- Liquid chromatography/tandem mass spectrometry study of forced degradation of azilsartan medoxomil potassium
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Rationale Azilsartan medoxomil potassium (AZM) is a new antihypertensive drug introduced in the year 2011. The presence of degradation products not only affects the quality, but also the safety aspects of the drug. Thus, it is essential to develop an efficient analytical method which could be useful to selectively separate and identify the degradation products of azilsartan medoxomil potassium. Methods AZM was subjected to forced degradation under hydrolytic (acid, base and neutral), oxidative, photolytic and thermal stress conditions. Separation of the drug and degradation products was achieved by a liquid chromatography (LC) method using an Acquity UPLC C18 CSH column with mobile phase consisting of 0.02% trifluoroacetic acid and acetonitrile using a gradient method. Identification and characterization of the degradation products was carried out using LC/electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-QTOFMS). Results A total of five degradation products (DP 1 to DP 5) were formed under various stress conditions and their structures were proposed with the help of tandem mass spectrometry (MS/MS) experiments and accurate mass data. A common degradation product (DP 4) was observed under all the degradation conditions. DP 1, DP 2 and DP 5 were observed under acid hydrolytic conditions whereas DP 3 was observed under alkaline conditions. Conclusions AZM was found to degrade under hydrolytic, oxidative and photolytic stress conditions. The structures of all the degradation products were proposed. The degradation pathway for the formation of degradation products was also hypothesized. A selective method was developed to quantify the drug in the presence of degradation products which is useful to monitor the quality of AZM.
- Swain, Debasish,Patel, Prinesh N.,Palaniappan, Ilayaraja,Sahu, Gayatri,Samanthula, Gananadhamu
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- AZILSARTAN ALKYL ESTER, METHOD FOR PRODUCING AZILSARTAN METHYL ESTER, AND METHOD FOR PRODUCING AZILSARTAN
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PROBLEM TO BE SOLVED: To provide azilsartan alkyl ester to be an intermediate of azilsartan, and a method for producing azilsartan methyl ester having a novel crystal form, and a method for producing high-purity azilsartan from an obtained compound. SOLUTION: The present invention provides a method for producing high-purity azilsartan alkyl ester and/or azilsartan methyl ester by crystallizing azilsartan alkyl ester and/or azilsartan methyl ester in acetone or a solvent mixture of acetone and alcohol. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2021,JPOandINPIT
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- Synthesis technology for continuously preparing azilsartan in micro-channel reactor
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The invention discloses a synthesis technology for continuously preparing azilsartan in a micro-channel reactor. The technology comprises the following steps: (1) adding SM-1, an aqueous hydroxylaminesolution and triethylamine into anhydrous ethanol, and performing a reaction to obtain an intermediate TAK1; (2) preparing a homogeneous solution A from the TAK1, triethylamine and dioxane; (3) preparing a homogeneous solution B from solid phosgene and dioxane; (4) dissolving sodium hydroxide in water to prepare a homogeneous solution C; (5) respectively pumping the homogeneous solution A and thehomogeneous solution B into a microstructure mixer I in a micro-channel reaction device at the same time, performing mixing, and introducing the obtained mixed solution into a microstructure reactorI; (6) respectively pumping the homogeneous solution C and the effluent of the microstructure reactor I into a microstructure mixer II in the micro-channel reaction device at the same time while step(5) is carried out, performing mixing, and introducing the obtained mixed solution into a microstructure reactor II; and (7) collecting the effluent of the microstructure reactor II to obtain the product azilsartan.
