147403-03-0

Basic information

• Product Name: Azilsartan
• Synonyms: AZILSARTAN;2-Ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid;Tak 536;Unii-F9nux55p23;2-ethoxy-3-((2'-(5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)Methyl)-3H-benzo[d]iMidazole-4-carboxylic acid;Azilsartan 2-Ethoxy-1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]Methyl]benziMidazole-7-carboxylic acid;1-[[2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]Methyl]-2-ethoxy-1H-benziMidazole-7-carboxylic Acid;Azilsartan (TAK-536)
• CAS NO: 147403-03-0
• Molecular Formula: C₂₅H₂₀N₄O₅
• Molecular Weight: 456.45
• EINECS: 1308068-626-2
• Product Categories: Aromatics;Heterocycles;Intermediates & Fine Chemicals;Pharmaceuticals;Intermediates
• Mol File: 147403-03-0.mol

Chemical Properties

• Melting Point: 188 °C(dec.)
• Appearance: white to beige/
• Density: 1.42
• Storage Temp.: 2-8°C
• Solubility: DMSO: soluble15mg/mL (clear solution)
• PKA: 2.05±0.10(Predicted)
• CAS DataBase Reference: Azilsartan(CAS DataBase Reference)
• NIST Chemistry Reference: Azilsartan(147403-03-0)
• EPA Substance Registry System: Azilsartan(147403-03-0)

Safety Data

• WGK Germany: 3
• Hazardous Substances Data: 147403-03-0(Hazardous Substances Data)

Usage

Uses

Used in Pharmaceutical Industry:
Azilsartan is used as an antihypertensive agent for the treatment of high blood pressure (hypertension). It functions as an angiotensin II receptor blocker (ARB), which helps in relaxing the blood vessels, thus lowering blood pressure and increasing the supply of blood and oxygen to the heart.
Used in Cardiovascular Applications:
Azilsartan is used as an analgesic and anti-inflammatory drug containing angiotensin II antagonists. It is particularly effective in reducing the maximal contractile response induced by angiotensin II in isolated rabbit aortic strips and inhibiting the angiotensin II-induced pressor response in conscious normotensive rats.
Used in Angiotensin II Receptor Antagonism:
Azilsartan is used as an angiotensin II type 1 (AT1) receptor antagonist with an IC50 of 2.6 nM. It is effective in blocking the angiotensin II-induced accumulation of inositol-1-phosphate in COS-7 cells expressing recombinant human AT1, making it a potent antagonist in this context.

Pharmacokinetics

Azilsartan differs structurally from candesartan only by replacement of candesartan’s five-membered tetrazole ring with a five-membered oxo-oxadiazole ring. Azilsartan is formulated as an ester prodrug, azilsartan medoxomil, which is rapidly hydrolysed to the bioactive molecule during gastrointestinal absorption. It produces dose-dependent reductions in vascular smooth muscle contraction, peripheral resistance, and the synthesis and effects of aldosterone on the kidneys. Azilsartan has a half-life of about 11 hours and is metabolized in the liver mainly via CYP2C9 and is eliminated in both the urine and feces.

Mechanism of Action

Edarbi, a prodrug, is hydrolyzed to azilsartan in the gastrointestinal tract during absorption. Azilsartan is a selective AT1 subtype angiotensin II receptor antagonist. Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzymes (ACE, kinase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Azilsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the AT1 receptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is, therefore, independent of the pathway for angiotensin II synthesis.

Biological Activity

Potent angiotensin II type 1 (AT1) receptor inverse agonist (IC50 = 2.6 nM at the human AT1 receptor). Inhibits angiotensin II-induced IP1 accumulation in COS-7 cells; decreases maximal contraction of rabbit aortic strips in a concentration-dependent manner (pD'2 = 9.9). Antihypertensive; prevents vascular cell proliferation and expression of PAI-1.

Side Effects

Overall, azilsartan is well-tolerated in most patients in terms of adverse effects. In a controlled, double-blind, randomized clinical trial comparing the efficacy of azilsartan medoxomil to the ACE inhibitor ramipril in 784 patients, the overall number of adverse events was reported to be much less frequent with azilsartan. During the treatment period, dizziness and hypotension occurred more often with the azilsartan treatment groups, and cough, a class side effect commonly encountered with ACE inhibitors, occurred more frequently with the ramipril group (8.2% of participants). Cough only occurred in 1% and 1.4% of azilsartan 40 and 80 mg groups, respectively. Another effect observed in the azilsartan group was a pertinent increase in serum potassium, sodium, and uric acid; no deaths resulted from this effect or the aforementioned adverse effects as well.

