211915-06-9

Basic information

• Product Name: Dabigatran etexilate
• Synonyms: BIBR-1048(Dabigatran etexilate);N-[2-[4-[N-(Hexyloxycarbonyl)aMidino]phenylaMinoMethyl]-1-Methyl-1H-benziMidazol-5-ylcarbonyl]-N-(2-;BIBR 1048;BIBR-1048;Prazaxa;N-[[2-[[[4-[[[(Hexyloxy)carbonyl]aMidino]iMinoMethyl]phenyl]aMino]Methyl]-1-Methyl-1H-benziMidazol-5-yl]carbonyl]-N-2-pyridyl-beta-alanine,ethyl ester;Pradaxa (dabigatran);Dabigatran Etexilate (free base)
• CAS NO: 211915-06-9
• Molecular Formula: C₃₄H₄₁N₇O₅
• Molecular Weight: 627.74
• EINECS: 1592732-453-0
• Product Categories: Pharmaceutical intermediate;API;Dabigatran etexilate;Other APIs
• Mol File: 211915-06-9.mol

Chemical Properties

• Melting Point: 128-129°
• Boiling Point: 827.9 °C at 760 mmHg
• Flash Point: 454.5 °C
• Appearance: white powder
• Density: 1.24 g/cm³
• Vapor Pressure: 1.49E-27mmHg at 25°C
• Refractive Index: 1.614
• Storage Temp.: Sealed in dry,Store in freezer, under -20°C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• PKA: 9.88±0.46(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: Dabigatran etexilate(CAS DataBase Reference)
• NIST Chemistry Reference: Dabigatran etexilate(211915-06-9)
• EPA Substance Registry System: Dabigatran etexilate(211915-06-9)

Safety Data

• Hazardous Substances Data: 211915-06-9(Hazardous Substances Data)

Usage

Indications and Usage

Dabigatran is the newest generation of oral anticoagulant drugs – direct thrombin inhibitors (DTIs), belonging to non-peptide thrombin inhibitors and instead specifically and selectively blocks the thrombin activity (free or bound) to prevent coagulation. Dabigatran targets the preventative and clinical treatment needs of acute and chronic thromboembolic disease.

Mechanisms of Action

It achieves anticoagulant effects through specific and selective inhibition of blood enzymes (free or bound). After oral ingestion and absorption through the digestive system, Dabigatran turns into Dabiga groups that have the direct anticoagulant abilities. By binding to thrombin in fibrin specific binding sites, Dabigatran stops fibrinogen from cleaving into fibrin, thus interrupting the blood clotting network and consequently thrombosis. Dabiga groups can also dissociate from the fibrin-thrombin coagulate and have an anticoagulating effect. Different from vitamin K antagonists, which affect different coagulants, Dabigatran can provide effective, predictable and stable anticoagulant effects. It will also have minimal reactions to other drugs or food, and does not require frequent monitoring or dosage adjustment.

Clinical Research

Compared to the control group treated with Warfarin, Dabigatran can significantly decrease the risk of stroke and embolic disease (including hemorrhagic stroke), greatly reduce the occurrence of bleeding (including fatal bleeding and intracranial hemorrhage), and greatly lower vascular mortality rate. Dabigatran provides effective and stable anticoagulant effects and does not require constant monitoring of anticoagulant functions or dosage adjustments.

Warnings and Precautions

1. Dabigatran is not to be used by patients with severe kidney damage (CrCl<30ml/min). 2. Patients with high bleeding risk should also not use Dabigatran. 3. Patients must be tested and monitored for signs of lack of bleeding or anemia; if there is severe bleeding, cease use of Dabigatran and identify the bleeding area. 4. Dabigatran is not suitable for patients with significant manifestations of rheumatic valvar heart disease or patients with artificial heart valves.

Uses

Different sources of media describe the Uses of 211915-06-9 differently. You can refer to the following data:
1. BIBR-1048 (Dabigatran) is an anticoagulant from the class of the direct thrombin inhibitors. It is being studied for various clinical indications and in many cases it offers an alternative to warfarin as the preferred orally administered blood thinner sin
2. Dabigatran Etexilate is an oral anticoagulant and direct thrombin inhibitor.