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- Azilsartan synthesis process
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The invention provides an azilsartan synthesis process which is characterized by comprising the following steps: dissolving hydroxylamine hydrochloride into dimethyl sulfoxide, adding sodium bicarbonate at 20-25 DEG C, increasing the temperature to 45-55 DEG C, performing stirring for 45-60 minutes, further adding AQST-SM, increasing the temperature to 80-85 DEG C, and performing a temperature-keeping reaction for 20-22 hours so as to obtain AQST-1; dissolving the AQST-1 into tetrahydrofuran, dropping DBU (diazabicyclo) at 20-25 DEG C, further adding carbonyl diazole, and performing a reactionfor 1.5-2.5 hours at 20-25 DEG C so as to obtain AQST-3; mixing the AQST-3 with a sodium hydroxide solution, increasing the temperature to 70-75 DEG C, and performing a temperature-keeping reaction for 1-2 hours so as to obtain a crude product of AQST; and adding methanol into the crude product of AQST, increasing the temperature to 60-65 DEG C, performing pulping for 45-50 minutes, reducing thetemperature to the room temperature, performing filtering, bleaching filter cakes by using methanol, performing suction filtration till dryness, and performing vacuum drying, so as to obtain an AQST product. By adopting the azilsartan synthesis process provided by the invention, the AQST product is prepared, the yield is high, the content of AQST is high, the content of impurities is low, the quality of the AQST product is remarkably improved, and the azilsartan synthesis process is well applied to production of high-quality azilsartan tablets.
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Paragraph 0042-0047; 0048-0051
(2019/11/13)
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- MANUFACTURING METHOD OF AZILSARTAN FINE CRYSTAL
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PROBLEM TO BE SOLVED: To provide a manufacturing method of Azilsartan fine crystal industrially. SOLUTION: A manufacturing method of fine particle powder of Azilsartan crystal form A shown in a general formula (I) includes a step separating crystal of Azilsartan by dropping acid water solution at 0-60°C after adding alcohol and water in alkalinity process liquid after hydrolysis of Azilsartan ester shown in a general formula (IV) or Azilsartan ester amine salt shown in a general formula (V) corresponding to it or Azilsartan ester salt shown in a general formula (VI). SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT
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Paragraph 0026
(2019/12/04)
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- High-purity, small-particle-diameter and low-solvent-residue azilsartan bulk drug and preparation method thereof
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The present invention discloses a high-purity, small-particle-diameter and low-solvent-residue azilsartan bulk drug and a preparation method thereof. The purity of the azilsartan bulk drug is more than or equal to 99.9%; the particle size of D90 is less than or equal to 20 [mu]m; and the solvent residue is less than or equal to 500 ppm. The present invention also discloses a high-purity intermediate used for preparing the azilsartan bulk drug and a preparation method thereof, wherein the purity of the intermediate is more than or equal to 99.9%.
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Paragraph 0100; 0103
(2019/01/06)
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- Novel preparation method of azilsartan
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The invention relates to a novel preparation method of azilsartan with relatively high yield and relatively high purity. A multi-refining or column chromatography method is not needed, in addition, the final yield reduction can not be caused. According to the preparation route provided by the application, the contents of an impurity A and an impurity B can be effectively reduced, the refining frequency is reduced, and the yield is also increased.
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Paragraph 0035; 0096-0234
(2018/11/22)
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- Method for greenly and efficiently synthesizing azilsartan in water phase
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The invention relates to a method for greenly and efficiently synthesizing azilsartan in water phase, belonging to the field of medicines. The method comprises the following steps: by taking water asa solvent and 1-[(2'-hydroxyamidino)[1,1-biphenyl]-4-yl]-2-ethoxyl-1H-benzimidazole-7-methyl formate and carbonylation reagent as starting raw materials, performing one-step reaction under base interaction to synthesize azilsartan. Esterification, cyclization and hydrolysis reactions are simplified into one step, so that the reaction time is extremely shortened, the reaction yield is increased, and the purity of the product is high. By taking water as a reactive solvent, the defects of the prior art that an organic solvent is high in toxicity, production is insafe and the like can be overcome,and a simple and efficient green synthesis method is provided for synthesis of azilsartan.
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Paragraph 0027; 0028
(2019/01/08)
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- A method for preparing [...]
