- 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.
- -
-
Paragraph 0050-0052
(2021/08/28)
-
- 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.
- -
-
Paragraph 0037; 0044-0046; 0053-0055; 0062-0063
(2019/07/04)
-
- 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.
- -
-
Paragraph 0075
(2018/03/06)
-
- 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.
- -
-
Paragraph 0093; 0098; 0120-0123; 0147; 0174; 0189; 0202
(2018/11/22)
-
- 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
- -
-
Paragraph 0077-0079
(2018/05/29)
-
- Method for purifying dabigatran etexilate mesylate intermediate
-
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.
- -
-
Paragraph 0063; 0064; 0065; 0066; 0067
(2017/06/02)
-
- 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.
- Sharif, Sd. Khasim,Ramudu, B. Sri,Nunna, Rambabu,Ramachandran
-
p. 1253 - 1257
(2017/05/02)
-
- PROCESSES FOR THE PREPARATION OF DABIGATRAN ETEXILATE AND INTERMEDIATES THEREOF
-
The present invention relates to a process for the preparation of dabigatran etexilate of Formula (I), or a pharmaceutically acceptable salt thereof, to processes for the preparation of intermediates of dabigatran etexilate, and to dabigatran etexilate in substantially pure form.
- -
-
Page/Page column 29
(2016/03/14)
-
- Preparation method of dabigatran etexilate mesylate
-
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.
- -
-
Paragraph 0091; 0092
(2016/10/27)
-
- Preparation technique of dabigatran methanesulfonate
-
The invention discloses a preparation technique of dabigatran methanesulfonate. The technique comprises the following steps: 1) by using a compound I and glycine as raw materials, carrying out condensation and salification to obtain a compound II; 2) by using p-halobenzonitrile (III) as a raw material, synthesizing p-halobenzamidine (IV) under the actions of a catalyst and an aminating agent, and carrying out condensation on the p-halobenzamidine (IV) and n-hexyl chloroacetate to obtain a compound V; and 3) carrying out condensation and salification on the compound V and the compound II to obtain the dabigatran methanesulfonate. The synthesis method has the advantages of mild reaction conditions for each step and high selectivity, and is simple to operate. The dabigatran methanesulfonate has high yield and purity. The technique has the advantages of less discharge of three wastes and environment friendliness, does not need column chromatography purification, and is suitable for industrial production.
- -
-
Paragraph 0075; 0077
(2016/10/10)
-
- Preparation method of high purity Pradaxa crystal form
-
The invention discloses a preparation method of a high purity Pradaxa crystal form. Specifically, the invention provides a preparation method of a high purity Pradaxa crystal form I, and the method includes: mixing Dabigatran etexilate alkali with an organic solvent, and adding a mixed solution of methanesulfonic acid/organic solvent dropwise under the condition of a temperature controlled above 30DEG C so as to obtain the high purity Pradaxa crystal form. The method provided by the ivnetion has the advantages of easily available raw materials, controllable quality, good process reproducibility and simple operation, and also has the characteristics of high yield, low cost and high sample purity, is more suitable for industrial production, and has very high economic benefits.
- -
-
Paragraph 0008; 0022; 0023
(2017/03/14)
-
- New crystals of dabigatran etexilate mesylate
-
The invention relates to a carbamimidoylphenylaminomethylbenzimidazole derivative with modified specific surface area and optionally particle size distribution compared to the compound known from the prior art.
- -
-
Paragraph 0078
(2015/02/25)
-
- PROCESS FOR THE PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND POLYMORPHS OF INTERMEDIATES THEREOF
-
The present invention provides crystalline form of intermediates of Formula 2A, The present invention also provides process for the preparation of dabigatran etexilate mesylate; polymorph of intermediates thereof; particularly processes for the preparation of crystalline form of intermediates. The present invention also relates to the use of crystalline intermediates for the preparation of dabigatran etexilate mesylate.
- -
-
Paragraph 0130-0131
(2015/02/18)
-
- Process For The Preparation Of Benzimidazole Derivatives And Salts Thereof
-
Provided are novel salts of benzimidazole derivatives, preferably salts of benzimidazole derivatives which are useful intermediates in the synthesis of pure 1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and its salts.
- -
-
Paragraph 0244-0245
(2015/03/31)
-
- A PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND INTERMEDIATES THEREOF
-
The present invention relates to an improved process for the preparation of Dabigatran etexilate and its acid addition salts thereof, wherein the said process substantially eliminates the potential impurities. The present invention also relates to an intermediate of Dabigatran etexilate and process for preparation thereof.
- -
-
Page/Page column 51; 52
(2015/09/28)
-
- AN IMPROVED PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE AND PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS THEREOF
-
The present invention provides an improved process for preparation of dabigatran etexilate and pharmaceutically acceptable acid addition salts thereof, particularly mesylate salt. The present invention also provides novel salts of intermediates of Dabigatran etexilate and their polymorphs.
- -
-
Page/Page column 26
(2014/12/12)
-
- SYNTHESIS OF DABIGATRAN
-
The present invention relates to a process for preparation of Dabigatran etexilate or pharmaceutically acceptable salt thereof. The present invention relates to novel compounds, in particular Ethyl-3-{[(2-formyl-l-methyl-lH-benzimidazole-5-yl) carbonyl] -(2-pyridinyl) amino} propanoate and Ethyl-3-{[(2-dichloromethyl-l-methyl -lH-benzimidazole-5-yl)carbonyl]- (2-pyridinyl) amino}propanoate and process for preparation thereof. The present invention further relates to the use of these novel compounds in the preparation of Dabigatran etexilate or pharmaceutically acceptable salt thereof.
