429658-95-7Relevant academic research and scientific papers
Main degradation products of dabigatran etexilate evaluated by LC-UV and LC-ESI-MS, degradation kinetics and in vitro cytotoxicity studies
Bernardi, Raquel M.,D'Avila, Felipe B.,Todeschini, Vítor,Andrade, Juliana M.M.,Fr?ehlich, Pedro E.,Bergold, Ana M.
, p. 660 - 666 (2015)
The present study reports the stability profile of an antithrombotic drug: dabigatran etexilate (DAB). The drug was subjected to thermal degradation at 60 °C and products formed were investigated by liquid chromatography-UV (LC-UV) and liquid chromatography-mass spectrometry (LC-ESI-MS). Chromatographic separation of the degradation products was performed on a GL Sciences Inc. Inertsil ODS-2 column (250 mm × 4.6 mm i.d., with a particle size of 5 μm and pore size of 110 ?) with mobile phase consisting of acetonitrile and ammonium acetate buffer (pH 5.5; 10 mmol L-1) (65:35, v/v) pumped at 1.0 mL min-1 flow rate. Column temperature was set at 30 °C and detection at 225 nm using a UV detector. LC-UV method previously validated was extended to LC-ESI-MS for the characterization of the degradation products (DP-01 and DP-02) formed, without complicated isolation or purification processes, based on retention times and confirmation of molecular weight. Degradation kinetics of DAB was also evaluated and could be described as a first-order process (R2 = 0.9900). Furthermore, no evidence of cytotoxicity in human mononuclear cells was observed for DAB degraded samples.
Improved method for preparing dabigatran etexilate intermediate
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Paragraph 0019; 0040-0049, (2020/10/30)
The invention belongs to the field of medical intermediate synthetic methods, and relates to an improved method for preparing a dabigatran etexilate intermediate, in particular, a synthetic method of3-[[[2-[[(4-amidinophenyl)amino]methyl]-1H-benzimidazole-5-yl]carbonyl](pyridine-2-yl)amino] ethyl propionate p-toluene sulfonate 1. According to the method, use of a large amount of solvents and hydrogen chloride is avoided, the reaction process is stable, the dosage of reactants is easy to control, on one hand, impurities generated by side reactions are reduced, and subsequent synthesized dabigatran etexilate is easier to purify; on the other hand, wastes caused by release of saturated hydrogen chloride gas are greatly reduced, the environmental pollution is reduced, meanwhile the steps aresimple and easy to control, and the method is suitable for large-scale production.
Preparation method of dabigatran etexilate intermediate
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Paragraph 0023; 0027-0029; 0033-0034, (2020/08/02)
The invention relates to a preparation method of a dabigatran etexilate intermediate. The preparation method comprises the following steps: (1) carrying out addition on a compound III as shown in thefollowing formula and hydroxylamine to obtain a compound II under the catalysis of an alkali reagent; and (2) putting the compound II obtained in the step (1) into an organic solvent, and carrying outhydrogenation reduction reaction under the action of a catalyst to obtain a compound I shown in the following formula, namely the target product ethyl 3-(2-(((4-formamidinophenyl) amino) methyl)-1-methyl-N-(pyridine-2-yl)-1H-benzimidazole-5-formamide) propionate. The compound III is used as an initial reactant, and the compound II is obtained through addition reaction so that the use of a large amount of hydrogen chloride gas for preparing the imine ester hydrochloride is avoided; the compound I is prepared by hydrogenating and reducing the compound II, the reaction conditions are mild, and the safety of the preparation process is improved; meanwhile, the preparation method is simple in process step, the product is easy to purify, large-scale synthesis can be realized, and the industrialdevelopment prospect is relatively high.
Preparation method of anticoagulant drug dabigatran etexilate and analogues thereof
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, (2020/05/01)
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
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Paragraph 0037; 0040-0041; 0046; 0049-0050; 0055; 0058-0059, (2019/07/04)
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.
Benzimidazole medicinal acid composition for injection and preparation method and application thereof
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Paragraph 0061-0066, (2019/01/22)
The invention discloses a benzimidazole medicinal acid composition for injection and a preparation method and application thereof. The composition comprises benzimidazole medicinal acid as shown in the formula I, a cosolvent, injection water, optional exi
Preparation method of non-peptide type thrombin inhibitor dabigatran
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Paragraph 0023; 0026; 0029; 0032; 0035; 0038, (2019/02/04)
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.
Purification method of benzimidazole derivatives
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Paragraph 0042-0064, (2019/04/29)
The invention relates to a purification method of a benzimidazole derivative. The benzimidazole derivative is a compound A shown in a formula (1), prepared from a compound B shown in a formula (2). The purification method is characterized by comprising the steps of (1) mixing a prepared compound A crude product with a porous medium to form an adsorption mixture; (2) washing the adsorption mixture by using a poor solvent or a mixed solution of the poor solvent and a good solvent of the compound A; (3) washing the adsorption mixture by using the good solvent of the compound A, concentrating obtained washing liquid, and performing re-crystallization by using a solvent to obtain a purified product.
Synthesis of dabigatran etexilate
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Paragraph 0007, (2018/07/06)
The present invention relates to synthesis of dabigatran etexilate, wherein substituted benzonitrile is subjected to alcoholysis in a saturated hydrochloric acid ethanol solution under the catalysis of lewis acid, a reaction is performed with ammonia, and
Production process of pradaxa mesylate
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, (2018/11/22)
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.