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The invention relates to an azilsartan (a hypertension treating medicine) preparation method, and belongs to the field of medicines. The method has the beneficial effects that a compound 1 serves as an initial raw material of the reaction, the azilsartan is prepared through three reaction steps of hydroxylammonium chloride addition, ethyl chloroformate acylation and cyclization hydrolysis under the alkali action, and the cyclization and hydrolysis reaction steps of the prior art are combined into one step, so that conventional 4-5 steps are reduced to three steps, and the reaction time is shortened; and the yield is increased, the content of ethyoxyl-removing impurities is greatly reduced, experimental operations are simplified, the cost is lowered, the azilsartan with high purity is obtained, the high performance liquid chromatography (HPLC) purity is more than 99.5%, and the ethyoxyl and amide-removing impurities are all less than 0.1%.
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Paragraph 0038; 0043-0044; 0045-0048
(2018/04/02)
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- Preparation 2 - ethoxy - 1 - {[2' - (5 - oxo - 4, 5 - dihydro - 1, 2, 4 - oxadiazol - 3 - yl) biphenyl - 4 - yl] methyl} - 1 H - benzimidazole - 7 - carboxylic acid
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The invention provides a novel method for preparing 2- ethyoxyl-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl) xenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid. The novel method comprises the steps of providing a novel intermediate in 2-ethyoxyl-1-{[2'-(5-carbonyl-4,5-dihydro-1,2,4-oxadiazole-3-yl)xenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (azilsartan) preparation, wherein the intermediate is as shown in formula (A); X is H or halogen. By preparing the intermediate with the formula (A), azilsartan can be conveniently and quickly prepared; and moreover, the novel method is short in reaction route, less in byproduct, high in total yield, gentle in condition and suitable for industrially preparing azilsartan.
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- Method for simply and conveniently synthesizing azilsartan
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The invention relates to the field of medicine, and discloses a method for simply and conveniently synthesizing azilsartan. According to the method, 1-[(2'-(hydroxyl guanyl)[1,1-biphenyl]-4-radical) methyl]-2-ethoxylated-1H-benzimidazole-7-methyl formate is mixed with a carbonylation reagent, water serves as a solvent, and reaction is performed at 25 DEG C to obtain O-acylation intermediate; the O-acylation intermediate is mixed with an alkaline reagent, water serves as a solvent, reflux reaction is carried out at 100 DEG C, filtration is carried out, 1mol/L of diluted hydrochloric acid is used for adjusting the pH value to 3-4, suction filtration is carried out, and the solvent is recrystallized to obtain the azilsartan. The method for simply and conveniently synthesizing the azilsartan has the advantages that two steps of reactions of cyclization and hydrolyzation are combined into one step under the alkali action, the azilsartan is obtained with two steps in an aqueous phase, the synthesis steps are reduced, the operation is simple and convenient, and the water is used as the solvent, so that method has very high industrial application value.
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Paragraph 0017; 0019; 0028; 0030; 0032
(2018/11/22)
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- A method for preparing [...]
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The invention provides a preparation method of azilsartan. The method comprises the following steps: enabling 2-ethyoxyl-1-(2'-cyanobiphenyl-4-yl) methylbenzimidazole-7-methyl formate used as a starting raw material to carry out addition with hydroxylamine hydrochloride and carry out cyclization with N',N-carbonyl diimidazole in sequence to obtain azilsartan methyl ester, and then, carrying out hydrolysis to prepare azilsartan. The azilsartan is prepared by two-step reaction. The preparation method has the advantages that the raw materials are easily available, the reaction conditions are gentle, the operation is simple and easy to implement, the synthesis route is short, the yield is high, the purity of the azilsartan is good, the industrial production is adapted, and the like.