- -
-
Page/Page column 43
(2014/10/29)
-
- IMPROVED PROCESS FOR PREPARATION OF DABIGATRAN ETEXILATE AND ITS NOVEL INTERMEDIATE
-
Provided are intermediates for preparing dabigatran etexilate i.e. isopropanol solvate of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide hydrochloride of formula (Vila) and crystalline form II of l-methyl-2-[N-(4-amidinophenyl)-aminomethyl] benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxy carbonyl ethyl)-amide hydrochloride of formula (VII).
- -
-
Paragraph 77; 78
(2013/03/26)
-
- PROCESS FOR THE PREPARATION OF DABIGATRAN ETEXILATE MESYLATE AND POLYMORPHS OF INTERMEDIATES THEREOF
-
The present invention provides crystalline form of intermediates of Formula 2A, Formula 2B and Formula E. The present invention also provides process for the preparation of dabigatran etexilate mesylate; polymorph of intermediates thereof; particularly processes for the preparation of crystalline form of intermediates. The present invention also relates to the use of crystalline intermediates for the preparation of dabigatran etexilate mesylate.
- -
-
Page/Page column 21
(2013/08/15)
-
- Solid forms of dabigatran etexilate mesylate and processes for their preparation
-
It relates to solid forms of dabigatran etexilate mesylate, in particular dabigatran etexilate mesylate in crystalline Form A, and in amorphous form; to processes for their preparation, and to pharmaceutical compositions comprising them. It also relates to a crystalline form of dabigatran etexilate base (Form A), and to a process for its preparation.
- -
-
Paragraph 0080
(2013/09/12)
-
- SOLID FORMS OF DABIGATRAN ETEXILATE MESYLATE AND PROCESSES FOR THEIR PREPARATION
-
It relates to solid forms of dabigatran etexilate mesylate, in particular dabigatran etexilate mesylate in crystalline Form A, and in amorphous form; to processes for their preparation, and to pharmaceutical compositions comprising them. It also relates to a crystalline form of dabigatran etexilate base (Form A), and to a process for its preparation.
- -
-
Page/Page column 18
(2013/09/12)
-
- PROCESSES FOR THE PREPARATION OF DABIGATRAN ETEXILATE
-
The present application relates to processes for preparing Dabigatran etexilate, including pharmaceutically acceptable salts or tautomers thereof.
- -
-
Page/Page column 30-31
(2013/10/21)
-
- DABIGATRAN ETEXILATE BISMESYLATE SALT, SOLID STATE FORMS AND PROCESS FOR PREPARATION THEREOF
-
Dabigatran etexilate bismesylate and crystalline forms thereof are described in the present application and processes for their preparation. The present invention also includes pharmaceutical compositions of such Dabigatran etexilate bismesylate and crystalline forms thereof, methods of their preparation and the use thereof in the treatment of a patient in need thereof.
- -
-
Page/Page column 15
(2012/04/17)
-
- Dabigatran etexilate and related substances, processes and compositions, and use of the substances as reference standards and markers
-
The present invention relates to dabigatran etexilate and related substances and use of the substances as reference standards and markers. There are also provided processes of detecting the substances in samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof, and also for analyzing the purity of samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof. There are still further provided processes of preparing dabigatran etexilate and related substances, and pharmaceutical compositions containing the same.
- -
-
Page/Page column 25
(2012/12/13)
-
- DABIGATRAN ETEXILATE AND RELATED SUBSTANCES, PROCESSES AND COMPOSITIONS, AND USE OF THE SUBSTANCES AS REFERENCE STANDARDS AND MARKERS
-
The present invention relates to dabigatran etexilate and related substances and use of the substances as reference standards and markers. There are also provided processes of detecting the substances in samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof, and also for analyzing the purity of samples of dabigatran etexilate, or pharmaceutically acceptable salts or solvates thereof.There are still further provided processes of preparing dabigatran etexilate and related substances, and pharmaceutical compositions containing the same.
- -
-
Page/Page column 46; 49-50
(2012/12/13)
-
- PROCESS FOR THE PREPARATION OF BENZIMIDAZOLE DERIVATIVES AND ITS SALTS
-
The Present Invention Provides An Improved Process For The Preparation Of 1-methyl-2-[n-[4-(n-n-hexyloxycarbonylamidino) Phenyl]aminomethyl]benzimidazol-5-yl-carboxylicacid-n-(2-pyridyl)-n-(2-ethoxycarbonylethyl)amide Compound Of Formula-1 And Its Methanesulfonate Salt Compound Of Formula-1a.
- -
-
Page/Page column 31
(2012/06/30)
-
- PROCESS FOR THE MANUFACTURE OF DABIGATRAN ETEXILATE
-
An improved process for preparing dabigatran etexilate, as well as analogous compounds of formula 7, is described.
- -
-
Page/Page column 6
(2011/11/13)
-
- NOVEL SALTS FOR THE MANUFACTURE OF PHARMACEUTICAL COMPOSITIONS
-
The present invention relates to novel polymorphous salts of dabigatran etexilate of the formula 11 and process for the preparation thereof.
- -
-
Page/Page column 45-46
(2011/10/05)
-
- A METHOD FOR THE PREPARATION OF DABIGATRAN AND ITS INTERMEDIATES
-
Intermediates for the preparation of dabigatran of formulae (VII-2HC1) and (VII-HC1), methods for their preparation and a method for preparation of dabigatran of formula (VIII) using these intermediates.
- -
-
Page/Page column 11
(2010/05/13)
-