Mol. mass 558.585 g/mol
Olmesartan medoxomil (trade names: Benicar in the US, Olmetec in EU, Canada and Japan, WinBP, Golme in India, Erastapex in Egypt) is an angiotensin II receptor antagonist used to treat high blood pressure.
Olmesartan is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.[1] The U.S. Food and Drug Administration (FDA) has determined that the benefits of Benicar continue to outweigh its potential risks when used for the treatment of patients with high blood pressure according to the drug label.[2]
Angiotensin-II receptor antagonists should be used with caution in renal artery stenosis. Monitoring of plasma-potassium concentration is advised, particularly in the elderly and in patients with renal impairment; lower initial doses may be appropriate in these patients. Angiotensin-II receptor antagonists should be used with caution in aortic or mitral valve stenosis and in hypertrophic cardiomyopathy. Those with primary aldosteronism, and Afro-Caribbean patients (particularly those with left ventricular hypertrophy), may not benefit from an angiotensin-II receptor antagonist.
Structure
The olmesartan molecule includes one tetrazole group (a 5-member heterocyclic ring of four nitrogen and one carbon atom) and one imidazole group (a 5-membered planar heterocyclic aromatic ring of two nitrogen and three carbon atoms, classified as an alkaloid).
Olmesartan as the starting material can be easily produced according to the method described in Japanese Examined Patent Application (Kokoku) No. Hei 7-121918 (Japanese Patent No. 2082519 ; US Patent No. 5616599 ) or the like
Olmesartan is a prodrug that works by blocking the binding of angiotensin II to the AT1 receptors in vascular muscle; it is therefore independent of angiotensin II synthesis pathways, unlike ACE inhibitors. By blocking the binding rather than the synthesis of angiotensin II, olmesartan inhibits the negative regulatory feedback on renin secretion. As a result of this blockage, olmesartan reduces vasoconstriction and the secretion of aldosterone. This lowers blood pressure by producing vasodilation, and decreasing peripheral resistance.
The usual recommended starting dose of olmesartan is 20 mg once daily. The dose may be increased to 40 mg after two weeks of therapy, if further reduction in blood pressure is desirable. Doses above 40 mg do not appear to have greater effect, and twice-daily dosing offers no advantage over the same total dose given once daily.[1] No adjustment of dosage is typically necessary for advanced age, renal impairment, or hepatic dysfunction. For patients with possible depletion of intravascular volume (e.g., patients treated with diuretics), olmesartan should be initiated with caution; consideration should be given to use of a lower starting dose in such cases.[1] If blood pressure is not controlled by Benicar alone, a diuretic may be added. Benicar may be administered with other antihypertensive agents. Benicar may be administered with or without food.[1]
Olmesartan and Sevikar HCT is marketed worldwide by Daiichi Sankyo, in India by Abbott Healthcare Pvt. Ltd. under the trade name WinBP, by Zydus Cadila under the trade name Olmy, by Ranbaxy Laboratories Ltd. under the trade name Olvance, and in Canada by Schering-Plough as Olmetec. Benicar HCT is the brand name of a medication containing olmesartan medoxomil in combination with hydrochlorothiazide, a thiazide diuretic. Three dosage combinations are available: 20 mg or 40 mg of olmesartan medoxomil combined with 12.5 mg of hydrochlorothiazide, or 40 mg of olmesartan medoxomil combined with 25 mg of hydrochlorothiazide. Benitec H, another medication containing olmesartan medoxomil and hydrochlorothiazide, is marketed by GlaxoSmithKline in India. In Poland as Olesartan Medoxomil by TEVA, Olimestra and Co-Olimestra (with HCTZ) by Miklich Lab., Elestar (with amlodipine) and Elestar HCT (with amlodipine, HCTZ) by Menarini, Sevikar HCT (with amoldipine, HCTZ) by Aiichi Sankyo.
Research
Two clinical studies (MORE [6] and OLIVUS [7])[8] report that Benicar reduced arterial plaque during therapy for high-blood pressure (hypertension).
- RxList Inc. (5 July 2007). “Benicar (olmesartan medoxomil)”. RxList Inc. Retrieved 22 July 2010.
- “FDA Alert: Benicar (olmesartan): Ongoing Safety Review”. Drugs.com. Retrieved 2013-06-27.