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Paragraph 0030-0031; 0040; 0045; 0050
(2018/01/20)
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- Preparation method of azilsartan medoxomil process impurities
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The invention provides a preparation method of azilsartan medoxomil process impurities. The method comprises the following steps: A) azilsartan medoxomil A4 is dissolved in an organic solvent; or azilsartan medoxomil A4 is hydrolyzed to obtain azilsartan, and the azilsartan is dissolved in the organic solvent; B) a catalyst and alkali are added and stirred at the temperature of 0-5 DEG C; C) a DMFsolution of 4-halomethyl-5-methyl-1,3-dioxole-2-ketone is added in a reaction system, after charging is completed, a heating reaction is carried out, acid addition is carried out to adjust a pH value, and filtering is carried out to obtain a product. A synthesis route f the azilsartan medoxomil process impurities is designed, the azilsartan medoxomil process impurities can be successfully obtained with high yield, and a qualified impurities reference substance is obtained.
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Paragraph 0124; 0125
(2018/11/27)
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- New technology for preparing azilsartan
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The invention relates to a preparation method for azilsartan. The method is characterized by comprising the following steps: enabling 2-fluorine-3-bromine nitrobenzene to react with a midbody 3 prepared from suzuki reaction, replacing 2 fluorines and then reducing by nitro group; reacting with tetraethyl orthocarbonate, closing the ring and forming a benzimidazole ring; reacting with hydroxylamine hydrochloride and compounding a phenyl substituted oxadiazole ring under the effect of CDI; forming formic acid with carbon dioxide under the catalysis of n-butyllithium, thereby acquiring the product. The preparation method has the advantages of easily acquired raw materials, simple process, high overall yield, few side products, simplicity in post-processing and suitability for industrial production.
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- A method for preparing arab League Qi Shatan
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The invention relates to a preparation method of azilsartan, and concretely relates to a alkali metal 2-ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carbonate, a preparation method, and a method for using the above compound to prepare azilsartan. The method for preparing azilsartan is simple to operate, and azilsartan prepared in the invention has high purity and very high yield.
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Paragraph 0051
(2017/08/25)
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- A method for reducing the impurity content
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The invention relates to an impurity content decreasing method, in particular to a preparation method of azilsartan medoxomil with low content of azilsartan tetramer impurities (4). The method comprises the step that azilsartan (2) reacts with 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (3) in the presence of an alkali. The method is characterized in that the usage amount of the alkali is higher than 2.5 equivalents relative to that of the azilsartan (2).
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Paragraph 0031; 0032
(2017/09/26)
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- Azilsartan crystal form I
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The invention relates to an azilsartan crystal form I. The crystal form exhibits diffraction peaks at the following diffraction angles: 9.135 +/- 0.2 degrees, 12.72 +/- 0.2 degrees, 18.295 +/- 0.2 degrees, 19.358 +/- 0.2 degrees, 20.350 +/- 0.2 degrees, 21.477 +/- 0.2 degrees, 23.530+/- 0.2 degrees, 25.287+/- 0.2 degrees, 26.690+/-0.2 degrees and 28.811 +/- 0.2 degrees. A preparation method of the azilsartan crystal form I comprises the steps: in an alkaline condition, adding an organic solvent to 2-ethoxy-1-[[2'-((5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-substituted) methyl]-benzimidazole-7-carboxylate for hydrolyzing, regulating the pH value with acid, insulating for grain growing, and collecting, washing and drying crystals to obtain the crystal form I. The method has a simple process and high purity and yield of products, is suitable for industrial production, and is of great importance for quality control and clinical curative effect of medicine.
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Paragraph 0029; 0030; 0031; 0032; 0033; 0034; 0035-0048
(2017/08/29)
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- Preparation method of azilsartan
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The invention discloses a preparation method of azilsartan. The method comprises the following steps: introducing an organic solvent solution of a compound 2 and carbon dioxide gas into a micro reactor, mixing and reacting at the temperature of 90 to 120 DEG C under the pressure of 0.8 to 1.2Mpa for 48 to 480 seconds to obtain azilsartan medoxomil, and discharging the azilsartan medoxomil out of the micro reactor; then, performing alkaline hydrolysis to obtain the azilsartan. A synthetic method disclosed by the invention has the advantages of use of readily-available raw materials, easiness in operation, less reaction side products in each step, high yield, extremely high purity of an obtained product, easiness in separating and purifying reaction products in each step, and suitability for industrial production. The structure of the azilsartan is shown in the description.
