- Novel and expeditious microwave-assisted three-component reactions for the synthesis of spiroimidazolin-4-ones
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Highly efficient methods for the syntheses of spiroimidazolinones via microwave-assisted three-component one-pot sequential reactions or one-pot domino reactions are described. The efficiency and utility of the methods have been demonstrated by quickly accessing the antihypertensive drug irbesartan (2).
- Ye, Ping,Sargent, Katie,Stewart, Ethan,Liu, Ji-Feng,Yohannes, Daniel,Yu, Libing
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Read Online
- One-pot method for preparing irbesartan
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The invention discloses a one-pot method for preparing irbesartan. The method comprises the following steps: with 2-butyl-1,3-diazaspiro[4,4]non-1-ene-4-one hydrochloride and 2-cyano-4'-bromomethylbiphenyl as raw materials, performing a reaction in an aprotic solvent containing an alkaline solution, performing an alkylation reaction under the action of a phase transfer catalyst to obtain 2-butyl-3-[(2'-cyano-1,1'-biphenyl-4-yl)methyl]-1,3-diazaspiro[4,4]non-1-ene-4-one, and performing a cyclization reaction on the 2-butyl-3-[(2'-cyano-1,1'-biphenyl-4-yl)methyl]-1,3-diazaspiro[4,4]non-1-ene-4-one and sodium azide under the action of a cyclization catalyst to obtain the irbesartan. The method has the advantages of simple operation, a short reaction time, high yield, high purity and suitability for industrial production.
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Paragraph 0026; 0029; 0032
(2018/12/13)
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- Preparation method of irbesartan isomer and irbesartan intermediate
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The invention relates to a preparation method of an irbesartan isomer and an irbesartan condensation compound isomer as an irbesartan intermediate. The method comprises the following steps: 1) a phase transfer catalyst and an organic solvent are added to an irbesartan ring compound hydrochloride and biphenyl bromide, a sodium hydroxide solution is added, a reaction liquid is filtered after sufficient reaction of the raw materials, a filter cake is subjected to column chromatographic separation, and the irbesartan condensation compound isomer is obtained; 2) triethylamine hydrochloride, sodium azide and an organic solvent A are added to the irbesartan condensation compound isomer, the materials are heated to 100-130 DEG C and reacted, the sodium hydroxide solution and an organic solvent B are added, the mixture is stirred, left to stand and subjected to organic layer removal, hydrochloric acid is added to an aqueous-layer solution to regulate pH to 3.5-6.0, the solution is stirred and filtered, a filter cake is subjected to recrystallization with an organic solvent C or subjected to column chromatographic separation, and the irbesartan isomer is obtained. The irbesartan isomer impurity and the irbesartan intermediate prepared with the method have higher purity and lower energy consumption and cost. Meanwhile, the preparation method is simple to operate and environment-friendly and has important value in irbesartan production and research.
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Paragraph 0046; 0047
(2017/01/02)
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- Synthesis of amido-N-imidazolium salts and their applications as ligands in suzuki-miyaura reactions: Coupling of hetero- aromatic halides and the synthesis of milrinone and irbesartan
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A new catalytic system based on palladium-amido-N-heterocyclic carbenes for Suzuki-Miyaura coupling reactions of heteroaryl bromides is described. A variety of sterically bulky, amido-N-imidazolium salts were synthesized in high yields from the corresponding anilines. This catalytic system effectively promoted Suzuki-Miyaura couplings of heteroaryl bromides and chlorides with a range of boronic acids to give the corresponding aryl compounds in high yield. The yield was increased with increasing steric bulkiness of the substituted group. Especially, 1-(2,6-diisopropylphenyl)-3-N-(2,4,6-tri-tert- butylphenylacetamido)imidazolium bromide (4bc) exhibited 850,000 TON in the coupling reaction of 2-bromopyridine and phenylboronic acid. In addition, pharmaceutical compounds such as milrinone and irbesartan were synthesized via Suzuki-Miyaura coupling using sterically bulky, amido-N-imidazolium salt (4bc) as a ligand. Copyright
- Kumar, Manian Rajesh,Park, Kyungho,Lee, Sunwoo
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experimental part
p. 3255 - 3266
(2011/02/23)
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- PROCESS FOR PURE IRBESARTAN
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The present invention provides an improved and commercially viable process for preparation of irbesartan intermediate, 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one, substantially free of 1-[(2′-cyanobiphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclopentane-2-imidazolin-5-one impurity, thereby producing irbesartan substantially free of the undesired propyl analog impurity, namely 2-propyl-3-[[2′-(1H-tetrazol-5-yl)[1,1′-biphenyl]-4-yl]methyl]-1,3 -diazaspiro[4.4]non-1-en-4-one. The present invention also provides a process for preparation of irbesartan substantially free of tin content. The present invention further provides a commercially viable process for preparation of irbesartan in high purity and in high yield.
