Dabigatran etexilate mesylate

Dabigatran etexilate mesylate (BIBR 1048MS) is the orally active prodrug of dabigatran. Dabigatran is a reversible and selective, direct thrombin inhibitor (DTI) with Ki value of 4.5 nM.IC50 Value: 4.5 nM (Ki); 10 nM(Thrombin-induced platelet aggregation) [1]in vitro: Dabigatran selectively and reversibly inhibited human thrombin(Ki: 4.5 nM) as well as thrombin-induced platelet aggregation (IC(50): 10 nM), while showing no inhibitory effect on other platelet-stimulating agents.Thrombin g

Dabigatran etexilate methanesulfonate is a methanesulfonate salt obtained by reaction of dabigatran etexilate with one equivalent of dabigatran etexilate. A prodrug for dabigatran, a thrombin inhibitor and anticoagulant which is used for the prevention of stroke and systemic embolism. It has a role as an EC 3.4.21.5 (thrombin) inhibitor, an anticoagulant and a prodrug. It contains a dabigatran etexilate(1+).|A THROMBIN inhibitor which acts by binding and blocking thrombogenic activity and the prevention of thrombus formation. It is used to reduce the risk of stroke and systemic EMBOLISM in patients with nonvalvular atrial fibrillation.

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.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).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 99.789percentEthyl 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.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).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

Nonpeptide, direct thrombin inhibitor. Antithrombotic. Dabigatran etexilate mesylate is a raw material for the blood system; an anticoagulant drug; it can be used in patients with non-valvular atrial fibrillation to reduce the risk of stroke and systemic embolism; dabigatran etexilate is a new type of synthetic Direct thrombin inhibitor, a prodrug of dabigatran, is a non-peptide thrombin inhibitor. Security Information

Molecular Weight:723.8
Hydrogen Bond Donor Count:3
Hydrogen Bond Acceptor Count:11
Rotatable Bond Count:17
Exact Mass:723.30503259
Monoisotopic Mass:723.30503259
Topological Polar Surface Area:217
Heavy Atom Count:51
Complexity:1100
Defined Bond Stereocenter Count:1
Covalently-Bonded Unit Count:2
Compound Is Canonicalized:Yes