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Paragraph 0039; 0040
(2017/10/13)
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- AZILSARTAN HAVING NOVEL CRYSTAL STRUCTURE AND MANUFACTURING METHOD THEREFOR
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PROBLEM TO BE SOLVED: To provide a novel crystal foam of Azilsartan, which is compound extremely useful as a therapeutic agent exhibiting excellent effect as an angiotensin II receptor antagonistic agent, having high solubility to an organic solvent. SOLUTION: There are provided a novel M type crystal of Azilsartan having characteristic peaks at at least 2θ=9.4°, 11.5°, 13.3°, 14.8°, 26.0° by an X-ray diffraction using a Cu-Kα ray and a manufacturing method of an Azilsartan M type crystal by adding a solvent of ketones or esters to a solution obtained by dissolving Azilsartan in dimethylformamide to precipitate the Azilsartan M type crystal. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0048; 0050; 0052; 0054; 0056; 0058; 0060; 0062
(2017/09/29)
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- Aitch sand smooth intermediate and its and Aitch of preparation method
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The invention discloses a preparation method of an intermediate 5B and azilsartan 1. The preparation method of the azilsartan 1 comprises the following steps: 1) in a solvent, mixing a compound 2B with hydroxylamine to react to obtain a compound 3B; 2) in a solvent, mixing the compound 3B prepared in the step 1) with chloroformate to react under the action of alkali to obtain a compound 4B; 3) in a solvent, carrying out cyclization reaction on the compound 4B prepared in the step 2) to obtain a compound 5B; and 4) in a solvent, carrying out esterolysis reaction on the compound 5B prepared in the step 3) under the action of alkali to obtain the azilsartan 1, wherein R is a C6-C10 aryl group or C1-C4 straight-chain or branched-chain alkyl group. The preparation method of the azilsartan intermediate 5B is described as the step 3). The preparation method has the advantages of fewer impurities, short reaction time, higher technical yield and higher product purity, and is suitable for industrial production.
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Paragraph 0171; 0172; 0173
(2017/01/26)
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- A arab League Qi Shatan crystal A and its preparation method
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The invention relates to 1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)- [1,1'-biphenyl]-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylate, that is, Azilsartan of crystal form A, and a preparation method thereof. The Azilsartan prepared in the invention has small particle sizes, can be used in preparation production after direct sieving without a crushing technology, has a low content of relevant substances, and is suitable for the industrial production.
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Paragraph 0053-0055
(2016/11/17)
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- Novel preparation method for azilsartan and intermediate thereof
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The invention relates to an intermediate for preparing azilsartan and a novel preparation method for the azilsartan. The method includes the following steps: 1) reducing 2-cyano-4'-bromomethylbiphenyl with hydroxylamine hydrochloride to generate (Z)-4'-bromomethyl-(N')-hydroxy-[1,1'-biphenyl]-2-amidine; 2) performing esterification with ethyl chloroformate to generate (Z)-4'-bromomethyl-(N')-((ethoxycarbonyl)oxyl)-[1,1'-biphenyl]-2-amidine; 3) performing ring closing to prepare 3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazole-5-(4H)-one; 4) performing a condensation reaction to 2-ethoxy-1H-benzimidazole-7-methyl carboxylate and the 3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazole-5-(4H)-one to prepare 2-ethoxy-1-((2'-(2,5-dihydro-5-oxy-1,2,4-oxadiazole-3-yl)biphenyl-4-yl)methyl)benzimidazole-7-methyl carboxylate; and 5) finally performing hydrolysis to prepare the azilsartan. The method employs the raw material being easy to obtain, is short in synthetic route, is low in device cost, is less in side products, is low in toxicity and pollution, is environment-friendly, is high in product purity and is suitable for industrial production.
