- Understanding and Controlling the Formation of an N-Alkyl Impurity in Olmesartan Medoxomil: A Derivative via Michael-Type Addition between Tetrazole and Mesityl Oxide in Situ Generated from Acetone
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An unknown impurity was detected in olmesartan medoxomil active pharmaceutical ingredient (API), which was determined as 2-methyl-4-oxopentan-2-yl-protected olmesartan medoxomil by NMR and mass spectrometry (MS). The formation mechanism of this impurity was investigated. In summary, the tetrazole of the final product was condensed with the potential genotoxic compound mesityl oxide generated from acetone self-condensation in acidic conditions to form the N-Alkyl impurity. Further quality control of the reaction was investigated using statistical methods (design of experiment, DoE) via a definitive screening design. The key factors of the reaction were determined to control the process parameters. Three batches of validation experiments showed that the generation of the N-Alkyl impurity was suppressed (0.1%) and the residual mesityl oxide was not detected (2.5 ppm).
- Lu, Jianwu,Shi, Yinfei,Li, Xiao,Liang, Xiaomin,Wang, Yinquan,Yuan, Shun,Wu, Taizhi
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Read Online
- 2,4-Dimethoxybenzyl Group for the Protection of Tetrazole: An Efficient Synthesis of Olmesartan Medoxomil through C-H Arylation
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The 2,4-dimethoxybenzyl (DMB) group was found to be effective for protecting tetrazoles. The DMB group is inert to various conditions, including those for ruthenium-catalyzed C-H arylation, but is readily cleaved under mild conditions. The use of a DMB protecting group permitted a synthesis of highly functionalized olmesartan medoxomil in a few steps.
- Seki, Masahiko
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Read Online
- Preparation method of high purity olmesartan medoxomi I
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The invention relates to a preparation method of high purity olmesartan medoxomi I. The preparation method comprises following steps: 1,5-(4'-bromomethyl-1,1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole (A) and ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-imidazole-5-carboxylate (B) are taken as raw materials to prepare an olmesartan medoxomi I intermediate 1 (C) through condensation reaction; theolmesartan medoxomi I intermediate 1 (C) is subjected to hydrolysis in the presence of sodium hydroxide so as to obtain a compound (D); without separation, the compound (D) and raw material 4-Cloromethyl-5-methyl-1,3-dioxol-2-one (E) are directly subjected to condensation reaction so as to obtain an olmesartan medoxomi I intermediate 2 (F); and the olmesartan medoxomi I intermediate 2 (F) is subjected to deprotection in a 75% acetic acid aqueous solution so as to obtain olmesartan medoxomi I crude product, and acetone is adopted for recrystallization so as to obtain high purity olmesartan medoxomi I (G). The reaction conditions are mild; side products are few; the finished product purity is high; the preparation method is safe, is friendly to the environment, and is suitable for industrialized production; residual solvent is less; and quality standards are achieved.
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- A trityl protecting group by removing method of preparing losartan medicine
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The invention discloses a method for preparation of a Sartan drug by removal of a triphenylmethyl protective group. The method includes: under the catalysis of an insoluble weak acid, subjecting a Sartan prodrug and methanol to deprotection reaction, and after complete reaction, conducting aftertreatment to obtain the Sartan drug. The method has the characteristics of low cost, few side product, high quality product, and simple aftertreatment. At the same time, montmorillonite can be taken as insoluble weak acid, and the cost is low, thus being convenient for industrial production.
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Paragraph 0032-0039; 0047-0051
(2018/07/30)
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- A olmesartan medoxomil and its preparation method (by machine translation)
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The invention discloses a olmesartan medoxomil and its preparation method, the present invention discloses a olmesartan medoxomil, its chemical structure is: The present invention novel method for preparation method, comprises the following steps: (1) preparing AMST - 3 C45 H44 N6 O3 ; (2) preparing C43 H39 N6 NaO3 AMST - 4; (3) preparing C48 H44 N6 O6 AMST - 6; (4) preparing olmesartan sha tanzhi thick; (5) to make the C29 H30 N6 O6 Olmesartan medoxomil. The invention separation effect is good, relatively low viscosity system, split-phase required time is short, the time is saved but also reduces energy consumption. Filtering and separating the high recovery rate, the product quality is high, the running cost is low; process without the need to add chemical, solvent solvent, not into the secondary pollution material; equipment and automatic operation, good stability, easy to realize industrial demand. (by machine translation)
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- Production of [orumesarutanmedokisomiru[orumesarutanmedokisomiru]
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PROBLEM TO BE SOLVED: To provide a method for easily producing a crystal of a high-purity (5-methyl-2-oxo-1,3-dioxolene-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(1H-tetrazole-5-yl)biphenyl-4-ylmethyl]imidazole-5-carboxylate in which the content of low polar impurities derived from olmesartan is reduced.SOLUTION: There is provided a method of carrying out a deprotection reaction of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trimethyltetrazole-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid(5-methyl-2-oxo-1,3-dioxolene-4-yl)methylester in an acid aqueous solution having a pKa of 2.5 to 6.0 at a temperature of 30 to 45°C.