Clinical Use

Azilsartan is an orally active angiotensin II blocker which was approved and launched in Japan for the treatment of arterial hypertension in May 2012. Azilsartan, which is marketed under the trade name Azilva?, was discovered and developed by Takeda—the same firm which had developed and launched a prodrug of azilsartan (azilsartan kamedoxomil, Edarbi?) in 2010. Azilsartan exhibits higher potency and slower off-rate kinetics for type 1 angiotensin II receptors, which contributes to azilsartan’s comparatively improved blood pressure lowering effect.

Synthesis

The most likely process-scale synthetic route likely mimics that which is disclosed in Takeda’s patents, and this is described in the scheme below. Commercial available benzoic acid 21 was activated as the correspndong acyl azide and underwent a Curtius rearrangement to give carbamate 22 in 57% yield (three steps from compound 21). The resulting aniline 22 was then alkylated with commercial 4- (bromomethyl)-2'-cyanobiphenyl 23 to give benzylamine 24 in 85% yield. Nitroamine 24 was then exposed to mildly acidic conditions to affect Boc-removal prior to reduction via ferric chloride hydrate in the presence of hydrazine hydrate. The resulting diamine 25 arose in 64% yield across the two-step sequence. Interestingly, tt was found that metal catalysts under conventional hydrogenation conditions caused partial debenzylation, which led the authors to arrive at the hydrazine/ferric chloride conditions. Next, benzimidazole formation was achieved upon treatment of diamine 25 with ethyl orthocarbonate in acetic acid. The resulting ethoxylbenzimidazole 26 was procured in 86% yield, and this benzonitrile was further reacted with hydroxylamine hydrochloride and sodium methoxide to provide amidoxime 27 in 90% as white powder. Next, activation with ethyl chlorocarbonate gave 28 followed by heating in refluxing xylene to give oxadiazolone 29 in 23% yield from hydroxyamidine 27. Finally ester 29 was saponified with 2N LiOH in methanol to give azilsartan (V) in 84% yield. An improved scalable route (Scheme below) to azilsartan was reported and features reproducibly better yields.43 Hydroxyamidine 30 was treated with dimethyl carbonate and sodium methoxide, which triggered they key cyclization along with concomitant transesterification to deliver 29. Milder aqueous sodium hydroxide hydrolysis converted this methyl ester 29 to azilsartan (V) in 88-90% yield.

Synthetic route

ethyl ester of 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]-imidazole-7-carboxylic acid (1403474-70-3) → azilsartan (147403-03-0)

Conditions	Yield
With water; sodium hydroxide at 50℃; for 4h;	98.5%
With sodium hydroxide In water at 70 - 75℃; for 1.5h; Temperature;	93.4%
With pyrographite; sodium hydroxide In water at 55℃; for 2h; Temperature;	91%

C25H19N4O5(1-)*Na(1+) → azilsartan (147403-03-0)

Conditions	Yield
With citric acid In water at 5℃; pH=5; Reagent/catalyst;	97.1%

methyl 2-ethoxy-1-((2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]-imidazole-7-carboxylate (147403-52-9) → azilsartan (147403-03-0)

Conditions	Yield
Stage #1: methyl 2-ethoxy-1-((2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]-imidazole-7-carboxylate With water; sodium hydroxide In methanol at 20℃; for 24h; Stage #2: With hydrogenchloride In water Product distribution / selectivity;	96.4%
With sodium hydroxide In methanol; water at 20℃; for 24h;	96%
With sodium hydroxide In water at 60 - 65℃; Temperature;	96.8%

C25H19N4O5(1-)*K(1+) → azilsartan (147403-03-0)

Conditions	Yield
With citric acid In water at 5℃; pH=5; Reagent/catalyst;	96.7%

0.36N-NaOH + pyrographite (7440-44-0) + methyl 2-ethoxy-1-((2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]-imidazole-7-carboxylate (147403-52-9) → azilsartan (147403-03-0)

Conditions	Yield
	96%

0.40N-NaOH + pyrographite (7440-44-0) + methyl 2-ethoxy-1-((2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]-imidazole-7-carboxylate (147403-52-9) → azilsartan (147403-03-0)

Conditions	Yield
	96%

C25H19N4O5(1-)*Li(1+) → azilsartan (147403-03-0)

Conditions	Yield
With citric acid In water at 5℃; pH=5; Reagent/catalyst;	95.8%

Azilsartan medoxomil (863031-21-4) → azilsartan (147403-03-0)