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- Angiotensin II receptor antagonists and its key process for the preparation of intermediates (by machine translation)
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This invention has offered a kind of angiotensin II receptor antagonists arab League Qi Shatan and its key intermediate 2-ethoxy-1 - [[ 2 - (N-hydroxy ammonia-methyl-imino) biphenyl-4-yl] - 1H-benzimidazole-7-carboxylic acid methyl ester preparation method, the 1 - [(2-cyano-biphenyl-4-yl) methyl] - 2-ethoxy-benzimidazole-7-carboxylic acid methyl ester with hydroxylamine hydrochloride in water and organic solvent in the mixed solvent prepared by reaction under alkaline conditions 2-ethoxy-1 - [[ 2 - (N-hydroxy ammonia-methyl-imino) biphenyl-4-yl] - 1H-benzimidazole-7-carboxylic acid methyl ester. The 2-ethoxy-1 - [[ 2 - (N-hydroxy ammonia-methyl-imino) biphenyl-4-yl] - 1H-benzimidazole-7-carboxylic acid methyl ester and the halogenated alkane ethyl chloroformate in a solvent, the reaction is under alkaline conditions 2-ethoxy-1 - [[ 2 - [[ ( ethoxycarbonyl ) oxy] amidino] [1,1-biphenyl] - 4-yl] methyl] - 1H-benzimidazole-7-carboxylic acid methyl ester, hydrolysis to obtain arab League Qi Shatan in alkaline conditions. The method of the invention greatly reduces the production cost, improving the yield and purity of product, is suitable for industrial production. (by machine translation)
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Paragraph 0026; 0054-0055
(2017/01/17)
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- A Aitch sand smooth intermediate and its crystal of the crystalline forms of preparation method
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The invention relates to an azilsartan intermediate compound, in particular to preparation methods of a crystal form and a crystal of azilsartan methyl ester. The crystal adopts a triclinic crystal system, the space group is P1, and the cell parameters and the cell volume are specified in the specification. According to the invention, a relatively simple crystallization method is adopted, single solvent is used for recrystallization, the purity of the obtained intermediate reaches higher than 99%, and on the basis, and a purification process of continuously synthesized azilsartan is simplified greatly.
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Paragraph 0052
(2017/06/23)
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- A METHOD OF PREPARING A HIGHLY PURE POTASSIUM SALT OF AZILSARTAN MEDOXOMIL
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A method of preparing the potassium salt of azilsartan medoxomil of formula I, in which a solvate of azilsartan medoxomil of formula II with a solvent selected from the group that consists of dimethyl acetamide or N-methyl pyrrolidone or their mixtures with other solvents is prepared, or re-crystallized from dimethyl acetamide or N-methyl pyrrolidine or their mixtures with other solvents, and, in the next step, converted to the potassium salt using a potassium source in a suitable solvent.
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- NOVEL PROCESS FOR PREPARATION OF AZILSARTAN MEDOXOMIL
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The present invention provides novel process for preparation of azilsartan medoxomil (II) comprising coupling of azilsartan (I) and 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (VII) in presence of carbonyl compound, R3COR4, wherein substituents R3 and R4 represent a heterocyclic ring selected from imidazole, benzimidazole, triazole; or in presence of carbodiimides and base wherein carbodiimide is selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-[3-(dimethyl-amino) propyl]-N'- ethylcarbodiimide. The present invention further provides novel Form I of azilsartan kamedoxomil.
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Page/Page column 8
(2014/04/17)
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- Improved process for azilsartan medoxomil: A new angiotensin receptor blocker
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An improved process for the active pharmaceutical ingredient of a new angiotensin II AT1 receptor antagonist, azilsartan medoxomil, has been developed. The results include reinvestigation of the described process as well as its novel modifications. This new process includes transformation of the CN group into amidoxime moiety by aqueous hydroxylamine, its cyclization into the corresponding oxadiazole by treatment with dialkyl carbonates, and the following hydrolysis of the ester and transformation into the medoxomil ester. Several thus far undocumented side products were identified, and some of them were synthesized and duly characterized as potential impurities. Formation and control of possible critical impurities are described.
