Ethoxy-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid (5.0 g, 0.011 mol), THF (54 mL) and water (6 mL) were mixed to dissolve. Activated charcoal (0.15 g) was added, and the mixture was stirred for about 30 minutes. Activated charcoal was removed by filtration, and washed with THF-water (THF : water = 9 : 1) (10 mL). Water (87.5 mL) was added dropwise to the combined filtrate and washing. After stirring for about 1 hour, the crystals were separated, and washed with THF-water (THF : water = 2:3) (20 mL). The resulting wet crystals and ethyl acetate (50 mL) were mixed, and stirred for about 30 minutes. The crystals were separated, and washed with ethyl acetate (20 mL). Drying afforded 4.0 g of Compound (I) (yield 80%). The crystals were analyzed by high performance liquid chromatography (condition(A)) and, as a result, ketone compound was 0.11% and ethyl ester compound was 0.12% as analogues in the crystals. The crystals were analyzed by Atomic Absorption Spectrometry and, as a result, the content of Sn in the crystals was below quantitation limit (0.6 ppm). |
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With lithium azide; lithium bromide; In N,N-dimethyl acetamide; at 140℃; |
General procedure: In the three-necked flask, 51 g of compound III-2 (R4 is H) and 62 g of lithium bromide were added.Lithium azide 25g and 300g N,N-dimethylacetamide,Stirring to 140 C reaction, after the end of the reaction, cooling, adding xylene,Hydrochloric acid was added dropwise to adjust the pH, and the xylene layer was collected by liquid separation.Extracted with 5% KOH aqueous solution, acid added to adjust pH to 7,Add 45% hydrogen peroxide solution (ferric chloride indicator)Detection system azide ion residue),After the quenching was completed, hydrochloric acid solution was added to adjust the pH to 3 to 4, and the crystals were decanted, washed, and dried to obtain a compound I-2, azide: not detected; NDMA was detected: not detected. |