Conditions	Yield
With water; sodium hydroxide at 75℃; for 1h; Temperature; Reagent/catalyst;	94.84%
With Bis(p-nitrophenyl) phosphate In acetonitrile at 37℃; for 0.0833333h; pH=7.4; Kinetics; Reagent/catalyst; Enzymatic reaction;

2-ethoxy-1-[[2′-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid ethyl ester di-n-butylamine → azilsartan (147403-03-0)

Conditions	Yield
With water; sodium hydroxide In ethanol at 45 - 56℃; for 2.5h;	93%

C28H28N4O5 → azilsartan (147403-03-0)

Conditions	Yield
With sodium hydroxide In tetrahydrofuran; water at 40 - 50℃; for 1h; Reagent/catalyst;	92.8%

ethyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (1397836-41-7) + chloroformic acid ethyl ester (541-41-3) → azilsartan (147403-03-0)

Conditions	Yield
Stage #1: ethyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate; chloroformic acid ethyl ester With triethylamine In toluene at 30℃; for 2h; Stage #2: With dmap; water In toluene for 3h; Reflux;	89%

2-ethoxy-1-[[2'-[N'((ethoxycarbonyl)oxy)carbamimidoyl][1,1-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid methyl ester (147404-82-8) → azilsartan (147403-03-0)

Conditions	Yield
With sodium hydroxide In water at 40℃; for 2h; Reagent/catalyst; Temperature;	87%
Multi-step reaction with 2 steps 1.1: xylene / 1.5 h / Reflux 2.1: sodium hydroxide; water / 1.5 h / 70 °C 2.2: pH 3 View Scheme
Multi-step reaction with 2 steps 1: xylene / 1.5 h / Reflux 2: sodium hydroxide; water / methanol / 24 h / 20 °C View Scheme

methyl 2-ethoxy-1-((2'-(N'-(phenoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (1403477-44-0) → azilsartan (147403-03-0)

Conditions	Yield
With water; sodium hydroxide at 100℃; for 3h; Reagent/catalyst;	84%
Multi-step reaction with 2 steps 1.1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 1 h / 20 °C 2.1: sodium hydroxide; water / 1.5 h / 70 °C 2.2: pH 3 View Scheme
Multi-step reaction with 2 steps 1: potassium carbonate / 1-methyl-pyrrolidin-2-one / 2 h / 20 °C 2: sodium hydroxide / water; methanol / 24 h / 20 °C View Scheme

1-[(2'-(N'-hydroxycarbamimidoyl)[1,1'-biphenyl]-4-yl)methyl]-2-ethoxy-1H-1,3-benzodiazole-7-carboxylic acid (1397836-49-5) + phenyl chloroformate (1885-14-9) → azilsartan (147403-03-0)

Conditions	Yield
With sodium hydroxide In water at 100℃; for 3h; Reagent/catalyst; Solvent;	82%

1-[(2'-(N'-hydroxycarbamimidoyl)[1,1'-biphenyl]-4-yl)methyl]-2-ethoxy-1H-1,3-benzodiazole-7-carboxylic acid (1397836-49-5) + methyl chloroformate (79-22-1) → azilsartan (147403-03-0)

Conditions	Yield
With sodium hydroxide In water at 100℃; for 3h;	80%

carbonic acid dimethyl ester (616-38-6) + methyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (147403-65-4) → azilsartan (147403-03-0)

Conditions	Yield
Stage #1: carbonic acid dimethyl ester; methyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate With potassium tert-butylate In dimethyl sulfoxide at 100℃; for 4h; Stage #2: With hydrogenchloride In water; dimethyl sulfoxide Product distribution / selectivity;	78.9%

1-[(2'-(N'-hydroxycarbamimidoyl)[1,1'-biphenyl]-4-yl)methyl]-2-ethoxy-1H-1,3-benzodiazole-7-carboxylic acid (1397836-49-5) + isopropyl chloroformate (108-23-6) → azilsartan (147403-03-0)

Conditions	Yield
With sodium hydroxide In water at 100℃; for 3h;	78%

carbon dioxide (124-38-9) + C24H19BrN4O3 → azilsartan (147403-03-0)

Conditions	Yield
With n-butyllithium In tetrahydrofuran at -70℃; Inert atmosphere;	71%

methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylate (139481-44-0) → azilsartan (147403-03-0)

