144689-63-4

Basic information

• Product Name: Olmesartan Medoxomil
• Synonyms: (5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-((2'-(1H-tetrazol-5-yl)-[1,1'-biphenyl] 4-yl)methyl)-4-(;OMST;OlMesartan MedoxoMil SynoyM:4-(1-Hydroxy-1-Methylethyl)-2-propyl-1-[[2'-(1H-tetazol-5-yl)[1,1'-biphenyl]-4-yl]Methyl]-1H-iMidazole-5-carboxylic acid (5-Methyl-2-oxo-1,3-dioxol-4-yl)Methyl ester;1H-Imidazole-5-carboxylic acid, 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-(2H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester;Olmesartan medoxomil for system suitability;Olmesartan MedoxomiI;Olmesartan Medoxomi;(5-Methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-((2'-(2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hyd
• CAS NO: 144689-63-4
• Molecular Formula: C₂₉H₃₀N₆O₆
• Molecular Weight: 558.585
• EINECS: 1308068-626-2
• Product Categories: API;OMNICEF;Cardiovascular APIs;Active Pharmaceutical Ingredients;Aromatics;Bases & Related Reagents;Heterocycles;Intermediates & Fine Chemicals;Nucleotides;Pharmaceuticals;Olmesartan;Inhibitor
• Mol File: 144689-63-4.mol
• Article Data: 49

Chemical Properties

• Melting Point: 180°C
• Boiling Point: 804.2 °C at 760 mmHg
• Flash Point: 180°C
• Appearance: white to beige/
• Density: 1.38 g/cm³
• Storage Temp.: -20°C Freezer
• Solubility: DMSO: soluble20mg/mL, clear
• PKA: 4.15±0.10(Predicted)
• CAS DataBase Reference: Olmesartan Medoxomil(CAS DataBase Reference)
• NIST Chemistry Reference: Olmesartan Medoxomil(144689-63-4)
• EPA Substance Registry System: Olmesartan Medoxomil(144689-63-4)

Safety Data

• RTECS: NI4014200
• Hazardous Substances Data: 144689-63-4(Hazardous Substances Data)

Usage

Description

Olmesartan medoxomil was launched in the US as benicar(R), an orally administered treatment for hypertension. Olmesartan, is a new selective and competitive nonpeptide angiotensin II type 1 receptor antagonist and potently inhibits the Ang.ll-induced pressor responses. The drug competitively inhibited binding of [125I1]-All to AT1 receptors in bovine adrenal cortical membranes, but had no effect on binding to AT2 receptors in bovine cerebellar membranes. In comparative clinical studies in patients with essential hypertension, olmesartan reduced sitting cuff diastolic blood pressure significantly more than losartan, valdesartan and ibesartan, while reductions in systolic blood pressure were similar for all treatments. Olmesartan medoxomil was also shown to reduce blood pressure significantly more effectively than losartan and the ACE inhibitor captopril and as effectively as the pbloker atenolol.

Chemical Properties

White to off-white crystalline powder

Originator

Sanky (Japan)

Uses

Olmesartan medoxomil is an angiotensin II receptor antagonist used to treat high blood pressure. Olmesartan works by blocking the binding of angiotensin II to the AT1 receptors in vascular muscle. By blocking the binding rather than the synthesis of angiotensin II, olmesartan inhibits the negative regulatory feedback on renin secretion. Olmesartan medoxomil is a pro-drug that is de-esterified to the active metabolite, olmesartan. Olmesartan has a dual method of elimination, with about 60% eliminated by the liver and the remainder by the kidney. In situations of impaired renal or hepatic function, the alternative excretion pathway can compensate for the compromised one. Olmesartan is not metabolized by the cytochrome P450 enzyme system and therefore has a low potential for metabolic drug interactions, a feature that may be of importance when treating patients on multiple drug regimens, such as the elderly. Olmesartan is well tolerated and has an excellent safety profile that is comparable to that of placebo. In addition, olmesartan provides 24-h blood pressure control with a once-daily dosing. In head-to-head studies, olmesartan delivered superior blood pressure reduction when compared with other angiotensin-II receptor antagonists at their recommended doses.