Definition

ChEBI: An aromatic amide obtained by formal condensation of the carboxy group of 2-{[(4-{N'-[(hexyloxy)carbonyl]carbamimidoyl}phenyl)amino]methyl}-1-methyl-1H-benzimidazole-5-carboxylic acid with the secondary amino group of thyl N-pyridin-2-yl-beta-alaninate. A prodrug for dabigatran, a thrombin inhibitor and anticoagulant which is used for the prevention of stroke and systemic embolism.

Brand name

Pradaxa

Clinical Use

#N/A

Synthesis

The chemical synthesis of dabigatran etexilate starts with the acylation of ethyl 3-(2-pyridylamino)propionate with 4-(methylamino)-3-nitrobenzoyl chloride to produce the corresponding amide. Subsequent reduction of the nitro group by catalytic hydrogenation, and cyclization of the resultant phenylenediamine with N-(4-cyanophenyl)glycine leads to a benzimidazole intermediate. The cyano group is then transformed into an amidine by employing the Pinner reaction. Finally, acylation of the amidino group with hexyl chloroformate gives rise to dabigatran etexilate.

in vitro

dabigatran showed anticoagulant effects in a concentration-dependent manner. it doubled the activated partrial thromboplastin time, prothrombin time and ecarin clotting in human ppp. [1]

Drug interactions

Potentially hazardous interactions with other drugs Analgesics: possible increased risk of bleeding with NSAID’s; increased risk of haemorrhage with ketorolac or IV diclofenac - avoid. Anti-arrhythmics: concentration increased by amiodarone, reduce dose of dabigatran; concentration increased by dronedarone - avoid. Antibacterials: concentration reduced by rifampicin - avoid; possibly increased risk of bleeding with clarithromycin. Anticoagulants: increased risk of haemorrhage with other anticoagulants - avoid. Antidepressants: possible increased risk of bleeding with SSRIs; concentration possibly reduced by St John’s wort - avoid. Antifungals: concentration increased by ketoconazole and possibly itraconazole - avoid Ciclosporin: concentration possibly increased by ciclosporin - avoid. Sulfinpyrazone: possible increased risk of bleeding. Tacolimus: concentration possibly increased by tacrolimus - avoid. Ticagrelor: concentration of dabigatran increased. Verapamil: reduce dose of dabigatran to 150 mg daily, 75 mg in GFR=30-50mL/min.

Metabolism

Dabigatran etexilate is a prodrug which does not exhibit any pharmacological activity. After oral administration, dabigatran etexilate is rapidly absorbed and converted to dabigatran by esterase-catalysed hydrolysis in plasma and in the liver. Dabigatran is a potent, competitive, reversible direct thrombin inhibitor and is the main active principle in plasma.Mainly excreted in the urine (85%) and 6% via the faeces.

references

1. wienen w, stassen jm, priepke h et al. in-vitro profile and ex-vivo anticoagulant activity of the direct thrombin inhibitor dabigatran and its orally active prodrug, dabigatran etexilate. thromb haemost. 2007 jul;98(1):155-62.2. connolly sj, ezekowitz md, yusuf s et al. dabigatran versus warfarin in patients with atrialfibrillation. n engl j med. 2009 sep 17;361(12):1139-51.

InChI:InChI=1/C34H41N7O5/c1-4-6-7-10-21-46-34(44)39-32(35)24-12-15-26(16-13-24)37-23-30-38-27-22-25(14-17-28(27)40(30)3)33(43)41(20-18-31(42)45-5-2)29-11-8-9-19-36-29/h8-9,11-17,19,22,37H,4-7,10,18,20-21,23H2,1-3H3,(H2,35,39,44)

Synthetic route

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 (211915-06-9)

Conditions	Yield
Stage #1: 3-({2-[(4-carbamimidoyl-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)-propionic acid ethyl ester dihydrochloride With potassium carbonate In tetrahydrofuran; water at 20℃; for 0.333333h; Stage #2: n-hexyl chloroformate In tetrahydrofuran; water at 20℃; for 5h;	63.3%
With potassium carbonate In tetrahydrofuran; water

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 (211915-06-9)

Conditions	Yield
Stage #1: 3-({2-[(4-carbamimidoyl-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-ylamino)propionic acid ethyl ester hydrochloride With potassium carbonate In tetrahydrofuran at 20℃; for 0.25h; Stage #2: n-hexyl chloroformate In tetrahydrofuran at 20℃; for 1h; Further stages.;	51%
With potassium carbonate In tetrahydrofuran; water at 20℃; for 2h;