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Paragraph 0042
(2017/05/23)
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- Method for preparing olmesartan medoxomil
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The invention provides a method for preparing olmesartan medoxomil and belongs to the field of medicine synthesis. The method comprises the steps that imidazole monoester and 5-(4'-Bromomethyl-1,1'-biphenyl-2-yl)-1-triphenylmethyl-1H-tetrazole (BBTT) are used as starting materials and subjected to condensation, hydrolysis and acidification through a one-pot method in an acetone system to obtain 4-(1-hydroxyl-1-methylethyl)-2-propyl-{4-[2-(triphenylmethyl tetrazole-5-base) phenyl] phenyl} methylimidazole-5-carboxylic acid; the obtained product is then esterified with 4-chloromethyl-5-methyl-1,3-dioxole-2-ketone, wherein the purity of the esterified product through purification is larger than or equal to 99.5%; the esterified product is subjected to deprotection under the action of a 22.5% sulfuric acid solution to obtain highly purified olmesartan medoxomil. Condensation and esterification are performed through the one-pot method, so that the operation procedure is simplified, control is facilitated, the key intermediate esterified product is purified and then subjected to deprotection in the reaction, the olmesartan medoxomil with purity larger than or equal to 99.5% can be obtained, the total yield can reach 60%-75%, the raw materials are easy to obtain, cost is low, and the method is applicable to industrial production.
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- A process for the preparation of olmesartan
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The invention discloses a preparation method of Olmesartan Medoxomil. The method is used for synthesizing an important intermediate 4-[2-(2-triphenylmethyl tetrazole-5-yl) phenyl] benzyl bromide (a compound III) so as to prepare the compound Olmesartan Medoxomil. The method is high in yield, easy to separate and purify, simple to operate and suitable for industrial production.
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- A process for the preparation of olmesartan
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The invention relates to a method for preparing a medicine olmesartan medoxomil for treating hypertension, belongs to the field of medicines, and provides a method for preparing the olmesartan medoxomil with low material cost and mild reaction condition. The method comprises the following steps of: feeding two initial raw materials ( a compound 1 and a compound 2) according to a mole ratio of 1:1 during the process; adding the polyethylene glycol/N,N-dimethylacetamide composite catalyst to be completely reacted with the two initial raw materials so as to avoid a necessary impurity control process caused by excessive raw materials during classic reaction; and removing triphenylmethyl from a methanol/organic solvent mixed system to avoid participation of acid. Based on the improvement, the operation is greatly simplified, the cost is reduced, and the industrial production is facilitated.
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- Preparation method of key intermediate of olmesartan medoxomil and olmesartan medoxomil
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The invention relates to a preparation and refinement method of a key intermediate of olmesartan medoxomil and the olmesartan medoxomil, and belongs to the technical field of medicine. The structural formula of the olmesartan medoxomil is shown as a formula I (Please see the specification).
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- A three phenylmethyl amazingel sha Tanzhi escapes process for preparing amazingel medoxomill protecting group
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The invention discloses a process for preparing olmesartan medoxomil with trityl olmesartan medoxomil deprotection base, which includes the following steps: 1 enabling trityl olmesartan medoxomil to be contacted with two phase mixed liquor of ethyl acetate/ diluted hydrochloric acid; 2 mixing for deprotection base reaction; 3 adding toluene for washing, and removing triphenylcarbinol and a part of impurities; 4 adding acetone to an aqueous layer in last step, and obtaining acetone/ aqueous solution; 5 the potential of hydrogen (pH) value of potassium bicarbonate or potassium carbonate is adjusted to 3-6, mixing and crystallizing; and 6 separating to obtain olmesartan medoxomil. The process has a high yield of approximately 90%, and is stable in quality, capable of effectively removing impurities, high in purity and suitable for industrial production.
