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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).
Stage #1: With potassium carbonate In water; acetone at 5℃; for 1 h; Stage #2: at 0 - 20℃; for 1 h;
By embodiments 2 - 4 prepared in the target product is 40g adding 3000 ml glass reaction in the bottle, sequentially adding potassium carbonate 33.0g, water 220 ml, acetone 350 ml, stirring the temperature to 5 °C, continuing to stir 10 minutes, slowly instillment chlorine formic acid oneself ester 16.0g, after finishing dropping to continue to 5 °C stirring 1 hours, to the reaction solution is added in dichloromethane 1600 ml, up to 28 °C extracting the organic layer, the saturated salt water for 1600 ml washing, the organic layer is dried with anhydrous sodium sulfate, vacuum concentrated solvent to obtain yellowish liquid. Dichloromethane is used for 80 ml dissolved concentrated residual liquid, adding 1000 ml in the reaction flask, lowering the temperature to 0 °C, in 0 °C slow the instillment uses acetone 640 ml of dissolved methanesulfonic acid 7.7g mixed solution, after the completion of the dropping the temperature to room temperature stirring 1 hour, filtering, dichloromethane 320 ml washing, in 40 °C vacuum drying 5 hours, to obtain 35.1g white compound A, HPLC analysis for 99.789percent
Reference：
[1] Patent: CN106397403, 2017, A, . Location in patent: Paragraph 0063; 0064; 0065; 0066; 0067
3-({2-[(4-carbamimidoyl-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-ylamino)propionic acid ethyl ester hydrochloride[ No CAS ]
[ 872728-81-9 ]
Yield
Reaction Conditions
Operation in experiment
Preparation of dabigatran mesylate. 9 g of compound VII-HCl (0.017 mol) were dissolved in 300 ml of chloroform. 6, ml of triethylamine were added to this solution and then a solution of 3.4 ml (0.02 mol) of hexyl chloroformate in chloroform was added dropwise. After one hour the reaction mixture is shaken with brine, the organic layer is separated, which is dried with sodium sulfate and concentrated. The obtained evaporation residue is crystallized from ethyl acetate. Yield: 9.6 g (90%)This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The separated evaporation residue is aspirated and dried at the laboratory temperature. Yield: 73%; content according to HPLC: 99.5%.
3-({2-[(4-carbamimidoyl-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)-propionic acid ethyl ester dihydrochloride[ No CAS ]
[ 872728-81-9 ]
Yield
Reaction Conditions
Operation in experiment
Preparation of dabigatran mesylate. To 9.1 g of compound VII-2HC1 (0.016 mol) 270 ml of chloroform and 9 ml (0.064 mol) of triethylamine are added. Then, a solution of 3.1 ml (0.018 mol) of hexyl chloroformate in chloroform is added dropwise at the laboratory temperature. After one hour the reaction mixture is shaken with brine and the organic layer is separated, which is dried with sodium sulfate and concentrated. The obtained evaporation residue is crystallized from ethyl acetate. Yield: 8.6 g (86%)This product is dissolved in acetone and an equimolar amount of methanesulfonic acid is added dropwise. The separated precipitate is aspirated and dried at the laboratory temperature. Yield: 75%; content according to HPLC: 99.5%. 27
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).
In ethyl acetate; at 20℃;Product distribution / selectivity;
Example 5In a 1 L 3 -neck round bottom flask, 500 ml ethyl acetate and 10 g (13.7 mmol) Dabigatran etexilate mesylate (Form I) were stirred at ambient temperature. 1.29 g (13.5 mmol) methanesulfonic acid dissolved in 62 ml ethyl acetate were added dropwise and the mixture was stirred overnight. The obtained precipitate was filtered off, washed with 20 ml acetone and dried at 40C in the vacuum (15 mbar) overnight. The product was analyzed by PXRD and found to be Dabigatran etexilate bismesylate form Ms2-A.Yield: 11.25 g (99.9%)Chemical purity (HPLC): 99.67 %DSC: peak of endotherm at 188.8C Residual solvent content (ethyl acetate): Below limit of detection
Multi-step reaction with 5 steps
1.1: palladium on activated charcoal / ethyl acetate / 0.33 h / 25 - 55 °C / High pressure
2.1: 1,1'-carbonyldiimidazole / toluene / 2 h / 55 - 60 °C
2.2: 6 h / 60 - 100 °C
3.1: hydrogenchloride / ethanol / 25 - 35 °C
4.1: potassium carbonate / water; acetone / 1 h / 10 °C
5.1: acetone / 2 h / 25 - 30 °C
Multi-step reaction with 5 steps
1.1: palladium on activated charcoal / ethyl acetate / 25 - 55 °C
2.1: 1,1'-carbonyldiimidazole / toluene / 25 - 60 °C
2.2: 6 h / 60 - 100 °C
3.1: hydrogenchloride / ethanol / 25 - 35 °C
4.1: potassium carbonate / water; acetone / 1 h
5.1: acetone / 2 h / 25 - 30 °C
Multi-step reaction with 5 steps
1.1: iron; hydrogenchloride / tetrahydrofuran; water / 2 h / Reflux
2.1: 1,1'-carbonyldiimidazole / tetrahydrofuran / 3 h / 25 - 35 °C
2.2: 24 h / 25 - 35 °C
2.3: 3 h / 0 - 10 °C
3.1: calcium chloride; hydrogenchloride / ethanol / 13 h / -15 - 35 °C
3.2: 23.66 h / -35 - 30 °C
4.1: dichloromethane / 3 h / 15 - 25 °C
4.2: 8 h / 25 - 50 °C
5.1: tetrahydrofuran / 5 h / 25 - 30 °C
By embodiments 2 - 4 prepared in the target product is 40g adding 3000 ml glass reaction in the bottle, sequentially adding potassium carbonate 33.0g, water 220 ml, acetone 350 ml, stirring the temperature to 5 C, continuing to stir 10 minutes, slowly instillment chlorine formic acid oneself ester 16.0g, after finishing dropping to continue to 5 C stirring 1 hours, to the reaction solution is added in dichloromethane 1600 ml, up to 28 C extracting the organic layer, the saturated salt water for 1600 ml washing, the organic layer is dried with anhydrous sodium sulfate, vacuum concentrated solvent to obtain yellowish liquid. Dichloromethane is used for 80 ml dissolved concentrated residual liquid, adding 1000 ml in the reaction flask, lowering the temperature to 0 C, in 0 C slow the instillment uses acetone 640 ml of dissolved methanesulfonic acid 7.7g mixed solution, after the completion of the dropping the temperature to room temperature stirring 1 hour, filtering, dichloromethane 320 ml washing, in 40 C vacuum drying 5 hours, to obtain 35.1g white compound A, HPLC analysis for 99.789%
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