4-methylamino-3-nitro-benzoic acid chloride (82357-48-0) → dabigatran etexilate (211915-06-9)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: Et3N / tetrahydrofuran / 20 °C 2.1: 65 percent / H2 / 10percent Pd/C / methanol / 20 °C 3.1: CDI / tetrahydrofuran / 50 °C 3.2: tetrahydrofuran / 24 h / Heating 4.1: glacial acetic acid / 1 h / Heating 5.1: HCl / ethanol / 0 °C 5.2: 71 percent / (NH4)2CO3 / ethanol / 20 °C 6.1: aq. K2CO3 / tetrahydrofuran / 0.25 h / 20 °C 6.2: 51 percent / tetrahydrofuran / 1 h / 20 °C View Scheme

4-(methylamino)-3-nitrobenzoic acid (41263-74-5) → dabigatran etexilate (211915-06-9)

Conditions

Yield

Multi-step reaction with 7 steps 1.1: SOCl2 / dimethylformamide / 0.5 h / Heating 2.1: Et3N / tetrahydrofuran / 20 °C 3.1: 65 percent / H2 / 10percent Pd/C / methanol / 20 °C 4.1: CDI / tetrahydrofuran / 50 °C 4.2: tetrahydrofuran / 24 h / Heating 5.1: glacial acetic acid / 1 h / Heating 6.1: HCl / ethanol / 0 °C 6.2: 71 percent / (NH4)2CO3 / ethanol / 20 °C 7.1: aq. K2CO3 / tetrahydrofuran / 0.25 h / 20 °C 7.2: 51 percent / tetrahydrofuran / 1 h / 20 °C View Scheme

ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (212322-56-0) → dabigatran etexilate (211915-06-9)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: CDI / tetrahydrofuran / 50 °C 1.2: tetrahydrofuran / 24 h / Heating 2.1: glacial acetic acid / 1 h / Heating 3.1: HCl / ethanol / 0 °C 3.2: 71 percent / (NH4)2CO3 / ethanol / 20 °C 4.1: aq. K2CO3 / tetrahydrofuran / 0.25 h / 20 °C 4.2: 51 percent / tetrahydrofuran / 1 h / 20 °C View Scheme

ethyl 3-{[{1-(methylamino)-2-nitrophen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate (429659-01-8) → dabigatran etexilate (211915-06-9)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: 65 percent / H2 / 10percent Pd/C / methanol / 20 °C 2.1: CDI / tetrahydrofuran / 50 °C 2.2: tetrahydrofuran / 24 h / Heating 3.1: glacial acetic acid / 1 h / Heating 4.1: HCl / ethanol / 0 °C 4.2: 71 percent / (NH4)2CO3 / ethanol / 20 °C 5.1: aq. K2CO3 / tetrahydrofuran / 0.25 h / 20 °C 5.2: 51 percent / tetrahydrofuran / 1 h / 20 °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 (211915-06-9)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: HCl / ethanol / 0 °C 1.2: 71 percent / (NH4)2CO3 / ethanol / 20 °C 2.1: aq. K2CO3 / tetrahydrofuran / 0.25 h / 20 °C 2.2: 51 percent / tetrahydrofuran / 1 h / 20 °C View Scheme

3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino-benzoyl}-pyridin-2-yl-amino)-ethyl propanoate (948551-71-1) → dabigatran etexilate (211915-06-9)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: glacial acetic acid / 1 h / Heating 2.1: HCl / ethanol / 0 °C 2.2: 71 percent / (NH4)2CO3 / ethanol / 20 °C 3.1: aq. K2CO3 / tetrahydrofuran / 0.25 h / 20 °C 3.2: 51 percent / tetrahydrofuran / 1 h / 20 °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) + n-hexyl chloroformate (6092-54-2) → dabigatran etexilate (211915-06-9)

Conditions	Yield
Alkaline conditions;
Stage #1: 1-methyl-2-[N-(4-amidino-phenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid N-(2-pyridyl)-N-2-(ethoxycarbonylethyl)-amide p-toluenesulfonic acid salt With potassium carbonate In water; acetonitrile at 27℃; for 0.5h; Stage #2: n-hexyl chloroformate In water; acetonitrile at 12 - 20℃; for 2h;	16.4 g

methanesulfonic acid (75-75-2) + dabigatran etexilate (211915-06-9) → 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridine-2-yl-amino]propionic acid ethyl ester methane sulphonate hemihydrate