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Paragraph 0026; 0027
(2017/02/09)
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- Method of manufacturing [...] (by machine translation)
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PROBLEM TO BE SOLVED: [...] from a solution of the roughness, a reduced amount of residual solvent [...] crystals of high purity. SOLUTION: [...] coarse body to obtain a solution of a solution preparation process, the solution is precipitated from the crystal [...] contg. crystallization processes, in the manufacturing method of a crystal [...], roughness of the [...] solvent for dissolving a mixture of water and an organic solvent, and the solvent is an organic solvent in which the total volume of water 100 and has a volume ratio of water when 5-15, and the organic solvent is acetone or a mixture of ethyl acetate and acetone, and the amount of the solvent to the [...] 5-10mL and coarse body 1g, crystallization temperature of the solution in the process 20-30 °C and held. Selected drawing: no (by machine translation)
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Paragraph 0054; 0057; 0064
(2016/10/09)
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- Preparation method of olmesartan medoxomil
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The invention discloses a preparation method of olmesartan medoxomil. The preparation method comprises the following steps of using 4-bromobenzaldehyde as a starting raw material, performing Suzuki coupling reaction with 2-(2'-triphenylmethyl tetrazole-5-yl)borophenylic acid (III), and reducing by NaBH4 (sodium borohydride), so as to obtain an olmesartan medoxomil intermediate of N-triphenylmethyl-5-(4'-hydroxymethyl biphenyl-2-yl)tetrazole (IV); directly reacting the intermediate (IV) and 2-propyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carboxylic acid ethyl ester, so as to obtain a compound VI; performing hydrolysis, esterification and deprotection, so as to obtain the olmesartan medoxomil. Compared with the prior art, the preparation method has the advantages that the obtaining of raw materials is easy, the amount of byproducts is fewer, the reaction line is shortened, the reaction condition is mild, the operation is simple, the total yield of product is improved, and the preparation method is suitable for industrialized production.
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Paragraph 0045; 0046; 0047; 0048
(2017/02/09)
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- Production of [...] (by machine translation)
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PROBLEM TO BE SOLVED: to provide a method for producing high purity [...]. SOLUTION: a) and acid [...], non-soluble in organic solvent, triphenylcarbinol [...] and precipitation of the process; b) to obtain a solution of a water-soluble or the reaction system by adding an organic solvent and water in a water layer [...], triphenylcarbinol org. layer after extraction, organic layer is removed; c) adding the water layer of the basic process to obtain a precipitate [...] : and d) [...][...] recovered. Selected drawing: no (by machine translation)
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Paragraph 0026
(2016/10/10)
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- DEPROTECTION METHOD FOR TETRAZOLE COMPOUND
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The present invention relates to a method of deprotecting a tetrazole compound, useful as an intermediate for angiotensin II receptor blockers, and provides a novel production method of angiotensin II receptor blockers. Provided is a production method of a compound represented by the formula [3] or [4] or a salt thereof, including (i) reducing a compound represented by the formula [1] or [2] or a salt thereof in the presence of a metal catalyst and an alkaline earth metal salt, or (ii) reacting the compound with a particular amount of Br?nsted acid: wherein each symbol is as defined in the present specification.
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Page/Page column 55-56
(2015/09/23)
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- Improved synthesis process of olmesartan medoxomil derivatives
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The present invention relates to an improved olmesartan medoxomil derivative preparation method. More specifically, the olmesartan medoxomil derivative preparation method includes the steps of: initiating a coupling reaction between imidazole compounds and biphenyl methyl halide compounds; initiating a de-esterification reaction of the products of the coupling reaction; and initiating a condensation reaction between the de-esterified products with dioxolen derivatives. The present invention can optimize the reaction conditions of the coupling and de-esterification reactions to minimixe the content of the conventionally produced byproducts and residual solvent to significantly increase the yield and purity of the target products. The final olmesartan medoxomil derivatives obtained by using the method has the residual solvent content less than or equal to 500 ppm, thereby being lowered to 1/10 or less of the ICH guidelines.
