47 results about "Dabigatran Etexilate Mesylate" patented technology

The invention provides a method for preparing a dabigatran etexilate hydrolysis impurity A. The method comprises steps as follows: (1) dabigatran etexilate or dabigatran etexilate mesylate is used as a raw material and dissolved in a mixed medium of an organic solvent and an alkaline aqueous solution for a hydrolysis reaction; (2) a mixed liquid obtained in Step (1) is adjusted to be acidic, and grease is separated out; (3) the organic solvent is added to the grease, crystals are separated out, and the impurity A is obtained. The invention further provides a method for preparing a dabigatran etexilate hydrolysis impurity B. The method comprises steps as follows: (1) the dabigatran etexilate hydrolysis impurity A is used as a raw material and dissolved in a mixed medium of the organic solvent and an acidic aqueous solution for a hydrolysis reaction; (2) a mixed liquid obtained in Step (1) is depressurized and distilled until grease is produced, and extraction is performed with dichloromethane; (3) an obtained extraction liquid is purified with medium-pressure preparation chromatography, the solvent is removed, and the grease is obtained; (4) ethyl acetate is added, crystals are separated out after dissolution, and the impurity B is obtained.

The invention discloses a preparation method of dabigatran etexilate mesylate, and belongs to the technical field of medicine. The preparation method comprises the following steps: taking 3-[(3-amino-4-methylaminobenzoyl)pyridine-2-ylamino]ethyl propanoate and N-(4-cyanphenyl)amino acetic acid as the raw materials to synthesize an intermediate (S3); making the intermediate (S3) carry out ring-closure reactions to generate an intermediate (S4); subjecting the intermediate (S4) to acid splitting in the presence of a hydrogen chloride-ethanol solution at first, then carrying out ammonification in the presence of ammonia water to generate an intermediate (S5); carrying out reactions between the intermediate (S5) and n-hexyl chloroformate under an alkaline condition to generate an intermediate (S6); dissolving the intermediate (S6), and finally carrying out reactions between the intermediate (S6) and methylsulfonic acid to obtain dabigatran etexilate mesylate. The preparation method has the advantages of simpleness, controllable and mild conditions, high yield, high product purity, stable product property, and suitability for industrial production.

The invention belongs to field of pharmaceutical analysis, and more specifically relates to a method for detecting a related substance imidazole in a starting material F of dabigatran etexilate mesylate. The method which can be operated simply, rapidly and accurately is used for detecting the related substance imidazole in the starting material F; concretely, liquid chromatogram is employed for detection, and key HPLC detection conditions are controlled: the proportion between a mobile phase acetonitrile and water is 10-30:90-100, an amide-bonded silica gel chromatographic column is used, and the detection wavelength is 200-230nm. Key detection parameters are controlled in order to realize the purposes of simple, rapid and accurate detection, and the method can be simply operated; the detection result is accurate and reliable; the specificity is good; the retention time of the starting material F is 3-4 minutes, the retention time of imidazole is 6-7 minutes, the detection time is short, and a brand new selection is provided for detecting related substances in the product, controlling product quality, and guarantying safety of medicines.

The invention relates to a method for preparing a dabigatran etexilate hydrolysis impurity C. The method comprises the following steps: (1) sufficiently dissolving dabigatran etexilate or dabigatran etexilate mesylate as a raw material in a mixed medium consisting of an organic solvent and an acid solution, and performing hydrolysis reaction at 10-50 DEG C, thereby obtaining a mixed liquid after the reaction is completed; (2) performing reduced pressure distillation on the obtained mixed liquid obtained in the step (1) till an oily matter is generated, removing the solvent, adding dichloromethane into the oily matter to extract, and collecting the extract; (3) purifying the extract of the step (2) by using a medium-pressure preparative chromatography method, performing pressure reduction distillation to remove the solvent so as to obtain an oily matter, and washing the oily matter with distilled water, wherein alkyl silica gel is adopted as the solid phase, and an organic solvent and an aqueous solution with the pH value of 4.0-5.0 are adopted as the flow phase; and (4) adding ethyl acetate into the oily matter obtained in the step (3), heating till the oily matter is completely dissolved, cooling, separating out crystals, performing suction filtration, and drying in vacuum, thereby obtaining a product, that is, the dabigatran etexilate hydrolysis impurity C.

The present invention relates to a dabigatran etexilate mesylate content detection method, which concretely comprises that: 1) the chromatographic conditions of HPLC for determining the dabigatran etexilate mesylate comprise that the chromatographic column is phenomenex GeminiC18 (150*4.6 mm, 5 um), the mobile phase A is a 0.01 mol/L ammonium acetate aqueous solution, the pH value is adjusted to 6.5 with acetic acid, the mobile phase B is methanol, isocratic elution is performed according to a ratio of A to B of 35:65, the flow rate is 1 ml/min, the column temperature is 30 DEG C, the detection length of the DAD detector is 272 nm, and the injection volume is 10 [mu]l. According to the present invention, through the effective high performance liquid chromatography, the dabigatran etexilate mesylate content is detected, the dabigatran etexilate mesylate content is precisely detected, the process is easily optimized, and the product quality is easily improved.

An embodiment of the invention discloses a preparing method of dabigatran etexilate mesylate crystal form I. The method includes the steps of adding dabigatran etexilate into acetone solution before heating for solution, and adding methylsulfonic acid to generate dabigatran etexilate mesylate; stirring the dabigatran etexilate mesylate in ester solvent or ether solvent under heating so that the dabigatran etexilate mesylate with low crystal form I (containing little crystal form II or part of semihydrate) is converted into the dabigatran etexilate mesylate with high content of the crystal form I. The dabigatran etexilate mesylate crystal form I prepared by the method is high in purity, lower in water content and more stable in quality.