Conditions	Yield
With water In ethanol; ethyl acetate at 35 - 40℃; for 1h;	99%

methanesulfonic acid (75-75-2) + dabigatran etexilate (211915-06-9) → ethyl N-{[2-({[4-((E)-amino{[(hexyloxy)carbonyl]imino}methyl)phenyl]amino}methyl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-N-pyridin-2-yl-β-alaninate methanesulfonate

Conditions	Yield
In acetone at 0 - 46℃; for 0.916667 - 2h;	90%
In acetone at 20 - 45℃; for 0.916667 - 1.66667h; Product distribution / selectivity;	90%

dabigatran etexilate (211915-06-9) → 3-({2-[(4-{amino-[(E)-hexyloxycarbonylimino]methyl}-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid (1415506-19-2, 212321-78-3)

Conditions	Yield
With sodium hydroxide In ethanol; water at 20℃; for 5h;	77.5%
With sodium hydroxide In ethanol; water
With water; sodium hydroxide In ethanol

dabigatran etexilate (211915-06-9) → C40H47N9O5 (1415901-76-6, 1416446-28-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydroxide / water; ethanol / 5 h / 20 °C 2: dmap; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride / N,N-dimethyl-formamide / 10.5 h / 0 - 20 °C View Scheme

dabigatran etexilate (211915-06-9) → ethyl N-{[2-({[4-((E)-amino{[(hexyloxy)carbonyl]imino}methyl)phenyl]-amino}methyl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-N-pyridin-2-yl-β-alaninate nitrate salt

Conditions	Yield
With nitric acid In acetone at 10 - 32℃; for 1h;	5 g

caffeic acid (331-39-5) + dabigatran etexilate (211915-06-9) → ethyl N-{[2-({[4-((E)-amino{[(hexyloxy)carbonyl]imino}methyl)phenyl]-amino}methyl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-N-pyridin-2-yl-β-alaninate caffeic acid salt

Conditions	Yield
In acetone at 10 - 45℃; for 2.5h;	4.7 g

3,4,5-trihydroxybenzoic acid (149-91-7) + dabigatran etexilate (211915-06-9) → ethyl N-{[2-({[4-((E)-amino{[(hexyloxy)carbonyl]imino}methyl)phenyl]-amino}methyl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-N-pyridin-2-yl-β-alaninate gallic acid salt

Conditions	Yield
In acetone at 0 - 35℃; for 5.25h;	4.7 g

(E)-3-(4-hydroxy-3-methoxyphenyl)acrylic acid (1135-24-6) + dabigatran etexilate (211915-06-9) → ethyl N-{[2-({[4-((E)-amino{[(hexyloxy)carbonyl]imino}methyl)phenyl]-amino}methyl)-1-methyl-1H-benzimidazol-5-yl]carbonyl}-N-pyridin-2-yl-β-alaninate bisferulate salt

Conditions	Yield
In acetone at 1 - 42℃; for 3h; Temperature;	5.5 g

Upstream product

• 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 
• 6092-54-2 n-hexyl chloroformate 
• 429658-95-7 3-({2-[(4-carbamimidoylphenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid ethyl ester 
• 211915-84-3 3-[[[2-[[(4-cyanophenyl)amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid ethyl ester 
• 212322-56-0 ethyl 3-{[{2-amino-1-(methylamino)phen-4-yl}carbonyl](pyridyn-2-yl)amino}propanoate 
• 42288-26-6 (4-cyanophenyl)glycine 
• 67036-15-1 p-nitrophenylcarbonate hexyl ester 
• 66630-74-8 4-amino-3-(methylamino)benzoic acid 
• 948551-71-1 3-({3-[2-(4-cyano-phenylamino)-acetylamino]-4-methylamino-benzoyl}-pyridin-2-yl-amino)-ethyl propanoate 
• 13048-32-3 bromomethylcarbonyloxyhexane 
• 872728-83-1 2-[4-(5-oxo-1,2,4-oxadiazol-3-yl)phenylamino]acetic acid ethyl ester 
• 873-74-5 4-Aminobenzonitrile 