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- METHOD FOR PRODUCING BIARYL COMPOUND
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Provided is a novel production method capable of producing a biaryl compound, which is useful as an intermediate for angiotensin II receptor blockers, economically under conditions suitable for industrial production. A production method of a biaryl compound of the formula [3] or a salt thereof, including reacting a 2-phenylazole derivative of the formula [1] or a salt thereof, with a benzene derivative of the formula [2] or a salt thereof in the presence of a metal catalyst, a base, and one or more kinds of compounds selected from the group consisting of (a) a monocarboxylic acid metal salt, (b) a dicarboxylic acid metal salt, (c) a sulfonic acid metal salt, and (d) a phosphate or phosphoric amide metal salt represented by RAxP(O)(OM)y wherein each symbol is as defined in the DESCRIPTION.
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- Method of manufacturing [...] (by machine translation)
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PROBLEM TO BE SOLVED: [...] of a small amount of residual solvent to produce a high purity. SOLUTION: [...][...] of adding water to a solution when the reaction, solvent for dissolving [...] is specified as a specific and water or an organic solvent using a mixture of organic solvent, a specific amount of water is added by adding speed is adjusted, a reduced amount of residual solvent [...] of crystals of high purity. Selected drawing: no (by machine translation)
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Paragraph 0040; 0042; 0045-0047; 0050; 0054
(2018/11/22)
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- Synthesis and physicochemical characterization of the process-related impurities of olmesartan medoxomil. Do 5-(Biphenyl-2-yl)-1-triphenylmethyltetrazole intermediates in sartan syntheses exist?
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During the process development for multigram-scale synthesis of olmesartan medoxomil (OM), two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API). The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl derivatives of OM. Both compounds, of which N-2 isomer of olmesartan dimedoxomil is a novel impurity of OM, were synthesized and fully characterized by differential scanning calorimetry (DSC), infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI). Their 1H, 13C and 15N nuclear magnetic resonance signals were fully assigned. The molecular structures of N-triphenylmethylolmesartan ethyl (N-tritylolmesartan ethyl) and N-tritylolmesartan medoxomil, the key intermediates in OM synthesis, were solved and refined using single-crystal X-ray diffraction (SCXRD). The SCXRD study revealed that N-tritylated intermediates of OM exist exclusively as one of the two possible regioisomers. In molecular structures of these regioisomers, the trityl substituent is attached to the N-2 nitrogen atom of the tetrazole ring, and not to the N-1 nitrogen, as has been widely reported up to the present. This finding indicates that the reported structural formula of N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, as well as their systematic chemical names, must be revised. The careful analysis of literature spectroscopic data for other sartan intermediates and their analogs with 5-(biphenyl-2-yl)tetrazole moiety showed that they also exist exclusively as N-2-trityl regioisomers.
- Dams, Iwona,Ostaszewska, Anna,Puchalska, Maria,Chmiel, Justyna,Cmoch, Piotr,Bujak, Iwona,Bia?ońska, Agata,Szczepek, Wojciech J.
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p. 21346 - 21363
(2016/01/25)
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- PROCESS FOR OLMESARTAN MEDOXOMIL
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The present invention provides a process for the preparation of substantially pure trityl olmesartan medoxomil. The present invention also provides a process for purification of trityl olmesartan medoxomil. The present invention further provides a process for purification of olmesartan medoxomil.
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Paragraph 0057
(2013/07/31)
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- PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
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The present invention provides novel process for preparation of olmesartan medoxomil (I) substantially free of olmesartan acid impurity (II) comprising, reacting trityl olmesartan medoxomil (III) with acid, filtering the precipitate of trityl alcohol, subjecting the filtrate to agitated thin film drying and recovering olmesartan medoxomil (I).
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Page/Page column 7
(2013/03/26)
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- PROCESS FOR OLMESARTAN MEDOXOMIL
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The present invention provides a process for the preparation of substantially pure trityl olmesartan medoxomil. The present invention also provides a process for purification of trityl olmesartan medoxomil. The present invention further provides a process for purification of olmesartan medoxomil.
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- PROCESS FOR PREPARING OLMESARTAN MEDOXOMIL
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The invention relates to a process for preparing olmesartan medoxomil by the reaction of sodium 5-(1-hydroxy-1-methylethyl)-2-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-imidazole-4-carboxylate, obtained by the reaction between ethyl 5-(1-hydroxy-1-methylethyl)-2-propyl-3H-imidazole-4- carboxylate from and 5-(4'-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole followed by saponification, with 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one, deprotection and purification.