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Page/Page column 3
(2010/09/18)
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- A ONE POT PROCESS FOR PREPARING 2-BUTYL-3-[[2'-(1H-TETRAZOL-5-YL)[1,1'-BIPHENYL]-4-YL]METHYL]-1,3-DIAZASPIRO [4, 4] NON-1-EN-4-ONE (IRBESARTAN)
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A one pot process for the synthesis of Irbesartan comprising reacting 2-n-Butyl-1, 3-Diazaspiro [4, 4] Non -1-en-4-one (Formula III) and Bromomethyl Cyanobiphenyl (Formula IV) in the presence of base and water with the optional use of PTC to give formula II from which Irbesartan is obtained by reacting with sodium azide and triethylamine hydrochloride in the presence of a non polar solvent.
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Page/Page column 13
(2010/11/03)
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- A new process for the preparation of irbesartan
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A process for the preparation of Irbesartan or a pharmaceutically acceptable salt thereof comprising the step of coupling the 1-pentanamidocyclapentanecarboxamide of formula (V) with 4'-substituted methyl biphenyl-2-carbonitrile or 1-(4'-substituted methyl biphenyl-2-yl)-1H-tetrazole wherein tetrazole can be protected or unprotected to obtain the N-[(2'-cyanobiphenyl-4-yl)methyl]-1-pentanamidocyclopentanecarboxamide or N-[1-({[2'-(1H-tetrazol-1-yl)biphenyl-4-yl]methylamino)methyl)cydopentyl]pentanamide wherein tetrazole can be protected or unprotected that is further processed to Irbesartan or a pharmaceutical acceptable salt thereof.
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Page/Page column 5; 9; 13
(2010/06/20)
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- PROCESS FOR PURE IRBESARTAN
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The present invention provides an improved and commercially viable process for preparation of irbesartan intermediate, 1-[(2''-cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one, substantially free of 1-[(2''-cyanobiphenyl-4-yl)methyl]-2-n-propyl-4-spirocyclopentane-2-imidazolin-5-one impurity, thereby producing irbesartan substantially free of the undesired propyl analog impurity, namely 2-propyl-3-[[2''-(1H-tetrazol-5-yl)[1,1''-biphenyl]-4-yl]methyl]-1,3-diazaspiro[4.4]non-1-en-4-one. The present invention also provides a process for preparation of irbesartan substantially free of tin content. The present invention further provides a commercially viable process for preparation of irbesartan in high purity and in high yield.
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Page/Page column 8
(2009/07/17)
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- IMPROVED PROCESS FOR PREPARING IRBESARTAN
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Disclosed herein is an improved, commercially viable and industrially advantageous process for the preparation of Irbesartan, or a pharmaceutically acceptable salt thereof, in high yield and purity.
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Page/Page column 8
(2008/12/07)
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- A novel and improved process for the preparation of Irbesartan, an angiotensin-II receptor antagonist for the treatment of hypertension
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2-Butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1,3-diaza-spiro[4,4]non-1-en-4-one (Irbesartan) is prepared by reacting 1-(2'-cyanobipehnyl-4-yl)methyl)-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one with sodium azide and zinc halide, in organic solvent.
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Page/Page column 3
(2008/12/04)
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- PROCESS FOR PRODUCING 2-(N-BUTYL)-3-[[2'-(TETRAZOL-5-YL)BIPHENYL- 4-YL]METHYL]-l,3-DIAZASPIRO[4.4] NON-1-EN-4-ONE
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Disclosed herein a process for producing 2- (n-butyl) -3- [ [2’ - (tetrazol-5-yl)biphenyl-4-yl]methyl] -1,3 -diazaspiro [4.4] non-l-en-4 -one of formula (I) in pure form by using selective solvent system and cost efficient raw materials and reagents.
