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Ethyl 3 - [(2- { [4-(hexyloxycarbonylarninoimmomemyl)phenylammo]methyl } -1 - methyl- lH-benzimidazole-5-carbonyl)pyridm-2-ylamino]propionate base (52.6 kg) (which has preferably been purified beforehand by recrystallization from ethyl acetate) is placed in an agitator apparatus which has been rendered inert and then 293 kg of acetone is added. The contents of the apparatus are heated to 40° C to 46° C with stirring. After a clear solution has formed, the contents of the apparatus is filtered into a second agitator apparatus through a lens filter and then cooled to 30° C to 36° C. 33 kg of acetone precooled to 0° C to 5° C, 7.9 kg of 99.5percent methanesulfonic acid, and for rinsing another 9 kg of acetone are placed in the suspended container of the second apparatus. The contents of the suspended container are added in metered amounts to the solution of ethyl 3-[(2-[4-(hexyloxycarbonylamino- iminomethyl)phenylamino]methyl} - 1 -methyl- 1 H-benzimidazole-5-carbonyl)pyridin-2- ylamino]propionate base at 26° C to 36° C within 15 to 40 minutes. Then the mixture is stirred for 40 to 60 minutes at 26° C to 33° C. It is then cooled to 17° C to 23° C and stirred for a further 40 to 80 minutes. The crystal suspension is filtered through a filter dryer and washed with a total of 270 L of acetone. The product is dried in vacuum at a maximum of 50° C for at least 4 hours. Yield: 54.5-59.4 kg;90percent-98percent of theory based on ethyl 3-[(2-[4-(hexyloxycarbonyl- ammoiminomethyl)phenylamino]methyl} - 1 -methyl- 1 H-benzimidazole-5-carbonyl)- pyridm-2-ylamino]propionate base.
24 g
at 28 - 45℃; for 1 h;
A solution of Dabigatran Etexilate (23g) in acetone (184 mL), at 39-45°C was filtered and then cooled to 30°C. Pre-cooled solution of methanesuiphonic acid (3.24g) inacetone (23 mL) was, slowly, added to the reaction mass and then stirred for lh, at 28-32°C. The reaction mass was cooled to 19-23°C and slurred for another hour. The precipitated product was filtered, washed with acetone and dried, under vacuum, at 50°C, to afford mesylate salt of Dabigatran Etexilate as pale yellow colored solid material (24 g, >99percent HPLC pure).
Ethyl 3 - [(2- { [4-(hexyloxycarbonylarninoimmomemyl)phenylammo]methyl } -1 - methyl- lH-benzimidazole-5-carbonyl)pyridm-2-ylamino]propionate base (52.6 kg) (which has preferably been purified beforehand by recrystallization from ethyl acetate) is placed in an agitator apparatus which has been rendered inert and then 293 kg of acetone is added. The contents of the apparatus are heated to 40 C to 46 C with stirring. After a clear solution has formed, the contents of the apparatus is filtered into a second agitator apparatus through a lens filter and then cooled to 30 C to 36 C. 33 kg of acetone precooled to 0 C to 5 C, 7.9 kg of 99.5% methanesulfonic acid, and for rinsing another 9 kg of acetone are placed in the suspended container of the second apparatus. The contents of the suspended container are added in metered amounts to the solution of ethyl 3-[(2-[4-(hexyloxycarbonylamino- iminomethyl)phenylamino]methyl} - 1 -methyl- 1 H-benzimidazole-5-carbonyl)pyridin-2- ylamino]propionate base at 26 C to 36 C within 15 to 40 minutes. Then the mixture is stirred for 40 to 60 minutes at 26 C to 33 C. It is then cooled to 17 C to 23 C and stirred for a further 40 to 80 minutes. The crystal suspension is filtered through a filter dryer and washed with a total of 270 L of acetone. The product is dried in vacuum at a maximum of 50 C for at least 4 hours. Yield: 54.5-59.4 kg;90%-98% of theory based on ethyl 3-[(2-[4-(hexyloxycarbonyl- ammoiminomethyl)phenylamino]methyl} - 1 -methyl- 1 H-benzimidazole-5-carbonyl)- pyridm-2-ylamino]propionate base.
24 g
In acetone; at 28 - 45℃; for 1h;
A solution of Dabigatran Etexilate (23g) in acetone (184 mL), at 39-45C was filtered and then cooled to 30C. Pre-cooled solution of methanesuiphonic acid (3.24g) inacetone (23 mL) was, slowly, added to the reaction mass and then stirred for lh, at 28-32C. The reaction mass was cooled to 19-23C and slurred for another hour. The precipitated product was filtered, washed with acetone and dried, under vacuum, at 50C, to afford mesylate salt of Dabigatran Etexilate as pale yellow colored solid material (24 g, >99% HPLC pure).
Example 1 : Preparation of beta-Alanine, N-[[2-[[[4-[[[(hexyloxy)carbonyl]amino] iminomethyl] phenyl]amino]methyl]-1 -methyl-1 H-benzimidazol-5-yl]carbonyl]-N-2- pyridinyl-, ethyl ester (dabigatran etexilate) in one pot 1 -Methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide (10 g) and ethanol (100 mL) were charged into a round bottom flask and cooled to about 5C, dry HCI gas was passed for about 8-10 hours at around 5-10C. The clear solution obtained was maintained for 14-16 hours at 25-30QC for the completion of the reaction and the solution was distilled under reduced pressure at below 40 C. To the crude compound obtained, ethanol (250 mL) and ammonium carbonate (20 g) were charged and the mixture was maintained for 14-16 hours at 25-30QC. To the above obtained reaction mass, water (100 mL) and tetrahydrofuran (200 mL) were charged and the resulting mixture was concentrated under reduced pressure at below 48QC. To the crude obtained, tetrahydrofuran (400 mL), potassium carbonate (18.7 g) were charged followed by slow addition of n-hexyl chloroformate (1 1 .75 g) at 25-30QC and maintained the reaction mass at 25-30QC for around 3 hours. After completion of the reaction, the organic layer was separated and distilled off under reduced pressure. The crude obtained was dissolved in dichloromethane (400 mL) and washed twice with water (2x100 mL) followed by washing twice with 10% sodium chloride solution (2x100 mL) and the layers were separated. The organic layer was concentrated under reduced pressure at below 40QC. To the crude obtained, ethyl acetate (80 mL) was charged and the solid was collected by filtration and washed with ethyl acetate (10 mL). The compound was dried in an oven at 50C for 5 hours to afford the title compound. Yield: 5.3 g; Purity by HPLC: 97.90%.
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