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- A METHOD OF OBTAINING OLMESARTAN MEDOXOMIL
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A method of obtaining olmesartan medoxomil of formula I, comprising the following steps: a) detritylation of trityl olmesartan medoxomil in the presence of an organic acid and water, to give olmesartan medoxomil and trityl alcohol; b) addition of water and separation of the resulting trityl alcohol; c) addition of a water-miscible aprotic solvent; d) addition of water, to give crystalline olmesartan medoxomil; e) isolation of crystalline olmesartan medoxomil of formula I. A pharmaceutical composition comprising olmesartan medoxomil of formula I obtained by the above described method.
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Page/Page column 7-8
(2012/05/19)
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- PROCESS FOR PREPARING OLMESARTAN MEDOXOMIL INTERMEDIATE
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The present invention discloses a process for preparing tritylolmesartan medoxomil with purity greater than 98% and further converting such an intermediate to olmesartan medoxomil.
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- PREPARATION OF OLMESARTAN MEDOXOMIL
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Processes for preparing olmesartan medoxomil. In embodiments, processes for preparing olmesartan medoxomil do not require isolating one or more intermediate compounds.
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- PROCESS FOR (5-METHYL-2-OXO-1,3-DIOXOLEN-4-YL)METHYL4-(1-HYDROXY-1-METHYLETHYL)-2-PROPYL-1-[4-[2-TETRAZOL-5-YL)PHENYL]PHENYL]METHYLIMIDAZOLE-5-CARBOXYLATE
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The present invention relates to an improved process for the preparation of (5-methyl-2-oxo- 1,3-dioxolen-4-yl)methyl4-(1-hydroxy- 1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5-yl)phenyl]phenyl]methyl imidazole-5-carboxylate.
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- METHOD OF REMOVING THE TRIPHENYLMETHANE PROTECTION GROUP
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The present invention relates to a method of removing triphenylmethane protection group. The method for preparing biphenyl benzoic acid derivatives of the present invention is economically advantageous and very excellent in the aspect of improving process in that: process safety is secured by using acidic ion exchange resin in the presence of organic solvent instead of using highly corrosive acid; the reaction takes much less time than do the conventional reactions which use only anhydrous methanol and few sub-reaction does occur; and the ion-exchange resin of the present invention is excellent for mass-processing because the resin can be collected and recycled only by filtration after being used.
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Page/Page column 18-19
(2010/07/02)
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- PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
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The present invention provides an improved process for the preparation of olmesartan medoxomil, which is free of OLM-acid and has lower amount of eliminate and acetic acid impurity.
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Page/Page column 8-9
(2010/12/18)
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- A process for the preparation or purification of olmesartan medoxomil
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The present invention relates to a process for the preparation and purification of olmesartan medoxomil. The invention also relates to products obtainable by the process of the invention, to pharmaceutical compositions comprising the products and to their use in medicine, particularly to treat hypertension.
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Page/Page column 8
(2009/03/07)
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- PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
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The present invention provides a process for the preparation of Olmesartan medoxomil] by condensing the ethyl 4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate with 4-[2-(trityl tetrazol-5-yl)phenyl]benzyl bromide to obtain ethyl 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1-{4-[2-(trityl tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate and then hydrolyzing ethyl 4-(1-hydroxy-1-methyl ethyl)-2-propyl-1-{4-[2-(trityl tetrazol-5-yl)phenyl]phenyl}methyl imidazole-5-carboxylate to obtain trityl Olmesartan dihydrate followed by reacting trityl Olmesartan dihydrate with 4-chloromethyl-5-methyl-2-oxo-1,3-dioxolene to obtain trityl Olmesartan medoxomil and then deprotecting trityl Olmesartan medoxomil to obtain Olmesartan medoxomil.
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Page/Page column 6
(2009/12/04)
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- Efficient synthesis of olmesartan medoxomil, an antihypertensive drug
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This document describes a simple and robust process for the synthesis of olmesartan medoxomil. This tailored process allows us to synthesize olmesartan medoxomil on a large scale with 50% overall yield. Also, our process has excellent control of the impurity profile in all the stages. Copyright Taylor & Francis Group, LLC.