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Page/Page column 8
(2010/11/25)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF IRBESARTAN
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The present invention relates to an improved process for the preparation of 2-n-butyl-3-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]-1,3-diazaspiro[4.4]non-1-en-4-one (Irbesartan)
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- AN IMPROVED PROCESS FOR PREPARATION OF IRBESARTAN
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A process for the preparation of Irbesartan of formula (I): Formula (I) comprising the steps of: (i) reacting 4' aminomethyl-2-cyano biphenyl of formula (VI) with 1-veleramido cyclopentane carboxylic acid of formula (V): Formula (VI) and Formula (V) in an organic solvent and in the presence of an acid, without activating the -COOH group of compound of formula (V) to give 1-(2'cyanobiphenyl-4-yl-methylaminocarbonyl)-1-pentanoylamino cyclopentane of formula (VII). Formula (VII) converting the compound of formula (VII) obtained in step (i) to Irbesartan of formula (I) by reacting the compound of the formula (VII) with tributyl tin azide in o-xylene to give Irbesartan of formula (I).
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Page/Page column 21
(2008/06/13)
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- Process for preparation of Irbesartan
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A process for the preparation of Irbesartan of formula (I) using the steps of: (i) reacting 4′ aminomethyl-2-cyano biphenyl of formula (VI) with 1-veleramido cyclopentane carboxylic acid of formula (V) ?in an organic solvent and in the presence of an acid, without activating the —COOH group of compound of formula (V) to give 1-(2′cyanobiphenyl-4-yl-methylaminocarbonyl)-1-pentanoylamino cyclopentane of formula (VII). ?converting the compound of formula (VII) obtained in step (i) to Irbesartan of formula (I) by reacting the compound of the formula (VII) with tributyl tin azide in o-xylene to give Irbesartan of formula (I).
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Page/Page column 13
(2008/06/13)
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- Synthesis and screening for acetylcholinesterase inhibitor activity of some novel 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-ones: Derivatives of irbesartan key intermediate
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The association of bioactive nucleus with other pharmacological agents is hoped to improve the efficacy of the treatment by combining the effects of different pharmacological mechanisms of action. Keeping this in view, a series of 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-one derivatives have been synthesized by interaction of 2-butyl-1,3-diaza-spiro[4,4]non-1-en-4-one with different bioactive aralkyl halides in presence of powdered potassium carbonate by two different methods viz., conventional and microwave irradiation. The yields under conventional and microwave irradiation methods were in the range of 60-65% and 80-90%, respectively. The structure elucidation of the new compounds has been carried out with the help of elemental analysis and spectral data. All the synthesized compounds have been screened for their efficacy as acetylcholinesterase (AChE) inhibitor. AChE inhibitory activity study was carried out by using Ellman colorimetric assay with neostigmine as a reference standard against targets from different species, such as pure electric eel AChE, human serum AChE, and rat brain AChE. Among the compounds synthesized, compounds 5a, 5b, 5j showed good inhibition against AChE.
- Kavitha,Gaonkar,Narendra Sharath Chandra,Sadashiva,Rangappa
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p. 7391 - 7398
(2008/09/17)
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- Method for preparing irbesartan and intermediates thereof
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A method for preparing irbesartan and intermediates thereof. Irbesartan has the structure of formula I,
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Page/Page column 3-5
(2008/06/13)
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- IRBESARTAN POLYMORPHS
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The present invention relates to novel hydrate of irbesartan, amorphous irbesartan hydrate and pharmaceutical compositions containing them. The present invention also relates to novel processes for preparing crystalline form-A, crystalline form-B and amorphous form of irbesartan. Thus, for example, irbesartan and water are stirred for 15 minutes, cooled to 5°C and pH is adjusted to 10.5 to 11 with 10% sodium hydroxide solution, the contents are stirred at 5°C - 10°C for 3 hours and the resulting solution is washed with methylene chloride, the aqueous solution is cooled to 5°C and the pH is adjusted to 5.0 with 10% HCl solution at 5°C - 10°C, and then the separated solid is filtered, washed with chilled water and dried to give amorphous irbesartan hydrate.
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Page/Page column 7
(2010/02/15)
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- A new entry to antihypertensive active pharmaceutical ingredient, Irbesartan and its analogues
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A new synthesis of Irbesartan, an antihypertensive active pharmaceutical ingredient and its analogues is reported.
- Satyanarayana, Bollikonda,Sumalatha, Yasareni,Sridhar, Chaganti,Venkatraman, Sundaram,Reddy, Padi Pratap
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p. 323 - 328
(2007/10/03)
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- PROCESSES FOR THE PREPARATION OF HIGHLY PURE IRBESARTAN
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The present invention relates to processes for synthesis of highly pure irbesartan or pharmaceutically acceptable salts thereof.