Brand name

Benicar

General Description

Olmesartan Medoxomil is a synthetic imidazole derivative prodrug with an antihypertensive property. Upon hydrolysis, olmesartan medoxomil is converted to olmesartan. Olmesartan selectively binds to the angiotensin type 1 (AT1) receptor of angiotensin II in vascular smooth muscle and adrenal gland, thereby competing angiotensin II binding to the receptor. This prevents angiotensin II-induced vasoconstriction and decreases aldosterone production, thereby preventing aldosterone-stimulated sodium retention and potassium excretion.

Biochem/physiol Actions

Olmesartan medoxomil is a selective Angiotensin II Type I receptor blocker and antihypertensive drug. Olmesartan medoxomil is converted enzymatically to the active form olmesartan.

Clinical Use

Angiotensin-II receptor antagonist: Hypertension

Side effects

Dizziness or lightheadedness may occur as your body adjusts to the medication. If any of these effects persist or worsen, tell your doctor or pharmacist promptly. To reduce the risk of dizziness and lightheadedness, get up slowly when rising from a sitting or lying position.

Synthesis

Olmesartan Medoxomil can be synthesized in 8 steps from diaminomaleonitrile by successive reactions with trialkylorthopropanoate to access 2-propyl-imidazole-45dicarbonitrile, conversion of the two nitrile functions to the corresponding ethyl esters, followed by methylmagnesium bromide addition to give the corresponding 4-(1-hydroxyalkyl)imidazole derivative. The imidazole ring of olmesartan (18) was constructed with diaminomaleonitrile 155 and trimethylorthobutyrate (156) in CH3CN then xylene to give 157 in 96% yield. Acid hydrolysis of 157 in 6N HCl gave the dicarboxylic acid intermediate. After esterification of the diacid in ethanol in the presence of HCl, diester 158 was treated with MeMgCl to give 4-(1-hydroxyalkyl) imidazole 159 in 95% yield. Alkylation of 159 with biphenyl bromide 160 in the presence of potassium tbutoxide afforded 161 in 80% yield. Ester 161 was then hydrolyzed to free carboxylic acid 162 under basic conditions, and 162 was treated with chloride 163 in the presence of K2CO3 to give ester 164 in 88% yield from 161.Lastly, the trityl group was removed with 25% aqueous acetic acid to give olmesartan (18) in 81% yield.

Drug interactions

Potentially hazardous interactions with other drugs Anaesthetics: enhanced hypotensive effect. Analgesics: antagonism of hypotensive effect and increased risk of renal impairment with NSAIDs; hyperkalaemia with ketorolac and other NSAIDs. Antihypertensives: increased risk of hyperkalaemia hypotension and renal impairment with ACE-Is and aliskiren. Ciclosporin: increased risk of hyperkalaemia and nephrotoxicity. Diuretics: enhanced hypotensive effect; hyperkalaemia with potassium-sparing diuretics. ESAs: increased risk of hyperkalaemia; antagonism of hypotensive effect. Lithium: reduced excretion (possibility of enhanced lithium toxicity). Potassium salts: increased risk of hyperkalaemia. Tacrolimus: increased risk of hyperkalaemia and nephrotoxicity.

Metabolism

Olmesartan medoxomil is an ester prodrug that is hydrolysed during absorption from the gastrointestinal tract to the active form olmesartan. It is excreted in the urine and the bile as olmesartan; about 35-50% of the absorbed dose is excreted in the urine and the remainder in the bile.

