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EPROSARTAN MESYLATE

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TEVETEN® (eprosartan mesylate) is a non-biphenyl non-tetrazole angiotensin II receptor (AT1) antagonist. A selective non-peptide molecule, TEVETEN® is chemically described as the monomethanesulfonate of (E)-2-butyl-1 -(p-carboxybenzyl)-α-2-thienylmethylimid-azole-5 -acrylic acid.

Its empirical formula is C23H24N2O4S•CH4O3S and molecular weight is 520.625. Its structural formula is:

Teveten (Eprosartan Mesylate) Structural Formula Illustration

EPROSARTAN MESYLATE

tevetenEprosartan mesilate, SK&F-108566-J(?, SK&F-108566, Teveten SB, Navixen, Regulaten, Tevetenz, Teveten

US 5656650 exp Aug 12, 2014

CAS EPROSARTAN

144143-96-4 

133040-01-4 

Chemical Name: Eprosartan mesylate
Synonyms: EPROSARTAN MESYLATE;Eprosartan Methanesulfonate;4-[[2-butyl-5-(2-carboxy-3-thiophen-2-yl-prop-1-enyl)-imidazol-1-yl]methyl]benzoic acid mesylate;4-({2-butyl-5-[(1E)-2-carboxy-2-(thiophen-2-ylMethyl)eth-1-en-1-yl]-1H-iMidazol-1-yl}Methyl)benzoic acid;(E)-α-[[2-Butyl-1-[(4-carboxyphenyl)Methyl]-1H-iMidazol-5-yl]Methylene]-2-thiophenepropanoic Acid Methanesulfonate;(αE)-α-[[2-Butyl-1-[(4-carboxyphenyl)Methyl]-1H-iMidazol-5-yl]Methylene]-2-thiophenepropanoic Acid MonoMethanesulfonate
CBNumber: CB4842192
Molecular Formula: C24H28N2O7S2
Formula Weight: 520.61832

Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It is marketed as Teveten byAbbott Laboratories in the United States.It is marketed as Eprozar by INTAS Pharmaceuticals in India and by Abbott Laboratorieselsewhere. It is sometimes paired with hydrochlorothiazide, marketed in the US as Teveten HCT and elsewhere as TevetenPlus.

The drug acts on the renin-angiotensin system in two ways to decrease total peripheral resistance. First, it blocks the binding ofangiotensin II to AT1 receptors in vascular smooth muscle, causing vascular dilatation. Second, it inhibits sympatheticnorepinephrine production, further reducing blood pressure.

As with other angiotensin II receptor antagonists, eprosartan is generally better tolerated than enalapril (an ACE inhibitor), especially among the elderly.[1]

Eprosartan is an angiotensin II receptor antagonist used for the treatment of high blood pressure. It acts on the renin-angiotensin system in two ways to decrease total peripheral resistance. First, it blocks the binding of angiotensin II to AT1 receptors in vascular smooth muscle, causing vascular dilatation. Second, it inhibits sympathetic norepinephrine production, further reducing blood pressure.

  1.  Ruilope L, Jäger B, Prichard B (2001). “Eprosartan versus enalapril in elderly patients with hypertension: a double-blind, randomized trial”. Blood Press. 10 (4): 223–9. doi:10.1080/08037050152669747PMID 11800061.

PAT            APR                EXP

Canada 2250395 2005-09-06 2017-03-26
Canada 2115170 2004-05-25 2012-08-12
United States 5656650 1994-08-12 2014-08-12
United States 5185351 1993-02-09 2010-02-09
Canada 2115170 2004-05-25 2012-08-12
United States 5656650 1994-08-12 2014-08-12
Canada 2250395 2005-09-06 2017-03-26

J Med Chem1991,34,(4):1514-7

J Med Chem1993,36,(13):1880-92

Synth Commun1993,23,(22):3231-48

AU 9056901, EP 403159, JP 91115278, US 5185351.

