- Polymorphs and solvatomorphs of azilsartan medoxomil: Elucidation of solvent-induced construction and conformational diversity
-
Two polymorphs (AM-A and AM-B) of azilsartan medoxomil (AM) and four AM solvatomorphs with toluene (AM-TOL), 1,4-dioxane (AM-DIO), chloroform (AM-TCM) and N,N-dimethylacetamide (AM-DMA) have been prepared by the hydrolysis of azilsartan medoxomil potassium in aqueous-organic solutions. In the crystal structures of two polymorphs and three solvatomorphs (AM-TOL, AM-DIO and AM-TCM), two asymmetric AM molecules form the dimeric cycle-like structures via intermolecular N[sbnd]H?N hydrogen bonds in R22 (26) ring, while AM-DMA shows intramolecular N[sbnd]H?O hydrogen bond between AM and DMA molecules. The hydrogen bonds (C[sbnd]H?O or C[sbnd]H?N) and π···π (or C[sbnd]H···π) interactions are helpful to stabilize the conformational diversity of AM. The solvent-induced experiment shows that solvent molecules have great influence on the solvatomorph formation and DIO can form the most steady solvatomorph than other solvents. The thermal study demonstrates that toluene molecules in three solvatomorphs (AM-TOL, AM-DIO and AM-TCM) are the most difficult to remove from the cage. Our results illustrate that the solvent plays significant role in tuning the size of the cage and producing the conformational diversity of AM molecules.
- Zhang, Xian-Rui,He, Sai-Fei,Zhang, Shuo,Li, Jing,Li, Shan,Liu, Jin-Song,Zhang, Lei
-
-
Read Online
- METHOD FOR PREPARING AZILSARTAN WITH ENVIRONMENT-FRIENDLY SOLVENT, AND KEY INTERMEDIATE COMPOUNDS THEREOF
-
The present invention relates to a method for preparing azilsartan medoxomil, including synthesizing azilsartan dihexylamine salt as a key intermediate through an efficient one-pot reaction, and synthesizing azilsartan medoxomil by means of an ionic liquid and a eutectic solvent as eco-friendly solvents. According to the present invention, cyclization and hydrolysis are carried out continuously in preparing azilsartan medoxomil to reduce the reaction time and to save the cost. Particularly, azilsartan dihexylamine salt as a key intermediate is synthesized through a one-pot reaction, and an ionic liquid and a eutectic solvent are used as eco-friendly solvents, instead of an organic solvent, and thus the reactivity is increased so that the reaction may be performed at a temperature of less than 50°C. In this manner, production of lead-containing materials is reduced, and high-purity and highly competitive azilsartan medoxomil can be produced with high yield in a large amount.
- -
-
Paragraph 0109-0122
(2021/03/03)
-
- Preparation method of azilsartan kamedoxomil hydrate
-
The invention provides a preparation method of azilsartan kamedoxomil hydrate. The preparation method at least comprises the following steps: (1) performing the chlorination; (2) performing the esterification; (3) forming azilsartan kamedoxomil; and (4) forming the azilsartan kamedoxomil hydrate. The preparation method has the characteristics of simple operation, high yield, high purity and good stability, and is suitable for industrialized production.
- -
-
Paragraph 0061; 0064
(2018/09/08)
-
- Novel preparation method of azilsartan medoxomil sylvite and its intermediate
-
The invention relates to a novel preparation method of azilsartan medoxomil sylvite and its intermediate. The method comprises the following steps: hydrolyzing a starting material VII to obtain an intermediate IX, then performing esterification with a side chain IV to obtain the intermediate X; reducing the other starting material VIII by hydroxylamine hydrochloride to obtain the intermediate XI, then performing esterification with ethyl chloroformate to obtain the intermediate XII, and closing ring to obtain the intermediate XIII; performing condensation of the intermediate X and the intermediate XIII to obtain the intermediate II, and finally performing reaction with potassium isooctanoate to obtain the azilsartan medoxomil sylvite. The method has the advantages of easy acquisition of raw materials, short synthesis route, less equipment investment, less by-product, low toxicity, little pollution, environment protection, and high product purity, and is suitable for industrial production.