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Page/Page column 7; 8
(2010/02/11)
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- PROCESS FOR PREPARING IRBESARTAN
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A process for preparing irbesartan comprises pentanoylation of cycloleucine in the presence of sodium hydroxide to form n-pentanoyl cycloleucine, condensing this product with 2-(4-aminomethyl phenyl) benzonitrile using dicyclohexyl carbodiimide and 1-hydroxy benzotriazole as a catalyst to form the 4-(?-N-pentanoyl amino) cyclopentamido methyl-2'-cyano biphenyl compound, and then cyclizing using trifluroacetic acid in the presence of an aromatic solvent to form cyano irbesartan. Cyano irbesartan is converted to irbesartan by reaction with tributyltin chloride and sodium azide in the presence of an aromatic solvent.
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Page/Page column 9
(2008/06/13)
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- Form of irbesartan, methods for obtaining said form and pharmaceutical compositions containing same
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The invention relates to a novel crystalline form of irbesartan, to pharmaceutical compositions containing it, to processes for preparing it, and to a method for treating cardiovascular diseases utilizing it.
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Page column 7
(2010/02/08)
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- METHOD FOR PREPARING AN N-SUBSTITUTED HETEROCYCLIC DERIVATIVE USING A PHASE-TRANSFER CATALYST
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Disclosed is a process for preparing N-substituted heterocyclic derivatives and its salts using phase transfer catalysis.
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- Method for preparing N-substituted heterocyclic derivatives using a phase-transfer catalyst
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Disclosed is a process for preparing N-substituted heterocyclic derivatives and its salts using phase transfer catalysis.
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- Radiosynthesis of [tetrazoyl-11C]irbesartan, a non-peptidic angiotensin II antagonist
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With the aim of visualizing myocardial angiotensin II receptors (AT1 subtypes), [tetrazoyl-11C]2-n-butyl-1-[(2'-(1H-tetrazol-5-yl)-1,1'-biphenyl-4-yl)methyl] - 4-spirocyclo-pentane-2-imidazoline-5-one ([tetrazoyl-11C]irbesartan (SR47436/BMS-186295)) 11 was synthesized in one pot in four steps from [11C]hydrogen cyanide. The labelling process which yielded [tetrazoyl-11C]irbesartan is described in detail and could be applied to the labelling of other ligands which possess the (1H-tetrazol-5-yl) moiety. Positron emission tomography (PET) studies were performed in dogs. Heart, lung and blood time-activity curves did not change. Therefore this new radioligand is not suitable for studying myocardial angiotensin II receptors with PET.
- Penchant,Demphel,Hinnen,Crouzel
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p. 747 - 752
(2007/10/03)
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- A New Series of Imidazolones: Highly Specific and Potent Nonpeptide AT1 Angiotensin II Receptor Antagonists
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Starting from the structure of the novel nonpeptide AT1 receptor antagonists DuP 753 (losartan), a new series of potent antagonists was designed.In these compounds the central imidazole nucleus was replaced by the dihydroimidazol-4-one structure.The most active compounds had a spirocyclopentane or a spirocyclohexane ring in position 5.Like the imidazole series, the best substituents were the linear butyl chain in position 2 and the methyl group in position 3.Antagonistic activity was assessed by the ability of the compounds to competively inhibit AII binding to the AT1 subtype receptor and to antagonize AII-induced contractions in rabbit aorta rings.The most active compounds had IC50 values in the nanomolar range.In conscious rats, compounds 4 and 21 antagonized the AII pressor response when administered orally.Compound 21 (SR 47436) was the most active; it was recently shown to also be active in cynomolgus monkeys both intravenously and orally.This molecule is now undergoing clinical trials for the treatment of hypertension.
- Bernhart, Claude A.,Perreaut, Pierre M.,Ferrari, Bernard P.,Muneaux, Yvette A.,Assens, Jean-Louis A.,et al.
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p. 3371 - 3380
(2007/10/02)
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- N-SUBSTITUTED HETEROCYCLIC DERIVATIVES, THEIR PREPARATION AND THE PHARMACEUTICAL COMPOSITIONS IN WHICH THEY ARE PRESENT
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The invention relates to N-substituted heterocyclic derivatives and its salts. These derivatives have the formula (I) in which the substituents are as defined in the specification. Application: Angiotensin II antagonists
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