Synthetic route

trityl olmesartan medoxomil (144690-92-6) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With acetic acid In water at 25℃; for 1h;	100%
With hydrogenchloride In water; toluene at 20℃; for 2.5h;	98.6%
With TRILITE SCR-10 gel type In methanol for 6h; Product distribution / selectivity; Reflux;	94%

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 1-({2'-[1-(2,4-dimethoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)-4-(1-hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylate → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With trifluoroacetic acid In dichloromethane at 25℃; for 6h; Time;	98%

trityl olmesartan medoxomil (144690-92-6) → triphenylmethyl alcohol (76-84-6) + olmesartan medoxomil (144689-63-4)

Conditions	Yield
Stage #1: trityl olmesartan medoxomil With sulfuric acid; water In acetone at 40℃; for 2 - 4h; Stage #2: With sodium hydrogencarbonate at 20℃; for 1h;	A n/a B 90%
With water In acetone for 14h; Product distribution / selectivity; Heating / reflux;	A n/a B 73%
With water In acetonitrile for 14h; Product distribution / selectivity; Heating / reflux;	A n/a B 71%

4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) + ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate (172875-59-1) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Stage #1: ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate With sodium hydroxide In N,N-dimethyl acetamide at 10 - 15℃; for 8h; Stage #2: 4-chloromethyl-5-methyl-1,3-dioxol-2-one With potassium carbonate In N,N-dimethyl acetamide at 0 - 65℃; for 10h;	90%

trityl olmesartan medoxomil → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With hydrogenchloride In water; toluene at 20℃; for 3h;	89%

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-1-({2'-[1-(4-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)-2-propyl-1H-imidazole-5-carboxylate → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With trifluoroacetic acid at 25℃; for 72h; Temperature;	83%

(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate (1020157-01-0) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With acetic acid at 80℃; for 2.5h;	81%
With sulfuric acid In water; acetone at 50 - 55℃; for 2h;	80%
With acetic acid In water at 55 - 60℃; for 2 - 3h; Product distribution / selectivity;
With hydrogenchloride In methanol; dichloromethane at 0 - 5℃; for 1 - 2h;

ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-({2'-[1-(triphenylmethyl)-1H-1,2,3,4-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl}methyl)-1H-imidazole-5-carboxylate (144690-33-5) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
	71%
Multi-step reaction with 2 steps 1.1: diisopropylamine; sodium hydroxide / toluene; ISOPROPYLAMIDE / 4 h / 25 - 45 °C 1.2: 8 h / 40 - 70 °C 1.3: 25 - 35 °C / pH ~ 6 - 7 2.1: hydrogenchloride; water / methanol / 1 h / 0 - 35 °C 2.2: 25 - 35 °C / pH ~ 3 - 4 View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate; water / acetone / 16 h / 20 °C 2.1: potassium carbonate; potassium iodide / acetone / 3 h / 50 - 55 °C 3.1: hydrogenchloride; water / toluene / 3 h / 20 °C 3.2: 15 - 20 °C / pH 4.5 - 5.5 View Scheme

2-propyl-1H-imidazole-4,5-dicarboxylic acid (58954-23-7) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 6 steps 1: 86 percent / HCl / Ambient temperature 2: 95 percent / diethyl ether; CH2Cl2 / 1 h / 10 - 15 °C 3: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 4: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 5: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 6: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme

N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole (133051-88-4) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 2: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 3: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 4: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme
Multi-step reaction with 4 steps 1: potassium iodide; potassium carbonate / N,N-dimethyl-formamide / 24 h / 20 °C 2: potassium hydroxide; water / N,N-dimethyl-formamide / 22 h / 54 - 56 °C 3: potassium iodide; potassium carbonate / 20 °C 4: sulfuric acid / water; acetone / 2 h / 50 - 55 °C View Scheme

2-propyl-1H-imidazole-4, 5-diethyl azodicarboxylate (144689-94-1) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 5 steps 1: 95 percent / diethyl ether; CH2Cl2 / 1 h / 10 - 15 °C 2: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 3: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 4: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 5: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme

ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate (144689-93-0) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 4 steps 1: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 2: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 3: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 4: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / toluene / 0.75 h / 45 - 50 °C 1.2: 10 h / 60 - 70 °C 2.1: diisopropylamine; sodium hydroxide / toluene; ISOPROPYLAMIDE / 4 h / 25 - 45 °C 2.2: 8 h / 40 - 70 °C 2.3: 25 - 35 °C / pH ~ 6 - 7 3.1: hydrogenchloride; water / methanol / 1 h / 0 - 35 °C 3.2: 25 - 35 °C / pH ~ 3 - 4 View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / tetrabutylammomium bromide / acetone / 15 h / 50 - 55 °C 2.1: potassium carbonate; water / acetone / 16 h / 20 °C 3.1: potassium carbonate; potassium iodide / acetone / 3 h / 50 - 55 °C 4.1: hydrogenchloride; water / toluene / 3 h / 20 °C 4.2: 15 - 20 °C / pH 4.5 - 5.5 View Scheme

ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate (172875-59-1) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 2: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 3: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme
Multi-step reaction with 3 steps 1: potassium hydroxide; water / N,N-dimethyl-formamide / 22 h / 54 - 56 °C 2: potassium iodide; potassium carbonate / 20 °C 3: sulfuric acid / water; acetone / 2 h / 50 - 55 °C View Scheme

4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5yl]biphenyl-4-yl]methyl]imidazole-5-carboxylic acid lithium salt → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 2: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme

2-propylimidazole-4,5-dicarbonitrile (51802-42-7) → olmesartan medoxomil (144689-63-4)

Conditions

Yield

Multi-step reaction with 7 steps 1: 80 percent / 6N aq. HCl / 8 h / Heating 2: 86 percent / HCl / Ambient temperature 3: 95 percent / diethyl ether; CH2Cl2 / 1 h / 10 - 15 °C 4: 1.) t-BuOK / 1.) DMA, 0 deg C, 10 min, 2.) DMA, RT, 1 h 5: LiOH*H2O / dioxane; H2O / 20 h / Ambient temperature 6: 88 percent / K2CO3 / N,N-dimethyl-acetamide / 4 h / 20 - 50 °C 7: 81 percent / 25percent aq. AcOH / 2.5 h / 80 °C View Scheme

olmesartan medoxomil hydrobromide → olmesartan medoxomil (144689-63-4)

Conditions	Yield
With sodium hydrogencarbonate In water; acetone at 0 - 20℃; for 2 - 3h; pH=5.6; Product distribution / selectivity;

trityl olmesartan medoxomil (144690-92-6) + 4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Stage #1: trityl olmesartan medoxomil With hydrogenchloride; ethanol; water at 24 - 26℃; for 3h; Stage #2: 4-chloromethyl-5-methyl-1,3-dioxol-2-one With sodium hydroxide In ethanol; water for 0.25h; pH=5;

N-(triephenylmethyl)-5-<4'-(bromomethyl)-biphenyl-2-yl>tetrazole (124750-51-2) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: potassium carbonate / toluene / 0.75 h / 45 - 50 °C 1.2: 10 h / 60 - 70 °C 2.1: diisopropylamine; sodium hydroxide / toluene; ISOPROPYLAMIDE / 4 h / 25 - 45 °C 2.2: 8 h / 40 - 70 °C 2.3: 25 - 35 °C / pH ~ 6 - 7 3.1: hydrogenchloride; water / methanol / 1 h / 0 - 35 °C 3.2: 25 - 35 °C / pH ~ 3 - 4 View Scheme
Multi-step reaction with 4 steps 1.1: potassium carbonate / tetrabutylammomium bromide / acetone / 15 h / 50 - 55 °C 2.1: potassium carbonate; water / acetone / 16 h / 20 °C 3.1: potassium carbonate; potassium iodide / acetone / 3 h / 50 - 55 °C 4.1: hydrogenchloride; water / toluene / 3 h / 20 °C 4.2: 15 - 20 °C / pH 4.5 - 5.5 View Scheme
Multi-step reaction with 3 steps 1.1: potassium tert-butylate / dimethyl sulfoxide; acetone / 2.5 h / 0 - 5 °C / Reflux 2.1: sodium hydroxide / dimethyl sulfoxide; tetrahydrofuran / 2 h / 17 - 60 °C 2.2: 2.5 h / 70 °C 3.1: hydrogenchloride / acetonitrile; water / 2 h / 5 °C 3.2: pH 5.7 View Scheme

potassium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate (936114-12-4) + 4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 2 steps 1: potassium carbonate; potassium iodide / N,N-dimethyl acetamide / 3 h / 0 - 45 °C 2: hydrogenchloride; water / methanol; ethyl acetate / 2 h / 20 °C View Scheme

benzoyl chloride (98-88-4) → olmesartan medoxomil (144689-63-4)

