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 clinical direct thrombin inhibitor and a new type of oral anticoagulant. It can inhibit the formation of thrombus by reversibly and potently competing with the fibrin-specific binding site of thrombin to block fibrin generation.

Chemical Properties

Off-White to Pale Yellow Solid

Definition

ChEBI: 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.

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

• 1307233-94-8 N-[[2-(chloromethyl)-1-methyl-1H-benzimidazol-5-yl]carbonyl]-N-2-pyridyl-β-alanine ethyl ester 
• 19563-04-3 p-chlorobenzamidine 
• 22265-36-7 4-bromobenzamidine 
• 1187067-68-0 ethyl 3-[[4-(methylamino)-3-nitrobenzoyl](pyridin-2-yl)amino]propanoate hydrochloride 
• 623-03-0 4-Cyanochlorobenzene 
• 623-00-7 4-bromobenzenecarbonitrile 
• 948551-71-1 3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino-benzoyl}-pyridin-2-yl-amino)-ethyl propanoate 
• 75-75-2 methanesulfonic acid 
• 1456889-80-7 ethyl 3-[(2-methyl-1-methyl-1H-benzimidazol-5-carbonyl)pyridin-2-yl-amino]propionate 

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.

Preparation process of Pradaxa

The invention discloses a preparation process of Pradaxa. After obtaining a compound 3 with the structural formula as shown in the description, an alkali liquor is added to separate out the compound 3; micro-molecule alcohol is used for refining; under the action of a reaction solvent and an organic alkali, the compound 3 and hexyl chloroformate conduct a condensation reaction to obtain a compound2 with the structural formula as shown in the description; an acid liquor is used for washing, and vacuum concentration is performed till the product is dry; an organic solvent is used for refining;and the compound 2 and methanesulfonic acid are salified to obtain Pradaxa. Through the continuous operation that solid-liquid separation is performed after the alkali liquor is added to separate outthe compound 3, the problems that lots of acid is evaporated to corrode equipment due to vacuum concentration and many degradation impurities are produced by heating are solved. The pickling process is adopted to control specific impurities in a reaction liquid of the compound 2. At last, an appropriate methanesulfonic acid charge ratio and an appropriate charging temperature are adopted to guarantee correct product crystal forms.

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