- Angiotensin II receptor blocker induced fetopathy: 7 cases. Hünseler C, Paneitz A, Friedrich D, Lindner U, Oberthuer A, Körber F, Schmitt K, Welzing L, Müller A, Herkenrath P, Hoppe B, Gortner L, Roth B, Kattner E, Schaible T. Klin Padiatr. 2011 Jan;223(1):10-4. Epub 2011 Jan 26.
- “BENICAR Prescribing Information”. Retrieved 2011-01-20.
- Rubio-Tapia, Alberto; Herman, Margot L.; Ludvigsson, Jonas F.; Kelly, Darlene G.; Mangan, Thomas F.; Wu, Tsung-Teh; Murray, Joseph A. (NaN undefined NaN). “Severe Spruelike Enteropathy Associated With Olmesartan”. Mayo Clinic Proceedings 87 (8): 732–738. doi:10.1016/j.mayocp.2012.06.003.
- as referenced in http://www.medicalnewstoday.com/releases/91285.php “Olmetec(R) Is First Angiotensin Receptor Blocker (ARB) To Suggest Atherosclerosis Regression (In Hypertensives With Cardiovascular Risk), UK”
- Cardiovascular Research Foundation (2008, October 16). Drug May Reduce Coronary Artery Plaque. ScienceDaily. Retrieved January 5, 2013, from http://www.sciencedaily.com /releases/2008/10/081012121318.htm
- (Review) R Preston Mason, Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, and Elucida Research, Beverly, MA, USA. Vascular Health and Risk Management, Dovepress, Published Date June 2011 Volume 2011:7 Pages 405 – 416. Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: focus on olmesartan medoxomil. Retrieved January 5, 2013, from http://www.dovepress.com/optimal-therapeutic-strategy-for-treating-patients-with-hypertension-a-peer-reviewed-article-VHRM
4-Isopropenyl-2-propyl-1-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]imidazole-5-carboxylic acid [olmesartan dehydrate, compound 34b described in J. Med. Chem., 39, 323-338 (1996)]
- Daiichi-Sankyo Benicar page
- Benicar HCT from RXlist.com
- Mayo Clinic Proceedings vol.87 Issue 8, pages 732-738
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Olmesartan medoxomil is known by two names,
- (a)(5-Methyl-2-oxo-1,3-dioxolen-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-(2(tetrazole-5yl)phenyl]phenyl]methylimidazole-5-carboxylate
- (b)4-(1-Hydroxy-1-methylethyl)-2-propyl-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-1H-imidazol-5-carboxylic acid (5-methyl-2-oxo-1,-3 dioxol-4-yl)methyl ester, and has a CAS No. [144689-63-4].
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The structural formula is represented below:
![Figure imgb0001]()
Olmesartan medoxomil, which is an angiotensin II receptor antagonist, is useful as an active ingredient in medicaments for treatment and prophylaxis of hypertension (for example, Patent documents 1 to 5 or Non-patent document 1 and 2). Techniques for producing high-purity olmesartan medoxomil are necessary for use of olmesartan medoxomil as a medicament. -
Olmesartan medoxomil is produced from olmesartan by the steps described below, but there is the problem that olmesartan which is a starting material, olmesartan medoxomil dehydrate which is a by-product, or the like, is present as an impurity.
![Figure imgb0001]()
![Figure imgb0002]()
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- Patent document 1: Japanese Examined Patent Application (Kokoku) No. Hei 7-121918 (Japanese Patent No. 2082519 )
- Patent document 2: US Patent No. 5616599
- Patent document 3: International Patent Publication No. WO2006/029056
- Patent document 4: International Patent Publication No. WO2006/029057
- Patent document 5: International Patent Publication No. WO2006/073519
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- Non-patent document 1: J. Med. Chem., 39, 323-338 (1996)
- Non-patent document 2: Annu. Rep. Sankyo Res. Lab. (Sankyo Kenkyusho Nempo) 55, 1-91 (2003)
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The prior art synthetic methods involve coupling reaction between the substituted imidazole and substituted biphenyl methyl bromide. J. Med. Chem. 1996 vol. 39 No.1, page 323-38 describes the synthesis of Olmesartan medoxomil as follow. [Scheme-1 ]
![Figure imgb0002]()
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US 5616599 describes a process for the preparation of olmesartan medoxomil as follows.