Conditions

Yield

Multi-step reaction with 10 steps 1.1: triethylamine / tetrahydrofuran / 3 h / 2 - 35 °C 2.1: phosphorus pentachloride / dichloromethane / 3 h / -15 - 21 °C 2.2: 4.5 h / -8 - 30 °C 3.1: triphenylphosphine; potassium carbonate; potassium bis(2-ethyl-n-hexyl)phosphate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 / 1-methyl-pyrrolidin-2-one / 8.5 h / 138 - 140 °C / Inert atmosphere 4.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 5.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 6.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 7.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 8.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 9.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 9.2: 12 h / 45 - 50 °C 10.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme

N-benzylbenzamide (1485-70-7) → olmesartan medoxomil (144689-63-4)

Conditions

Yield

Multi-step reaction with 9 steps 1.1: phosphorus pentachloride / dichloromethane / 3 h / -15 - 21 °C 1.2: 4.5 h / -8 - 30 °C 2.1: triphenylphosphine; potassium carbonate; potassium bis(2-ethyl-n-hexyl)phosphate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 / 1-methyl-pyrrolidin-2-one / 8.5 h / 138 - 140 °C / Inert atmosphere 3.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 4.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 5.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 6.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 7.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 8.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 8.2: 12 h / 45 - 50 °C 9.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme

1-benzyl-5-phenyl-1H-tetrazole (28386-90-5) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: triphenylphosphine; potassium carbonate; potassium bis(2-ethyl-n-hexyl)phosphate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 / 1-methyl-pyrrolidin-2-one / 8.5 h / 138 - 140 °C / Inert atmosphere 2.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 3.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 4.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 5.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 6.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 7.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 7.2: 12 h / 45 - 50 °C 8.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 8 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 138 - 140 °C / Inert atmosphere 2: acetic acid; hydrogen bromide / 18 h / 0 - 30 °C 3: potassium carbonate / acetonitrile / 18 h / 84 °C 4: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 5: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 6: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 7: potassium iodide / butanone / 20 h / 50 °C 8: acetic acid / water / 1 h / 25 °C View Scheme
Multi-step reaction with 8 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 12 h / 138 °C / Inert atmosphere 2: 2,2'-azobis(isobutyronitrile); 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione / ethyl acetate / 6 h / Reflux 3: potassium carbonate / acetonitrile / 18 h / 84 °C 4: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 5: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 6: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 7: potassium iodide / butanone / 20 h / 50 °C 8: acetic acid / water / 1 h / 25 °C View Scheme

4-bromobenzyl benzoate (38612-13-4) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 8 steps 1.1: triphenylphosphine; potassium carbonate; potassium bis(2-ethyl-n-hexyl)phosphate; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 / 1-methyl-pyrrolidin-2-one / 8.5 h / 138 - 140 °C / Inert atmosphere 2.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 3.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 4.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 5.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 6.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 7.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 7.2: 12 h / 45 - 50 °C 8.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 8 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 138 - 140 °C / Inert atmosphere 2: acetic acid; hydrogen bromide / 18 h / 0 - 30 °C 3: potassium carbonate / acetonitrile / 18 h / 84 °C 4: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 5: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 6: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 7: potassium iodide / butanone / 20 h / 50 °C 8: acetic acid / water / 1 h / 25 °C View Scheme

{2'-(1-benzyl-1H-tetrazol-5-yl)-[1,1'-biphenyl]-4-yl}methyl benzoate → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: hydrogen bromide / acetic acid / 18.25 h / 0 - 30 °C 2.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 3.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 4.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 5.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 6.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 6.2: 12 h / 45 - 50 °C 7.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 7 steps 1: acetic acid; hydrogen bromide / 18 h / 0 - 30 °C 2: potassium carbonate / acetonitrile / 18 h / 84 °C 3: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 4: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 5: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 6: potassium iodide / butanone / 20 h / 50 °C 7: acetic acid / water / 1 h / 25 °C View Scheme

