872728-81-9

Basic information

• Product Name: Dabigatran Etexilate Mesylate
• Synonyms: Dabigatran etexilate mesylate;N-[[2-[[[4-[[[(Hexyloxy)carbonyl]amino]iminomethyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridinyl-beta-alanine ethyl ester monomethanesulfonat;Pradaxa;(E)-hexyl 2-(4-((5-((3-ethoxy-3-oxopropyl)(pyridin-2-yl)carbaMoyl)-1-Methyl-1H-benzo[d]iMidazol-2-yl)MethylaMino)benzylidene)hydrazinecarboxylate Methanesulfonate;N-[[2-[[[4-[[[(Hexyloxy)carbonyl]aMino]iMinoMethyl]phenyl]aMino]Methyl]-1-Methyl-1H-benziMidazol-5-y;BIBR 1048MS;N-[[2-[[[4-[[[(Hexyloxy)carbonyl]aMino]iMinoMethyl]phenyl]aMino]Methyl]-1-Methyl-1H-benziMidazol-5-yl]carbonyl]-N-2-pyridinyl-β-alanine Ethyl Ester Methanesulfonate;Dabigatran etexilate Methanesulfonate
• CAS NO: 872728-81-9
• Molecular Formula: CH₄O₃S*C₃₄H₄₁N₇O₅
• Molecular Weight: 723.84
• EINECS: 1592732-453-0
• Product Categories: Aromatics;Bases & Related Reagents;Heterocycles;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;Dabigatran etexilate mesylate
• Mol File: 872728-81-9.mol
• Article Data: 29

Chemical Properties

• Boiling Point: 827.9 °C at 760 mmHg
• Flash Point: 454.5 °C
• Appearance: /
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly, Heated), Methanol (Slightly)
• CAS DataBase Reference: Dabigatran Etexilate Mesylate(CAS DataBase Reference)
• NIST Chemistry Reference: Dabigatran Etexilate Mesylate(872728-81-9)
• EPA Substance Registry System: Dabigatran Etexilate Mesylate(872728-81-9)

Safety Data

• Hazardous Substances Data: 872728-81-9(Hazardous Substances Data)

Usage

Description

Dabigatran Etexilate Mesylate is a prodrug for dabigatran, a direct thrombin inhibitor and anticoagulant. It is an off-white to pale yellow solid that can inhibit the formation of thrombus by reversibly and potently competing with the fibrin-specific binding site of thrombin to block fibrin generation. This makes it a new type of oral anticoagulant used for the prevention of stroke and systemic embolism.
Used in Pharmaceutical Industry:
Dabigatran Etexilate Mesylate is used as an oral anticoagulant for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. It is also used to treat and prevent deep vein thrombosis and pulmonary embolism.
Used in Cardiovascular Applications:
Dabigatran Etexilate Mesylate is used as an anticoagulant to prevent blood clot formation in patients with atrial fibrillation, deep vein thrombosis, and pulmonary embolism. It helps to reduce the risk of stroke and other thrombotic events by inhibiting the activity of thrombin, a key enzyme in the blood clotting process.
Used in Research and Development:
Dabigatran Etexilate Mesylate is used as a research tool in the study of thrombin inhibition and blood clotting mechanisms. It can be used to investigate the effects of thrombin inhibition on various physiological and pathological processes, as well as to develop new anticoagulant drugs with improved safety and efficacy profiles.

Biological Activity

Dabigatran etexilate mesylate (BIBR 1048MS) is an orally active prodrug of Dabigatran. Dabigatran etexilate mesylate has anticoagulant properties and can prevent venous thromboembolism and stroke due to atrial fibrillation.

Mechanism of action

Dabigatran etexilate mesylate is a prodrug of dabigatran that is metabolized in the body and converted to the active dabigatran. Compared with warfarin, dabigatran etexilate mesylate does not require frequent monitoring of coagulation function and dose adjustment during treatment, and there are fewer interactions between drugs and is not affected by eating, thus improving patients' medication compliance.

in vivo

Dabigatran etexilate mesylate (BIBR 1048MS; oral; 10, 20 and 50 mg/kg for rats and 1, 2.5 and 5 mg/kg for monkeys) has dose- and time-dependent anticoagulant effects and has maximum effects between 30 and 120 min after administration, respectively.Dabigatran etexilate mesylate maximally and significantly prolongs partial thromboplastin time (aPTT) to 25.2, 38.4 and 78.3 s in 30 min after 10, 20 and 50 mg/kg oral doses, respectively.Dabigatran etexilate mesylate maximally prolongs the aPTT to 34.3 s, 44.0 s, and 63.0 s, respectively, 2h after 1, 2.5 or 5 mg/kg doses in the monkey.