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[0006]4-(1-hydroxyl-1-methylethyl)-2-propyl imidazole-5carboxylic acid is reacted with 5-methyl-2-oxo-1, 3-dioxolene-4-yl)methyl chloride using N,N-diisopropylethyl amine as base in N,N-dimethyl acetamide at 60°C to give (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl imidazole-5-carboxylate. The resulting product is coupled with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole [herein referred to as TTBB] at 60°C in N, N-dimethyl acetamide using potassium carbonate as base to give protected olmesartan medoxomil. The protected olmesartan medoxomil is deprotected using 75 % acetic acid to give olmesartan medoxomil.
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This process involves column chromatographic purification of intermediates which is not desirable on commercial scale operation.
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US 5616599 describes another process for the preparation of olmesartan Medoxomil which involves addition of methyl Magnesium chloride on diethyl 2-propylimidazole-4, 5-dicarboxylate in tetrahydrofuran at -30 to -20°C to give ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole -5-carboxylate, which is coupled with TTBB using sodium hydride as base in N, N-dimethylformamide at 60°C to give ethyl-4-(1-hydroxy-1-methylethyl)2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-. 5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate. The product thus formed is hydrolyzed using lithium hydroxide monohydrate as base in 1,4-dioxane at 5-10°C to give lithium salt of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, which is then coupled with 5-methyl-2-oxo-(1,3-dioxolene-4-yl)methyl chloride using K2CO3 as base in N,N-dimethylacetamide at 50°C to give trityl protected olmesartan medoxomil which on deprotection using 75% acetic acid gives Olmesartan Medoxomil.
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During the condensation of ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole -5-carboxylate, with TTBB using sodium hydride as base in N, N-dimethylformamide, various impurities are formed, and isolation of the product involves extractive workup.
, Ian R. Baxendale, Steven V. Ley and Nikzad Nikbin Corresponding author emailThe structurally related imidazole core of olmesartan is formed in a different fashion (Scheme 36). Condensation between diaminomaleonitrile and trimethyl orthobutyrate furnishes the trisubstituted imidazole 181 in high yield [53,54]. Acid-mediated nitrile hydrolysis followed by esterification results in the corresponding diester unit 182. Treatment of 182 with four equivalents of methylmagnesium chloride in a mixture of diethyl ether and dichloromethane selectively provides tertiary alcohol 183. In subsequent steps this imidazole is alkylated with the tetrazole containing biphenyl appendage, followed by ester hydrolysis and alkylation of the resulting carboxylate with 4-(chloromethyl)-5-methyl-2-oxo-1,3-dioxole to yield olmesartan (Scheme 36).
![[1860-5397-7-57-i36]](http://beilstein-journals.org/bjoc/content/inline/1860-5397-7-57-i36.png?max-width=550&background=FFFFFF)
- 53…….Yanagisawa, H.; Fujimoto, K.; Amemiya, Y.; Shimoji, Y.; Kanazaki, T.; Koike, H.; Sada, T. Angiotensin II Antagonist 1-Biphenylmethylimidazole Compounds and their Therapeutic Use. U.S. Patent 5,616,599, April 1, 1997.
Return to citation in text: [1] - 54……….Yanagisawa, H.; Amemiya, Y.; Kanazaki, T.; Shimoji, Y.; Fujimoto, K.; Kitahara, Y.; Sada, T.; Mizuno, M.; Ikeda, M.; Miyamoto, S.; Furukawa, Y.; Koike, H. J. Med. Chem. 1996, 39, 323–338. doi:10.1021/jm950450f
Return to citation in text: [1]
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.
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To a 3M solution of MeMgCl(55.86 g, 0.74 mol) in tetrahydrofuran was added a solution of diethyl 2-propyl imidazole- 4,5-dicarboxylate (50 g,0.19 mol) in tetrahydrofuran (200 ml) at -10 to 0°C under N2 atmosphere. The mixture was stirred at -5 to 0°C for 10 minutes. Reaction mass was quenched into 400 ml 25 % ammonium chloride solution followed by extraction with ethyl acetate (300 ml). The organic phase was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo to give a syrup, which was crystallized using diisopropyl ether.
Yield: 85-90 %,
Purity by HPLC: 88-93 %.
1H-NMR (CDCl3) δ: 7.8-8.1 (s, 1H), 5.8(s, 1H)., 4.35(q, 2H), 2.68(t, 2H), 1.78(m, 2H), 1.61(s, 6H), 1.36(t, 3H), 0.96(t, 3H).