- Babu, Karrothu Srihari,Reddy, Mallepalli Srinivasa,Tagore, Amirisetty Ravindranath,Reddy, Gade Srinivas,Sebastian, Sony,Varma, Mudunuru Satish,Venkateswarlu, Gandu,Bhattacharya, Apurba,Reddy, Padi Pratap,Anand, Ramasamy Vijaya
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experimental part
p. 291 - 298
(2009/05/07)
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- PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
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The present invention relates to an improved process for the manufacture of olmesartan and pharmaceutically acceptable salts and esters thereof as an active ingredient of a medicament for the treatment of hypertension and related diseases and conditions.
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Page/Page column 8
(2009/05/28)
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- A PROCESS FOR THE PREPARATION OF PHENYLTETRAZOLE COMPOUNDS
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A process for the preparation of olmesartan medoxomil, and derivatives thereof, by use of novel phenyltetrazole intermediates.
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Page/Page column 5-6
(2008/06/13)
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- A process for the preparation of phenyltetrazole compounds
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A process for the preparation of olmesartan medoxomil, and derivatives thereof, by use of novel phenyltetrazole intermediates.
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Page/Page column 8
(2010/11/30)
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- Unusual detritylation of tritylated tetrazole in Sartan molecules
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Tritylated tetrazole of 2a underwent unusual detritylation under basic reaction condition during the synthesis of methyl ether of olmesartan medoxomil 1. The unusual detritylation was found to be a common feature in the case of all tetrazole containing Sartan molecules (3-7).
- Srimurugan, Sankareswaran,Suresh, Paulsamy,Babu, Balaji,Hiriyanna, Salmara Ganeshbhat,Pati, Hari Narayan
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p. 383 - 384
(2008/09/20)
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- PROCESS FOR PREPARING TRITYL OLMESARTAN MEDOXOMIL AND OLMESARTAN MEDOXOMIL
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A process for the preparation of trityl olmesartan comprising (a) condensing 4-(1-hydroxy- 1-methylethyl)-2-propyl-imidazol-5-carboxylic acid alkyl ester with trityl biphenyl bromide in the presence of a polar aprotic solvent and a base selected from the group consisting of alkali metal carbonates, alkali metal hydroxides, alkali metal alkoxides, and tertiary amines to obtain a compound of formula (V): b) deesterifying the compound of formula (V) with a base; and c) reacting the product of step (b) with 4-halomethyl-5-methyl-2-oxo-1,3-dioxolene of formula (IV): wherein X is halogen selected from F or Cl or Br or I, to obtain trityl olmesartan medoxomil of formula. The trityl olmesartan medoxomil may be deprotected to produce olmesartan medoxomil.
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Page/Page column 16-18
(2008/06/13)
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- AMORPHOUS OLMESARTAN MEDOXOMIL
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The present invention is directed towards amorphous olmesartan medoxomil, to methods for preparing the compound, to compositions comprising the compound, and to the use of said compound and compositions for the treatment or prevention of an angiotensin II receptor mediated disorder, in particular hypertension.
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Page/Page column 15
(2009/01/24)
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- INTERMEDIATE COMPOUNDS FOR THE PREPARATION OF ANGIOTENSIN II ANTAGONISTS
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The present invention relates to novel substituted biphenyltetrazole compounds useful as intermediates in the preparation of angiotensin II antagonists, to a process for the synthesis of them and to a process for the conversion thereof to said molecules.
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Page/Page column 23; 35-36
(2010/11/30)
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- An improved process for the preparation of olmesartan medoxomil
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Olmesartan medoxomil of high purity (99.3-99.7% by HPLC ) is prepared using an improved process of its intermediate, namely- ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate, comprising: Reacting ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole-5-carboxylate with N-(Triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2- yl]tetrazole in an organic solvent in presence of a base and a phase transfer catalyst in non-aqueous system to give after workup, ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate, which is further processed, by following improved reaction conditions in three steps to provide substantially pure [HPLC purity 99.3 to 99.7 %] olmesartan medoxomil. A further process relates to the purification of olmesartan medoxomil by treatment with isopropyl alcohol and methyl ethyl ketone.