Synthetic route

dabigatran etexilate (211915-06-9) + methanesulfonic acid (75-75-2) → dabigatran etexilate mesylate (872728-81-9)

Conditions	Yield
In acetone at 26 - 36℃; Industry scale;	98%
In acetone at 28 - 45℃; for 1h;	24 g

methanesulfonic acid (75-75-2) + n-hexyl chloroformate (6092-54-2) + 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazole-5-ylcarboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride salt → dabigatran etexilate mesylate (872728-81-9)

Conditions	Yield
Stage #1: n-hexyl chloroformate; 3-({2-[(4-carbamimidoyl-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-ylamino)propionic acid ethyl ester hydrochloride With triethylamine In chloroform Stage #2: methanesulfonic acid In acetone

methanesulfonic acid (75-75-2) + n-hexyl chloroformate (6092-54-2) + 3-({2-[(4-carbamimidoyl-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)-propionic acid ethyl ester dihydrochloride → dabigatran etexilate mesylate (872728-81-9)

Conditions	Yield
Stage #1: n-hexyl chloroformate; 3-({2-[(4-carbamimidoyl-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)-propionic acid ethyl ester dihydrochloride With triethylamine In chloroform at 20℃; Stage #2: methanesulfonic acid In acetone

1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-ylcarboxylic acid N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide p-toluenesulfonate → dabigatran etexilate mesylate (872728-81-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / ethanol / 18 h / -10 - 17 °C / Inert atmosphere 2: potassium carbonate / acetone; water / 1.5 h / 12 - 25 °C 3: acetone / 1 h / 28 - 45 °C View Scheme

1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-2-(ethoxycarbonylethyl)-amide p-toluenesulfonic acid salt (872728-85-3) → dabigatran etexilate mesylate (872728-81-9)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate / acetone; water / 1.5 h / 12 - 25 °C 2: acetone / 1 h / 28 - 45 °C View Scheme

(4-cyanophenyl)glycine (42288-26-6) → dabigatran etexilate mesylate (872728-81-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: Imidazole hydrochloride; 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 35 - 40 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere; Reflux 1.3: 1 h / 85 - 90 °C / Inert atmosphere 2.1: hydrogenchloride / ethanol / 18 h / -10 - 17 °C / Inert atmosphere 3.1: potassium carbonate / acetone; water / 1.5 h / 12 - 25 °C 4.1: acetone / 1 h / 28 - 45 °C View Scheme
Multi-step reaction with 4 steps 1.1: Imidazole hydrochloride; 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 45 - 50 °C / Inert atmosphere 1.2: 1 h / 45 - 50 °C / Inert atmosphere 1.3: 6 h / Inert atmosphere; Reflux 2.1: hydrogenchloride / ethanol / 18 h / 0 - 17 °C 3.1: potassium carbonate / acetone; water / 1.5 h / 12 - 25 °C 4.1: acetone / 1 h / 28 - 45 °C View Scheme

ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (212322-56-0) → dabigatran etexilate mesylate (872728-81-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: Imidazole hydrochloride; 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 35 - 40 °C / Inert atmosphere 1.2: 1 h / Inert atmosphere; Reflux 1.3: 1 h / 85 - 90 °C / Inert atmosphere 2.1: hydrogenchloride / ethanol / 18 h / -10 - 17 °C / Inert atmosphere 3.1: potassium carbonate / acetone; water / 1.5 h / 12 - 25 °C 4.1: acetone / 1 h / 28 - 45 °C View Scheme
Multi-step reaction with 4 steps 1.1: Imidazole hydrochloride; 1,1'-carbonyldiimidazole / dichloromethane / 1 h / 45 - 50 °C / Inert atmosphere 1.2: 1 h / 45 - 50 °C / Inert atmosphere 1.3: 6 h / Inert atmosphere; Reflux 2.1: hydrogenchloride / ethanol / 18 h / 0 - 17 °C 3.1: potassium carbonate / acetone; water / 1.5 h / 12 - 25 °C 4.1: acetone / 1 h / 28 - 45 °C View Scheme