Drugs Fut1997,22,(10):1079

Eprosartan mesylate was developed successfully by SmithKline Beecham Corporation in 1997, and marketed in Germany in 1998 under the trade-name Teveten and in the United States later in 1999. Eprosartan mesylate, as an angiotensin II receptor blocker, is an antihypertensive drug of the latest generation. Eprosartan mesylate is potent to lower systolic and diastolic pressures in mild, moderate and severe hypertensive patients, and is safe and tolerable. Eprosartan mesylate is rapidly absorbed when administrated orally, with a bioavailability of 13% and a protein binding rate of 98%. The blood peak concentration and AUC (Area Under Curve) can be elevated by about 50% in patients with liver and kidney dysfunction, or fullness after administration, and can be elevated by 2 to 3 folds in elderly patients. Eprosartan mesylate has a structure shown as follows:

Figure US20110046391A1-20110224-C00001

U.S. Pat. No. 5,185,351 discloses a method for preparing eprosartan mesylate using Eprosartan and methanesulfonic acid in isopropanol (U.S. Pat. No. 5,185,351, Example 41 (ii)). However, it is found when following this method for preparing eprosartan mesylate in industry, an esterification reaction can occur between eprosartan and isopropanol and the following two impurities can be generated:

Figure US20110046391A1-20110224-C00002

In addition to the above two esterification impurities, the salifying method provided by the above patent is prone to produce isopropyl mesylate. Considering currently known potential risk of gene toxicity of methylsulfonic acid ester on human as well as the stringent requirements of methylsulfonic acid ester from the Europe and the America authorities, it is important to produce eprosartan mesylate in a non-alcohol solvent during the process of producing eprosartan mesylate, since it avoids the formation of methylsulfonic acid ester and the residue thereof in the final product. Since the dosage of eprosartan mesylate is high, it is particularly important to strictly control methylsulfonic acid ester in eprosartan mesylate.

In addition, for the above salifying method, solid eprosartan is suspended in propanol at a low temperature, then methanesulfonic acid is added, about ten seconds later a great deal of eprosartan mesylate precipitate is obtained. Therefore, solid eprosartan may be embedded by the precipitated eprosartan mesylate. Since isopropyl alcohol has a high viscosity at low temperature, a heavy filtering operation burden is needed to obtain solid from isopropanol, and the obtained solid contains quite an amount of isopropanol.

Eprosartan has been obtained by several different ways: 1) The iodination of 2-butylimidazole (I) with I2 and Na2CO3 in dioxane/water gives 2-butyl-4,5-diiodoimidazole (II), which is treated with benzyl chloromethyl ether (III) and K2CO3 in DMF yielding the imidazole derivative (IV). The condensation of (IV) with N-methyl-N-(2-pyridyl)formamide (V) by means of butyllithium in THF affords 1-(benzyloxymethyl)-2-butyl-4-iodoimidazole-5-carbaldehyde (VI), which is deprotected with concentrated HCl ethanol to give 2-butyl-4-iodoimidazole-5-carbaldehyde (VII). The acylation of (VII) with methyl 4-(bromomethyl)benzoate (VIII) by means of K2CO3 in hot DMF yields 4-(2-butyl-5-formyl-4-iodoimidazol-1 ylmethyl)benzoic acid methyl ester (IX), which is deiodinated by hydrogenation with H2 over Pd/C in methanol affording compound (X). The condensation of (X) with methyl 3-(2-thienyl)propionate (XI) by means of lithium diisopropylamide (LDA) in THF gives (XII), which is acylated with acetic anhydride and dimethylaminopyridine (DMAP) in dichloromethane yielding the corresponding acetate (XIII). Elimination of acetic acid from (XIII) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in hot toluene affords the expected propenoic ester (XIV), which is finally saponified with NaOH or KOH in ethanol/water.

…………………………………………………………………………………………………….

WO 1998035962 A1

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Eprosartan mesylate.png


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DR ANTHONY CRASTO

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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