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Page/Page column 6
(2008/06/13)
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- PROCESS FOR THE PREPARATION OF OLMESARTAN MEDOXOMIL
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The present invention relates to an improved process for the manufacture of olmesartan and pharmaceutically acceptable salts and esters thereof as an active ingredient of a medicament for the treatment of hypertension and related diseases and conditions.
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Page/Page column 5; 21-22
(2010/11/25)
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- A METHOD OF REMOVING THE TRIPHENYLMETHANE PROTECTING GROUP FROM PRECURSORS OF ANTIHYPERTENSIVE DRUGS
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A method of removing the triphenylmethane protecting group from precursors of antihypertensive drugs of general formula I, wherein R is a metabolically degradable group, B is a heterocyclic moiety with one or two 5- or 6-membered rings at least one of which contains two nitrogen heteroatoms, in which the compound of formula I is reacted with water in the presence of a solvent which is partially or completely miscible with water.
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Page/Page column 12
(2008/06/13)
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- Process for the preparation of olmesartan medoxomil
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The present invenion relates to an improved process for the manufacture of olmesartan and pharmaceutically acceptable salts and esters thereof as an active ingredient of a medicament for the treatment of hypertension and related diseases and conditions.
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Page/Page column 12
(2010/11/28)
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- PROCESS FOR PREPARING OLMESARTAN MEDOXOMIL
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A process for preparing olmesartan medoxomil.
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Page/Page column 22-23; 26-27
(2008/06/13)
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- Olmesartan medoxomil with reduced levels of impurities
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The present invention provides the preparation of olmesartan medoxomil containing less than about 0.1% of one or more of the impurities OLM-Me, OLM-Cl, and OLM-eliminate.
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Page/Page column 4-5
(2008/06/13)
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- PREPARATION OF OLMESARTAN MEDOXOMIL
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The present invention provides a process for preparing olmesartan medoxomil.
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Page/Page column 5-6
(2008/06/13)
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- Process for preparing olmesartan medoxomil AT pH higher than 2.5
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The present invention provides a process for preparing olmesartan medoxomil at pH higher than 2.5.
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Page/Page column 3
(2008/06/13)
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- ANGIOTENSIN II ANTAGONIST 1-BIPHENYLMETHYLIMIDAZOLE COMPOUNDS AND THEIR THERAPEUTIC USE
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Compounds of the following formula (I) or the formula (I) p : STR1 wherein R 1 is alkyl or alkenyl; R 2 and R 3 are hydrogen, alkyl, alkenyl, cycloalkyl, aralkyl, aryl, or aryl fused to cycloalkyl; R 4 is hydrogen, alkyl, alkanoyl, alkenoyl, arylcarbonyl, alkoxycarbonyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothienyl, tetrahydrofuryl, a group of formula--SiR a R b R c, in which R a, R b and R c are alkyl or aryl, alkoxymethyl, (alkoxyalkoxy)methyl, haloalkoxymethyl, aralkyl, aryl or alkanoyloxymethoxycarbonyl; R 5 is carboxy or--CONR 8 R 9, wherein R 8 and R 9 hydrogens or alkyl, or R 8 and R 9 together form alkylene; R 6 is hydrogen, alkyl, alkoxy or halogen; R. sup.7 is carboxy or tetrazol-5-yl; R p. sup.1 is hydrogen, alkyl, cycloalkyl or alkanoyl; R p 2 is a single bond, alkylene or alkylidene; R p 3 and R p 4 are each hydrogen or alkyl; R. sub.p 6 is carboxy or tetrazol-5-yl; and X p is oxygen or sulfur; and pharmaceutically acceptable salts and esters thereof. The compounds are AII receptor antagonists and thus have hypotensive activity and can be used for the treatment and prophylaxis of hypertension. The compounds may be prepared by reacting a biphenylmethyl compound with an imidazole compound.
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- Nonpeptide angiotensin II receptor antagonists: Synthesis, biological activities, and structure - Activity relationships of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds
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A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)-methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2′-1H-tetrazol-5-ylbiphenyl-4-yl) -methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken.
- Yanagisawa, Hiroaki,Amemiya, Yoshiya,Kanazaki, Takuro,Shimoji, Yasuo,Fujimoto, Koichi,Kitahara, Yoshiko,Sada, Toshio,Mizuno, Makoto,Ikeda, Masahiro,Miyamoto, Shuichi,Furukawa, Youji,Koike, Hiroyuki
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p. 323 - 338
(2007/10/03)
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