3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester (211915-84-3) → dabigatran etexilate mesylate (872728-81-9)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride / ethanol / 18 h / 0 - 17 °C 2: potassium carbonate / acetone; water / 1.5 h / 12 - 25 °C 3: acetone / 1 h / 28 - 45 °C View Scheme

methanesulfonic acid (75-75-2) + n-hexyl chloroformate (6092-54-2) + C25H25N7O3*C7H8O3S → dabigatran etexilate mesylate (872728-81-9)

Conditions	Yield
Stage #1: n-hexyl chloroformate; C25H25N7O3*C7H8O3S With potassium carbonate In water; acetone at 5℃; for 1h; Stage #2: methanesulfonic acid In dichloromethane at 0 - 20℃; for 1h;	35.1 g

methanesulfonic acid (75-75-2) + dabigatran etexilate mesylate (872728-81-9) → dabigatran etexilate bismesylate

Conditions	Yield
In ethyl acetate at 20℃; Product distribution / selectivity;	99.9%

Upstream product

• 75-75-2 methanesulfonic acid 
• 6092-54-2 n-hexyl chloroformate 
• 211915-06-9 dabigatran etexilate 
• 872728-85-3 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-2-(ethoxycarbonylethyl)-amide p-toluenesulfonic acid salt 
• 42288-26-6 (4-cyanophenyl)glycine 
• 212322-56-0 ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate 
• 211915-84-3 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester 
• 111-27-3 hexan-1-ol 
• 873-74-5 4-Aminobenzonitrile 
• 429658-95-7 3-({2-[(4-carbamimidoylphenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid ethyl ester 
• 1381757-41-0 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide oxalate 
• 140-88-5 ethyl acrylate 
• 96-99-1 4-chloro-3-nitrobenzoate 
• 504-29-0 2-aminopyridine 

Relevant articles and documents

Method for refining dabigatran etexilate and method for controlling specific degradation impurities of dabigatran etexilate

The invention provides a method for refining dabigatran etexilate and a method for controlling specific degradation impurities of dabigatran etexilate. The dabigatran etexilate compound is 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridine-2-yl-amino]-ethyl propionate mesylate, the invention also relates to a control method of specific degradation impurities in the refining process of the compound. The method comprises the following steps: stirring and mixing dabigatran etexilate and acetonitrile, then heating to a reflux state, carrying out heat preservation for 1-2 hours in the reflux state, then carrying out slow cooling, filter pressing, vacuum drying and other technological processes to obtain dabigatran etexilate, and salifying the dabigatran etexilate and methanesulfonic acid to obtain dabigatran etexilate mesylate. The dabigatran etexilate obtained by the refining method provided by the invention has the advantages of high purity, no solvent residue, mild reaction conditions and easiness in industrial production.

Production process of pradaxa mesylate

The invention discloses a production process of pradaxa mesylate. The production process comprises the following steps: (1) preparing an intermediate PR-I; (2) preparing an intermediate PR-II; (3) preparing pradaxa PR-III; (4) refining the pradaxa PR-III; and (5) preparing pradaxa mesylate. The production process is mild in reaction condition, simple in reaction route, convenient in operation, high in selectivity, and capable of shortening the production period; and the obtained pradaxa intermediate is low in water content, the prepared pradaxa mesylate is high in yield and purity, and the maximum impurity is low in impurity content; and the production process is less in emission of three wastes, environmentally friendly, free from requiring the columnar chromatography purification, suitable for the industrialized production, capable of avoiding the requirement of palladium-on-carbon high-pressure hydrogenation on equipment and capable of reducing the risk.

Novel hemi-salt of dabigatran etexilate and preparation method thereof

The present invention relates to a dabigatran etexilate hemic acid added salt and a method for manufacturing the same. More specifically, the present invention relates to a dabigatran hemi fumarate and hemi citrate, and a method for manufacturing the same. Since the crystalline dabigatran etexilate hemi fumarate and hemi citrate of the present invention are stable to heat and excellent in filtering and drying properties, the hemic acid added salt of the present invention can be used as an active ingredient of a pharmaceutical composition for preventing and treating stroke of patients suffering from thromboembolism and atrial fibrillation.COPYRIGHT KIPO 2018