1-benzyl-5-[4'-(bromomethyl)biphenyl-2-yl]-1H-tetrazole → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: potassium carbonate; tetrabutylammomium bromide / acetone / 20.25 h / 0 - 45 °C 2.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 3.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 4.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 5.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 5.2: 12 h / 45 - 50 °C 6.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 6 steps 1: potassium carbonate / acetonitrile / 18 h / 84 °C 2: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 3: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 4: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 5: potassium iodide / butanone / 20 h / 50 °C 6: acetic acid / water / 1 h / 25 °C View Scheme

ethyl 4-(1-hydroxy-1-methylethyl)-1-({2′-[1-(phenylmethyl)-1H-tetrazol-5-yl][1,1′-biphenyl]-4-yl}methyl)-2-propyl-1H-imidazole-5-carboxylate → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: ammonium formate; 5% palladium on barium sulphate / isopropyl alcohol; water / 12 h / 55 - 60 °C 2.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 3.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 4.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 4.2: 12 h / 45 - 50 °C 5.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 5 steps 1: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 2: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 3: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 4: potassium iodide / butanone / 20 h / 50 °C 5: acetic acid / water / 1 h / 25 °C View Scheme

ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (144689-23-6) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: triethylamine / dichloromethane / 15.5 h / 0 - 30 °C 2.1: potassium hydroxide; water / acetone / 5.25 h / 0 - 45 °C 3.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 3.2: 12 h / 45 - 50 °C 4.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 2: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 3: potassium iodide / butanone / 20 h / 50 °C 4: acetic acid / water / 1 h / 25 °C View Scheme

potassium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate (936114-12-4) → olmesartan medoxomil (144689-63-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium carbonate; potassium iodide / acetone / 0.17 h / 25 - 30 °C 1.2: 12 h / 45 - 50 °C 2.1: sulfuric acid / acetic acid; water / 1 h / 25 - 30 °C View Scheme
Multi-step reaction with 2 steps 1: potassium iodide / butanone / 20 h / 50 °C 2: acetic acid / water / 1 h / 25 °C View Scheme

para-bromotoluene (106-38-7) → olmesartan medoxomil (144689-63-4)

Conditions

Yield

Multi-step reaction with 8 steps 1: triphenylphosphine; potassium carbonate; [RhCl2(p-cymene)]2; potassium bis(2-ethyl-n-hexyl)phosphate / 1-methyl-pyrrolidin-2-one / 12 h / 138 °C / Inert atmosphere 2: 2,2'-azobis(isobutyronitrile); 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione / ethyl acetate / 6 h / Reflux 3: potassium carbonate / acetonitrile / 18 h / 84 °C 4: 5% palladium on barium sulphate; sodium formate / water; isopropyl alcohol / 4 h / 55 °C 5: triethylamine / dichloromethane / 4.5 h / 0 - 25 °C 6: potassium hydroxide / isopropyl alcohol / 4 h / 40 °C 7: potassium iodide / butanone / 20 h / 50 °C 8: acetic acid / water / 1 h / 25 °C View Scheme

olmesartan medoxomil (144689-63-4) → 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylic acid dipotassium salt

Conditions	Yield
With water; sodium hydroxide In methanol at 20℃; for 24h;	96%

olmesartan medoxomil (144689-63-4) → olmesartan

Conditions	Yield
With sodium hydroxide In methanol; water at 20 - 30℃; for 20h;	90%
In water for 24h; Reflux;	88%
With water for 24h; Reflux;	88%
With Bis(p-nitrophenyl) phosphate In dimethyl sulfoxide; acetonitrile at 37℃; for 0.0333333h; pH=7.4; Reagent/catalyst; Enzymatic reaction;

methanol (67-56-1) + olmesartan medoxomil (144689-63-4) → 4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-tetrazol-5-yl) phenyl}phenylmethylimidazole-5-carboxylic acid (1039762-40-7)