- -
-
-
- A method for preparing arab League Qi Shatan ester (by machine translation)
-
The invention relates to a method of synthesizing arab League Qi Shatan ester, the method to the 4 [...] -bromo methyl-2-cyano biphenyl as the raw material and then by the hydroxylamine compound II is prepared by cyclization; to 2-ethoxylbenzimidazole-7-carboxylic acid as raw materials to carry out the esterification reaction to make compound V, then utilize the compound prepared with compound II arab League Qi Shatan ester V reaction. The method of the present invention the synthetic route is short, the operation is simple, high yield, at the same time reduces the raw material 4 the [...] -bromomethyl-2-cyanobiphenyl consumption, the cost is reduced. (by machine translation)
- -
-
Paragraph 0018 - 0021; 0046 - 0049
(2016/10/08)
-
- arab League Qi Shatan ester or its salt synthetic method and intermediates thereof, and method for synthesizing intermediate (by machine translation)
-
The invention relates to the field of medicines and in particular relates to a synthesis method for azilsartan medoxomil or salt thereof, an intermediate of the azilsartan medoxomil or the salt thereof and a synthesis method for the intermediate. According to the novel method for the azilsartan medoxomil or the salt thereof, the problems of low synthesized azilsartan medoxomil yield and large number of byproducts are solved. Furthermore, the invention further provides a synthesis intermediate of the azilsartan medoxomil or the salt thereof and two preparation methods. In a synthesis process, an alcohol fragment of the azilsartan medoxomil is introduced at first, so that a part of the azilsartan medoxomil is formed, and a cyclization structure fragment is synthesized; therefore, the problem that the yield is reduced because of side reaction caused by active hydrogen in a carbonyldimidazole structure of an azilsartan acid structure is solved in a reaction process; the reaction yield is greatly improved, so that a finished product is easier to purify; the synthesis method is particularly suitable for industrial production.
- -
-
Paragraph 0075; 0076; 0077; 0078
(2016/10/08)
-
- PROCESS FOR THE PREPARATION OF AZILSARTAN MEDOXOMIL OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
-
The present invention relates to a process for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof.
- -
-
-
- Commercial synthesis of azilsartan kamedoxomil: An angiotensin II receptor blocker
-
A commercially viable process for the preparation of azilsartan kamedoxomil, an angiotensin II receptor blocker, has been developed. The present work describes the novel synthesis of azilsartan medoxomil from amidoxime methyl ester. The present work also describes the improved synthesis of amidoxime methyl ester and azilsartan kamedoxomil. This process features a high overall yield (36%) with 99.52% HPLC purity.
- Garaga, Srinivas,Misra, Nimesh C.,Raghava Reddy, Ambati V.,Prabahar, Koilpillai Joseph,Takshinamoorthy, Chandiran,Sanasi, Paul Douglas,Babu, Korupolu Raghu
-
supporting information
p. 514 - 519
(2015/04/27)
-
- NOVEL POLYMORPHS OF AZILSARTAN MEDOXOMIL
-
The present invention provides a novel amorphous Form of azilsartan acid, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides novel crystalline Forms of azilsartan medoxomil, processes for their preparations and pharmaceutical compositions comprising them. The present invention further provides a novel amorphous Form of azilsartan medoxomil potassium, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides a novel process for the preparation of azilsartan medoxomil potassium crystalline Form II.
- -
-
Paragraph 0148
(2015/07/15)
-
- NOVEL PROCESS FOR PREPARATION OF AZILSARTAN MEDOXOMIL
-
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.
- -
-
-
- A METHOD OF PREPARING A HIGHLY PURE POTASSIUM SALT OF AZILSARTAN MEDOXOMIL
-
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.
- -
-
-
- NOVEL POLYMORPHS OF AZILSARTAN MEDOXOMIL
-
The present invention provides a novel amorphous Form of azilsartan acid, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides novel crystalline Forms of azilsartan medoxomil, processes for their preparations and pharmaceutical compositions comprising them. The present invention further provides a novel amorphous Form of azilsartan medoxomil potassium, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides a novel process for the preparation of azilsartan medoxomil potassium crystalline Form II.
- -
-
Page/Page column 12-13
(2014/03/25)
-
- PROCESS FOR THE PREPARATION OF AZILSARTAN MEDOXOMIL OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF
-
The present invention relates to a process for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof.
- -
-
Page/Page column 21 - 22
(2013/08/15)
-
- PROCESS FOR THE PREPARATION OF AZILSARTAN MEDOXOMIL
-
The present invention relates to processes for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof.
- -
-
Page/Page column 7
(2013/04/10)
-
- Improved process for azilsartan medoxomil: A new angiotensin receptor blocker
-
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
-
-
- METHOD OF PREPARING POTASSIUM SALT OF AZILSARTAN MEDOXOMIL OF HIGH PURITY
-
The present solution relates to new forms of (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester of 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-2-ethoxy-1H- benzimidazole-7-carboxylic acid (azilsartan medoxomil) of formula I and a method of their preparation. The solution also relates to use of these new forms in preparing the potassium salt of azilsartan medoxomil.
- -
-
Page/Page column 10
(2013/11/05)
-
- AN IMPROVED PROCESS FOR THE PREPARATION OF AZILSARTAN MEDOXOMIL
-
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.
- -
-
-
- Benzimidazole derivative and use thereof
-
The present invention relates to a compound represented by the formula (I) wherein R1 is a group represented by the formula wherein R2, R3, R4, R5, R6, R7 and R8 are each independently a hydrogen atom or a C1-6 alkyl, or a salt thereof. The compound of the present invention is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension and the like and metabolic diseases such as diabetes and the like.
- -
-
Page/Page column 12-13
(2008/06/13)
-