Example-2Preparation of Ethyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylaiethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole
- -5-
carboxylate
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Mixture of Ethyl-4-(1-hydroxy-1-methylethyl)-2-propylimidazole -5-carboxylate (41 g, 0.17 mol), potassium carbonate (47g, 0.34 mol) and tetrabutylammonium bromide (4.9 g, 0.01 mol) in acetone was stirred at room temperature for 1hr. Then TTBB (93% Purity, 92.89g, 0.15 mol) was charged, refluxed for 14hrs. Potassium salts were filtered off from the reaction mass and the filtrate was charcoalised for 1hr. It was filtered over celite bed and the filtrate was distilled off completely to get a semi solid mass. 250 ml of Methanol was added to the residue and stirred for 2-3 hrs to give a solid product, which was filtered and washed with chilled methanol and dried.
Yield: 80-85%,
Purity by HPLC: 85-90%.
1H-NMR (CDCl3) δ: 7.8-8.1 (m, 1H), 6.7-7.61 (m, 22H), 5.78 (bs, 1H), 5.38(s, 2H), 4.12 (q, 2H), 2.52 (t, 2H), 1.64(s, 6H), 1.5-1.8(m, 2H), 1.08(t, 3H), 0.88(t, 3H).
Example-3Preparation of lithium salt of 4-(1-hydroxy-1-methylethyl) 2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl] biphenyl-4-yl] methyl] imidazole -5-carboxylic acid
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To a solution of Ethyl-4-(1-hydroxy-1-methylethyl) 2-propyl- 1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate (105 g, 0.14 mol) in tetrahydrofuran , was added LiOH.H2O (7.8 g, 0.18 mol) solution below 10°C. The reaction mixture was stirred at room temperature for 15 hours. Reaction mass was concentrated under vacuum at 35°C to 1/4 th of its volume. 300 ml of ethyl acetate and NaCl (130 g) were added to the residue under stirring. The organic phase was separated, dried over sodium sulphate and concentrated under vacuum to get the product. The crude product was taken as such to the next stage.
Example-4Preparation of trityl protected olmesartan medoxomil
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To the solution of lithium salt of 4-(1-hydroxy-1-methylethyl) 2-propyl- 1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl] biphenyl-4-yl] methyl] imidazole -5-carboxylic acid , (97 g, 0.13 mol) in N, N-dimethyl acetamide(200 ml) was added triethylamine(12.7 g, 0.12 mol), stirred at room temperature for 0.5 hours. 5-methyl-2-oxo-(1,3-dioxolene-4-yl)methyl chloride (85% purity, 37.3 g, 0.25 mol) was added below 10°C. The mixture was stirred at 50-55°C for 4 hours, checked TLC. Dichloromethane (400 ml) and chilled water (500 ml) were added under stirring. The organic phase was separated, given brine wash (50 ml), dried over sodium sulphate and concentrated under vacuum to get a residue. To the residue methanol was added, stirred for 1hr, cooled to 5-10°, filtered and washed with chilled methanol and dried.
Yield: 75-80%,
Purity by HPLC: 96-98%.
1H-NMR (CDCl3) δ: 7.87(d, 1H), 6.90-7.52(m, 20H), 6.68(d, 2H), 5.61(s, 1H), 5.3(s, 2H), 4.7(s, 2H), 2.54(t, 2H), 1.97(s, 3H), 1.6-1.75(m, 2H), 1.62(s, 6H), 0.87(t, 3H).
Example-5Preparation of olmesartan medoxomil
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To the suspension of trityl protected olmesartan medoxomil (50g, 0.06 mol) in 250 ml 75% acetic acid was stirred at 50-55°C for 1.5hrs and cooled to 5-10°C. The by-product trityl alcohol was filtered off and washed with 75% acetic acid. The filtrate was concentrated under vacuum to get syrup, which was crystallized using isopropyl alcohol.
Yield: 85-88%,
Purity by HPLC: 95-98%.
The material was further purified with ethyl methyl ketone. It was filtered and washed with ethyl methyl ketone and dried to give substantially pure olmesartan medoxomil.
Yield: 70-75%,
Purity by HPLC: 99.3-99.7%.
1H-NMR (CDCl3) δ: 7.81(dd, 1H), 7.43-7.6(m, 3H), 7.09d, 2H), 6.79(d, 2H), 5.41(s, 1H),4.95(s, 1H), 2.56(t, 3H), 2.17(s, 3H), 1.58-1.69(m, 2H), 1.58(s, 6H), 0.92(t,3H).
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