Downstream Products

• 1415506-19-2 3-({2-[(4-{amino-[(E)-hexyloxycarbonylimino]methyl}-phenylamino)methyl]-1-methyl-1H-benzoimidazole-5-carbonyl}pyridin-2-yl-amino)propionic acid 
• 1415901-76-6 C₄₀H₄₇N₉O₅ 
• 1210812-30-8 ethyl 3-[(2-{[4-(amino-hexyloxycarbonylimino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazole-5-carbonyl)-pyridin-2-yl-amino]-propionate maleic acid salt 
• 1408238-40-3 ethyl 3-[[[2-[[[4-[[[(hexyloxy)carbonyl]amino]carbonyl]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propanoate 
• 1408238-37-8 3-(2-(((4-(((hexyloxy)carbonyl)carbamoyl)phenyl)amino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propionic acid 
• 1415506-19-2 3-[[[2-[[[4-[amino[[[(hexyloxy)carbonyl]amino]methyl]]phenyl]amino]methyl]-1-methyl-1H-benzimidazol-5-yl]carbonyl](pyridin-2-yl)amino]propionic acid 
• 1381757-44-3 2-(N-(3-ethoxy-3-oxopropyl)-2-((4-(N'-(hexyloxycarbonyl)carbamimidoyl)phenylamino)methyl)-1-methyl-1H-benzo[d]imidazole-5-carboxamido)pyridine-1-oxide 
• 1210812-15-9 dabigatran etexilate sulfuric acid salt 

Relevant articles and documents

Synthesis, crystal structural, and spectral characterisation of dabigatran etexilate tetrahydrate

Dabigatran etexilate tetrahydrate, C34H49N7O9, has been crystallised at ambient conditions. The colourless crystal was investigated using X-ray crystallography with single crystals and powder techniques, and was characterised by thermogravimetric-differential thermal analysis (TG-DTA) and infrared spectroscopy (IR). The compound was shown to be a tetrahydrate. A dabigatran etexilate molecule and four water molecules form a large ring structure, and intra-molecular hydrogen bonds contribute to the formation of a stable molecule in the unit cell.

An improved process for preparation of dabigatran etexilate mesylate

An improved process for the preparation of dabigatran etexilate mesylate, wherein the process is substantially free to eliminates the potential impurities. The impurities are formed due to presence of contaminated starting ingredients that is present in commercially available n-hexyl chloro formate. The present invention is to control impurities by using pure n-hexanol in place of n-hexyl chloro formate. Over all yields is good and process can't requires expensive catalysts. Dabigtran is used to prevent strokes in those with arterial fibrillation due to heart valve causes, as well as deep venous thrombosis (DVT). Moreover, the present invention is providing simple, industrial scalable and cost-effective process, which affords good quality and yield.

Benzenesulfonate and preparation method thereof, and application of benzenesulfonate in preparation of dabigatran etexilate

The invention relates to benzene sulfonate represented by a formula 7, a preparation method of the benzene sulfonate, and application of the benzene sulfonate in preparation of dabigatran etexilate. The invention also discloses a method for preparing dabigatran etexilate, wherein the method comprises the following steps: (1) in the presence of a solvent and an acid-binding agent, carrying out an addition reaction on a compound 1 and hydroxylamine hydrochloride to obtain a compound 5; (2) under the action of a reducing agent, carrying out a reduction reaction on the compound 5 and hydrogen, andsalifying with benzenesulfonic acid to obtain benzene sulfonate represented by a formula 7; and (3) carrying out an amidation reaction on the benzene sulfonate represented by the formula 7 and n-hexyl chloroformate to obtain a compound 4, namely dabigatran etexilate. According to the preparation method of the dabigatran etexilate, hydrogen chloride which pollutes the environment and corrodes equipment is not used in a cyano amidination process while industrial iron acetate powder to be eliminated is prevented from being used for reduction, and high-purity dabigatran etexilate can be obtained.

Preparation method of anticoagulant drug dabigatran etexilate and analogues thereof

The invention discloses a preparation method of an anticoagulant drug dabigatran etexilate and analogues thereof. The preparation method comprises the following steps: 3-[(3-amino-4-methylaminobenzoyl)pyridin-2-ylamino]propionic acid ethyl ester (DGM1) and isopropyl 2-(4-cyanophenylamino)acetate (DGM2) which are taken as reaction initial raw materials undergo a docking reaction under the action ofan alkali reagent and a condensing agent to prepare an intermediate DG1; the intermediate DG1 reacts in an alcohol solvent to produce imino ester, and acid catalysis and ammonia reaction are carriedout to prepare a formamidine compound; an intermediate DG2 reacts with n-hexyl chloroformate under the action of the alkali reagent to remove one molecule of water and form an amido bond in order to obtain dabigatran etexilate; and the dabigatran etexilate analogues DG-D1 to DG-D4 are prepared from the dabigatran etexilate and its intermediate DG2. The preparation method of the dabigatran etexilate and analogues thereof has the advantages of short and feasible synthesis route, simplicity in operation, high product yield is high, and suitableness for large-scale industrial production.