Conditions	Yield
for 24h; Reflux;	85%
for 24h; Reflux;	85%
for 24h; Reflux;	85%

p-methoxybenzyl chloride (824-94-2) + olmesartan medoxomil (144689-63-4) → (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 4-(1-hydroxy-1-methylethyl)-1-({2'-[1-(4-methoxybenzyl)-1H-tetrazol-5-yl]biphenyl-4-yl}methyl)-2-propyl-1H-imidazole-5-carboxylate

Conditions	Yield
With tetrabutylammomium bromide; sodium carbonate In chloroform; water at 10 - 55℃; for 11h;	20.6%

olmesartan medoxomil (144689-63-4) → olmesartan medoxomil hemihydrate

Conditions	Yield
With water In dimethyl sulfoxide at 20℃;

olmesartan medoxomil (144689-63-4) → (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl1-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)-4-(prop-1-en-2-yl)-2-propyl-1H-imidazole-5-carboxylate (879562-26-2)

Conditions	Yield
Stage #1: olmesartan medoxomil With sulfuric acid In ISOPROPYLAMIDE at 100℃; for 2.5h; Inert atmosphere; Stage #2: With sodium hydroxide In dichloromethane; ISOPROPYLAMIDE; water at 40℃; pH=4.2;

olmesartan medoxomil (144689-63-4) → 4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-tetrazol-5-yl) phenyl}phenylmethylimidazole-5-carboxylic acid (1039762-40-7)

Conditions	Yield
Multi-step reaction with 2 steps 1: water / 24 h / Reflux 2: 24 h / Reflux View Scheme
Multi-step reaction with 2 steps 1: water / 24 h / Reflux 2: 24 h / Reflux View Scheme

olmesartan medoxomil (144689-63-4) → 4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-tetrazol-5-yl) phenyl}phenylmethylimidazole-5-carboxylic acid (1039762-40-7) + olmesartan methyl ester

Conditions	Yield
Multi-step reaction with 2 steps 1: water / 24 h / Reflux 2: triphenylphosphine; di-isopropyl azodicarboxylate / dichloromethane / 5 h / 20 °C View Scheme

Upstream product

• 133051-88-4 N-(triphenylmethyl)-5-<4'-(bromomethyl)biphenyl-2-yl>tetrazole 
• 144689-93-0 ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylate 
• 144689-94-1 diethyl 2-(n-propyl)-1H-imidazole-4,5-dicarboxylate 
• 58954-23-7 2-propyl-1H-imidazole-4,5-dicarboxylic acid 
• 1020157-01-0 (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2′-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate 
• 124750-51-2 N-(triephenylmethyl)-5-<4'-(bromomethyl)-biphenyl-2-yl>tetrazole 
• 144690-33-5 ethyl 4-(2-hydroxypropan-2-yl)-2-propyl-1-({2'-[1-(triphenylmethyl)-1H-1,2,3,4-tetrazol-5-yl]-[1,1'-biphenyl]-4-yl}methyl)-1H-imidazole-5-carboxylate 
• 144690-92-6 trityl olmesartan medoxomil 
• 51802-42-7 2-propylimidazole-4,5-dicarbonitrile 
• 172875-59-1 ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl]methyl-1H-imidazole-5-carboxylate 
• 936114-12-4 potassium 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[[2'-[1-(triphenylmethyl)-1H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole-5-carboxylate 
• 144689-23-6 ethyl 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate 
• 38612-13-4 4-bromobenzyl benzoate 
• 28386-90-5 5-benzyl-1-phenyl-1H-tetrazole 

Downstream Products

• 1039762-40-7 4-(1-methoxy-1-methylethyl)-2-propyl-1-{4-(2-tetrazol-5-yl) phenyl}phenylmethylimidazole-5-carboxylic acid 
• 172875-98-8 1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(prop-1-en-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid 
• 879562-26-2 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl1-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)-4-(prop-1-en-2-yl)-2-propyl-1H-imidazole-5-carboxylate 
• 752179-89-8 1-((2'-(2-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl)-4-(2-hydroxypropan-2-yl)-2-propyl-1H-imidazole-5-carboxylic acid 

Relevant articles and documents

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

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).

Preparation method of high purity olmesartan medoxomi I

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.

A olmesartan medoxomil and its preparation method (by machine translation)

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)