- Radl, Stanislav,Cerny, Josef,Stach, Jan,Gablikova, Zuzana
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- Different hydrolases involved in bioactivation of prodrug-type angiotensin receptor blockers: Carboxymethylenebutenolidase and carboxylesterase 1
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Olmesartan medoxomil (OM) is a prodrug-type angiotensin II type 1 receptor blocker (ARB). We recently identified carboxymethylenebutenolidase homolog (CMBL) as the responsible enzyme for OM bioactivation in humans. In the present study, we compared the bioactivating properties of OM with those of other prodrug-type ARBs, candesartan cilexetil (CC) and azilsartan medoxomil (AM), by focusing on interspecies differences and tissue specificity. In invitro experiments with pooled tissue subcellular fractions of mice, rats, monkeys, dogs, and humans, substantial OM-hydrolase activities were observed in cytosols of the liver, intestine, and kidney in all the species tested except for dog intestine, which showed negligible activity, whereas lung cytosols showed relatively low activities compared with the other tissues. AM-hydrolase activities were well correlated with the OM-hydrolase activities. In contrast, liver microsomes exhibited the highest CC-hydrolase activity among various tissue subcellular fractions in all the species tested. As a result of Western blot analysis with the tissue subcellular fractions, the band intensities stained with anti-human CMBL and carboxylesterase 1 (CES1) antibodies well reflected OM- and AM-hydrolase activities and CC-hydrolase activity, respectively, in animals and humans. Recombinant human CMBL and CES1 showed significant AM- and CC-hydrolase activities, respectively, whereas CC hydrolysis was hardly catalyzed with recombinant carboxylesterase 2 (CES2). In conclusion, OM is bioactivated mainly via intestinal and additionally hepatic CMBL not only in humans but also in mice, rats, and monkeys, while CC is bioactivated via hepatic CES1 rather than intestinal enzymes, including CES2. AM is a substrate for CMBL. Copyright
- Ishizuka, Tomoko,Yoshigae, Yasushi,Murayama, Nobuyuki,Izumi, Takashi
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p. 1888 - 1895
(2013/11/06)
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- Synthesis of azilsartan and its selected potential impurities
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Synthesis of angiotensin II AT1 receptor antagonist azilsartan is described. The results include reinvestigation of the described process as well as its novel modification. This new process includes transformation of the CN group into amidoxime moiety by aqueous hydroxylamine, its treatment with alkyl chloroformates and a base-initiated cyclization of the formed (alkoxycarbonyl-oxy)carbamimidoyl intermediates. Several so far undescribed side-products were identified and some of them were synthesized and duly characterized as potential impurities.
