- 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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Paragraph 0096
(2021/04/17)
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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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Paragraph 0053-0059
(2020/02/19)
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- A method for preparing [...] (by machine translation)
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The invention belongs to the field of drug synthesis; a [...] preparation method, characterized in that comprises the following steps: a [...] preparation method, characterized in that includes: 1) compound 5 under the alkaline condition and act on the hydroxylamine hydrochloride, heating the reaction to produce compound 6; 2) compound 6 in three ethylene diamine with carbonyl diimidazole role, reaction to produce compound 4; 3) compound 4 in the hydrolysis reaction under alkaline conditions, obtain arab league qi shatan thick; 4) coarse [...] refined [...]. The invention states arab league qi shatan preparation method has the short reaction time, high purity of the product, the advantage of high yield, it is suitable for large-scale industrial production. (by machine translation)
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Paragraph 0021; 0048; 0051; 0053; 0058
(2018/11/03)
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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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- 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 0029; 0038; 0043; 0046-0048
(2018/01/20)
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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 0092
(2019/01/06)
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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 0033; 0034; 0035; 0036; 0037; 0038-0040
(2017/10/13)
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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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- Aitch sand smooth intermediate and its preparation method (by machine translation)
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The invention discloses Aitch sand smooth intermediate and its preparation method. The preparation method comprises the following steps: in the solvent, compound 2B with hydroxylamine mixing, reaction, get compound 3B can be. The invention method for preparing the Aitch of less impurity, short reaction time, the higher process yield, high purity of the product, is suitable for industrial production. (by machine translation)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE AZILSARTAN
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The present invention relates to an improved process for the preparation of substantially pure compound of 2-Ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol- 3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan) of Formula I, with a reduced content of desethyl impurity less than 0.1% and an efficient, commercially viable process for the preparation of pure intermediates of Azilsartan.
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Page/Page column 11; 12
(2016/10/04)
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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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- 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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- 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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- 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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- 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 16-17
(2012/11/06)
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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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Page/Page column 13-14
(2012/08/28)
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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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