Dabigatran etexilate mesylate preparation method

The invention belongs to the field of pharmaceutical synthesis, and provides a dabigatran etexilate mesylate preparation method, which comprises: carrying out a ring closure reaction on 3-[(3-amino-4-methylaminobenzoyl)(pyridine-2-yl)amino] ethyl propionate and chloroacetic anhydride to generate N-[[2-(chloromethyl)-1-methyl-1H-benzimidazole-5-yl]carbonyl]-N-2-pyridyl-beta-alanine ethyl ester, carrying out a condensation reaction on the N-[[2-(chloromethyl)-1-methyl-1H-benzimidazole-5-yl]carbonyl]-N-2-pyridyl-beta-alanine ethyl ester and 4-aminobenzamidine dihydrochloride to obtain 3-({2-[(4-amidino-phenylimino)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl}-pyridine-2-imine)-ethyl propionate, carrying out ester forming on the 3-({2-[(4-amidino-phenylimino)-methylene]-1-methylene-1H-benzimidazole-5-carbonyl}-pyridine-2-imine)-ethyl propionate and hexyl chloroformate to obtain dabigatran etexilate, and carrying out salt forming on the dabigatran etexilate and methanesulfonic acid to obtain dabigatran etexilate mesylate. According to the present invention, the route of the method has characteristics of high yield, mild condition and convenient intermediate purification, and meets the requirements of industrial production.

Preparation method of non-peptide type thrombin inhibitor dabigatran

The invention discloses a preparation method of a non-peptide type thrombin inhibitor dabigatran and belongs to the technical field of medicine chemistry. The technical scheme is characterized by providing the preparation method of the non-peptide type thrombin inhibitor dabigatran; and a synthesis route is as follows: a formula is shown in the description. The preparation method has the advantages of moderate reaction conditions, relatively high yield and low cost and is suitable for industrial production.

Darbey adds the group ester for an intermediate and its preparation method

The invention discloses a novel intermediate form of dabigatran etexilate, wherein the novel intermediate is a salt of 3-[[[2-[[[4-[[ethyoxyl] formimino]phenyl]amino]methyl]-1-methyl-1H-benzimidazole-5-yl]carbonyl](pyridine-2-yl)amino]ethyl propionate as shown in a formula V-A as shown in the specification, and the salt has good purity and stability, can be stored for a long time and can be taken as a process intermediate or a starting raw material for use; and moreover, in the preparation of the subsequent intermediate and the dabigatran etexilate, the reaction operation is simple and convenient, the product purity is high and the industrial application is facilitated.

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.

Preparation method of dabigatran etexilate

The invention discloses a preparation method of dabigatran etexilate. The preparation method comprises that (a) an intermediate I or its salt reacts with haloacetic acid or haloacetate under basic conditions to produce an intermediate II, and (b) the intermediate II and DBSM are condensed by a condensing agent and undergo a ring closing reaction to produce dabigatran etexilate. The preparation method has the advantages of mild reaction conditions, cheap and easily available raw materials, simple reaction steps, high atomic utilization rate, simple and controllable operation, high reaction yield, high product purity, controllable quality, less three-waste discharge, and environmental friendliness and is suitable for large-scale industrial production.

Preparation method of dabigatran etexilate

The invention belongs to the technical field of medicine preparation and particularly relates to a preparation method of dabigatran etexilate. A compound 2 adopted in the preparation method has the characteristics of stable property, no pungent smell, low price and the like. According to the preparation method, the defect that anhydride or acyl chloride compounds are adopted in an existing synthetic route of dabigatran etexilate is overcome, and the compounds have the disadvantages of pungent smell, hygroscopicity and high anhydrous requirement on a reaction system. The reaction process is relatively easily operated and controlled, the synthetic route is short, the byproducts are few, and the cost is low.