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.

The invention relates to a pharmaceutical composition containing pradaxa mesylate and a preparation method thereof. Compared with prior art, the preparation method has the advantages of simple process, low production cost and environmental protection. The obtained pharmaceutical composition has the advantages of stable crystal form of active substance, good storage stability and high dissolvability.

Belongs to the technical field of medicines, the invention in particular relates to a hydrate of dabigatran etexilate mesylate and a preparation method thereof. The hydrate of dabigatran etexilate mesylate obtained by the invention contains a crystal water, and has the advantages of high purity, good stability, and non-obvious moisture absorption weight gain even under a high humidity condition.

The invention provides a dabigatran etexilate mesylate oral solid preparation. With a specification of 110mg (based on free dabigatran etexilate), each tablet of the dabigatran etexilate mesylate oral solid preparation comprises the following components: 127mg of dabigatran etexilate mesylate (110mg of dabigatran etexilate), 180-190mg of water-soluble polymer, 15-20mg of disintegrant and 3.0-5.0mg of lubricant. According to the solid medicinal preparation provided by the invention, main drugs are dispersed in a water-soluble carrier, thus the dissolution rate of the preparation is increased, and the drug content uniformity is guaranteed. The dabigatran etexilate mesylate oral solid preparation provided by the invention is simple in preparation technology and suitable for industrial production.

The invention relates to a method for purifying a kilogram-grade dabigatran etexilate free alkali crude product, wherein a compound specifically refers to 3-(2-(4-amidino(hexyloxy carbonyl)-phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-amido)ethyl propionate, and has the main use for preparing an anti-coagulant drug dabigatran etexilate mesylate. With adopting of a relatively simple purification method, the content of new impurities appearing in a process of kilogram-grade preparation of the dabigatran etexilate free alkali is effectively reduced, so that design and development of new pharmacological and toxicological tests are avoided. The purity of the product is also improved, and the preparation cost is reduced.

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.

The invention relates to a method for purifying a dabigatran etexilate mesylate intermediate. The method comprises the following step: purifying the dabigatran etexilate mesylate intermediate in benign solvent through control of gradient crystallization. The purification method can make the purity of the dabigatran etexilate mesylate intermediate be more than 95%, and make other unknown single impurity be less than 0.15%; the intermediate can be used for preparing a dabigatran etexilate mesylate product which meets the quality requirement of a first-researching drug factory.

The invention relates to the field of medicinal preparations, and in particular relates to a stable capsule preparation containing dabigatran etexilate mesylate and a preparation method of the stablecapsule preparation. Under the state of water solution, especially in acidic and alkaline media, dabigatran etexilate mesylate is prone to oxidation and hydrolysis. Due to the adoption of a specific process and selection for specific auxiliary materials, the preparation is good in stability, the loading differences conform to the limitation requirement, in addition, a preparation process has repeatability, and large-scale production can be realized.

The invention belongs to the technical field of medicine preparation, and in particular relates to a preparation method of a novel oral anticoagulant drug dabigatran etexilate mesylate; the method comprises the following steps: (1) adding and mixing 3-[[[2-[[(4-amidino-ylphenyl)amino]methyl]-1-methyl-1H-benzimidazole-5-carbonyl](pyridine-2-yl)amino]-ethyl propionate tosilate and potassium carbonate in a solvent; (2) adding hexyl chloroformate for reaction; (3) adding a refining solvent to dissolve to obtain dabigatran etexilate; 4) adding a reactive solvent for dissolving, and dropwise addingmethanesulfonic acid for reaction; in general, the preparation method of the dabigatran etexilate mesylate provided by the application has mild reaction conditions, short reaction period, and no toxicand harmful substance in purification process of a finished product, and the yield of the final product dabigatran etexilate mesylate is high, so the preparation method has better practical value andpopularization and application significance.

The invention relates to a dabigatran etexilate mesylate crystal V and a preparation method thereof. The crystal V is defined by characteristic peaks of an X-ray powder diffraction spectrum at a diffraction angle 2 theta and DSC. The preparation method of the dabigatran etexilate mesylate crystal V comprises the following steps: adding an amorphous dabigatran etexilate mesylate crystal solid or a known dabigatran etexilate mesylate crystal solid with any crystal form to an alcohol solvent so as to prepare 400-600g/L of suspension liquid, completely dissolving the solid at the temperature of 5-15 DEG C, then cooling a solution to -5 DEG C to 5 DEG C, and then dropwise adding a solventing-out agent to the mixed solution, wherein the using amount of the solventing-out agent is 6-10 times of the volume of the solvent; and carrying out suction filtration on the formed suspension liquid, and drying a dabigatran etexilate mesylate crystal product to constant weight, thus obtaining the dabigatran etexilate mesylate crystal V. The preparation method of the dabigatran etexilate mesylate crystal V has the advantages that a technology is simple, the consumed time is short, and the prepared product has high purity, good thermodynamic stability and the like.

The invention provides a novel crystal form of dabigatran etexilate mesylate and a preparation method of the novel crystal form. The method comprises the following steps: dissolving dabigatran etexilate mesylate into dichloromethane; and adding tetrahydrofuran to perform recrystallization.