- Radl, Stanislav,Cerny, Josef,Stach, Jan,Holec, Jan,Pisa, Ondrej,Gablikova, Zuzana
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p. 929 - 936
(2013/08/23)
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- A METHOD OF PREPARING 2-ETHOXY-1-((2'-(5-OXO-4,5-DIHYDRO-1,2,4-OXADIAZOL-3-YL)BIPHENYL- 4-YL)METHYL)-1H-BENZO[D]IMIDAZOLE-7-CARBOXYLATES AND CONVERSION THEREOF TO AZILSARTAN
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A method of preparing alkyl 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylates of the general formula I, wherein R is either a branched or unbranched C1-C4 alkyl, ArCH2, Ar2CH, or Ar3C, wherein Ar is a substituted or unsubstituted phenyl, in which an alkyl 2-ethoxy-1 -((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)- 1H-benzo[d]imidazole-7-carboxylate of the general formula V is reacted with a cyclization agent in a solvent in the presence of suitable bases. (I) (V)
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Page/Page column 24-25
(2012/11/06)
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- A METHOD OF PREPARING 2-ETHOXY-1-((2'-(5-OXO-4,5-DIHYDRO-1,2,4-OXADIAZOL-3-YL)BIPHENYL- 4-YL)METHYL)-1H-BENZO[D]IMIDAZOLE-7-CARBOXYLATES AND CONVERSION THEREOF TO AZILSARTAN
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An improved method of preparing alkyl 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro- 1,2,4-oxadiazol-3- yl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylates of formula (I), wherein R is either a branched or unbranched C1-C4 alkyl, ArCH2, Ar2CH, or Ar3C, wherein Ar is a substituted or unsubstituted phenyl, and of conversion thereof to azilsartan of formula (II). This compound is an efficient angiotensin II AT1 receptor antagonist, which is used in the form of the prodrug azilsartan medoxomil of formula (III) in the treatment of hypertension.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF AZILSARTAN MEDOXOMIL
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The present invention relates to an improved process for the preparation of azilsartan or its esters or salts thereof. Specifically, the invention provides a method for the preparation of highly pure methyl 1-[[2,-(4,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazo!e-7 -carboxylate an intermediate compound of formula (4) for azilsartan medoxomil with reduced content of dcsethyl impurity. The invention also involves the use of highly pure methyl 1-[[2'-(4,5-dihydro- 5-oxo-4H-1,2,4-oxadiazol-3-yl) biphenyl-4-yl] methyl]-2-ethoxy-1H-benzirnidazole-7- carboxylate in the preparation of azilsartan or its esters or salts thereof, preferably medoxomil with reduced content of desethyl impurity.
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- PHARMACEUTICAL COMPOSITION
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The present invention provides a solid pharmaceutical composition superior in the stability and dissolution property, wherein the drug dissolution property of a solid dosage form containing a fat and oil-like substance having a low melting point is improved. The present invention provides a solid pharmaceutical composition containing an active ingredient, a fat and oil-like substance having a low melting point and a low viscosity binder, and a method of improving dissolution of an active ingredient from a solid pharmaceutical composition containing the active ingredient and a fat and oil-like substance having a low melting point, which includes using a low viscosity binder.
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- Synthesis and angiotensin II receptor antagonistic activities of benzimidazole derivatives bearing acidic heterocycles as novel tetrazole bioisosteres
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The design, synthesis, and biological activity of benzimidazole-7- carboxylic acids bearing 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4-thiadiazole, 5- thioxo-1,2,4-oxadiazole, and 2-oxo-1,2,3,5-oxathiadiazole rings are described. These compounds were efficiently prepared from the key intermediates, the amidoximes 4. The synthesized compounds were evaluated for in vitro and in vivo angiotensin II (AII) receptor antagonistic activities. Most were found to have high affinity for the AT1 receptor (IC50 value, 10-6-10-7M) and to inhibit the AII-induced pressor response (more than 50% inhibition at 1 mg/kg po). The 5-oxo-1,2,4-oxadiazole, 5-oxo-1,2,4- thiadiazole, and 5-thioxo-1,2,4-oxadiazole derivatives showed stronger inhibitory effects than the corresponding tetrazole derivatives, while their binding affinities were weaker. This might be ascribed to their improved bioavailability by increased lipophilicity. The 5-oxo-1,2,4-oxadiazole derivative 2 (TAK-536) and 5-oxo-1,2,4-thiadiazole derivative 8f showed efficient oral bioavailability without prodrug formation. This study showed that the 5-oxo-1,2,4-oxadiazole ring and its thio analog, the 5-oxo-1,2,4- thiadiazole ring, could be lipophilic bioisosteres for the tetrazole ring in nonpeptide AII receptor antagonists.
- Kohara, Yasuhisa,Kubo, Keiji,Imamiya, Eiko,Wada, Takeo,Inada, Yoshiyuki,Naka, Takehiko
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p. 5228 - 5235
(2007/10/03)
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