Conditions	Yield
Multi-step reaction with 4 steps 1: 55 percent / hydroxylamine / dimethylsulfoxide / 15 h / 75 °C 2: pyridine / dimethylformamide / 0.5 h / 0 °C 3: xylene / 2 h / Heating 4: 94 percent / 0.4 N aq. NaOH / 1.5 h / 70 °C View Scheme
Multi-step reaction with 3 steps 1.1: hydroxylamine hydrochloride; sodium hydrogencarbonate / dimethyl sulfoxide / 18 h / 25 - 90 °C 2.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran / 20 - 25 °C 3.1: sodium hydroxide; water / 0.5 h / 50 - 55 °C 3.2: 0.5 h / 20 - 25 °C / pH 2 - 3 View Scheme
Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride / dimethyl sulfoxide; water / 18 h / 90 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / dimethyl sulfoxide / 4 h / 20 °C 3: sodium hydroxide; water / 3 h / 50 °C View Scheme

methyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (147403-65-4) → azilsartan (147403-03-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: pyridine / dimethylformamide / 0.5 h / 0 °C 2: xylene / 2 h / Heating 3: 94 percent / 0.4 N aq. NaOH / 1.5 h / 70 °C View Scheme
Multi-step reaction with 2 steps 1.1: 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran / 20 - 25 °C 2.1: sodium hydroxide; water / 0.5 h / 50 - 55 °C 2.2: 0.5 h / 20 - 25 °C / pH 2 - 3 View Scheme
Multi-step reaction with 3 steps 1.1: triethylamine / dichloromethane; tetrahydrofuran / 2 h / 20 °C / Cooling with water-ice 2.1: xylene / 1.5 h / Reflux 3.1: sodium hydroxide; water / 1.5 h / 70 °C 3.2: pH 3 View Scheme

C34H40N4O6 → azilsartan (147403-03-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: xylene / 2 h / Heating 2: 94 percent / 0.4 N aq. NaOH / 1.5 h / 70 °C View Scheme
Multi-step reaction with 2 steps 1.1: xylene / 2 h / Reflux 2.1: sodium hydroxide; water / 1.5 h / 70 °C 2.2: pH 3 View Scheme
Multi-step reaction with 2 steps 1: xylene / 2 h / Reflux 2: sodium hydroxide; water / methanol / 24 h / 20 °C View Scheme

chloroformic acid ethyl ester (541-41-3) + methyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (147403-65-4) → azilsartan (147403-03-0)

Conditions	Yield
Stage #1: chloroformic acid ethyl ester; methyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate With pyridine In N,N-dimethyl-formamide for 6h; Inert atmosphere; Cooling with ice-cold bath; Stage #2: With potassium tert-butylate In dimethyl sulfoxide at 20℃; for 5h; Stage #3: With hydrogenchloride In water; dimethyl sulfoxide

methyl 2-ethoxy-1-((2'-(N'-(methoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (1403477-45-1) → azilsartan (147403-03-0)

Conditions	Yield
With sodium methylate In tetrahydrofuran at 20℃; for 4h;	71.2 %Chromat.
Multi-step reaction with 2 steps 1.1: sodium methylate / 1-methyl-pyrrolidin-2-one / 4 h / 20 °C 2.1: sodium hydroxide; water / 1.5 h / 70 °C 2.2: pH 3 View Scheme
Multi-step reaction with 2 steps 1.1: potassium tert-butylate / 1-methyl-pyrrolidin-2-one / 4 h / 20 °C 2.1: pyridine / N,N-dimethyl-formamide / 6 h / Inert atmosphere; Cooling with ice-cold bath 2.2: 5 h / 20 °C View Scheme

methyl 2-ethoxy-1-((2'-(N'-(methoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (1403477-45-1) → azilsartan (147403-03-0) + methyl 2-ethoxy-1-((2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]-imidazole-7-carboxylate (147403-52-9)

Conditions	Yield
With sodium methylate In 1-methyl-pyrrolidin-2-one at 20℃; for 4h;	A 11.3 %Chromat. B 72.7 %Chromat.
With sodium methylate In dimethyl sulfoxide at 20℃; for 4h;	A 77.9 %Chromat. B 17.1 %Chromat.

methyl 2-ethoxy-1-((2'-(N'-(methoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (1403477-45-1) → methyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (147403-65-4) + azilsartan (147403-03-0)

Conditions	Yield
With potassium tert-butylate In 1-methyl-pyrrolidin-2-one at 20℃; for 4h; Product distribution / selectivity;	A 7.9 %Chromat. B 74.8 %Chromat.

ethyl 2-ethoxy-1-((2'-(N'-((ethoxycarbonyl)oxy)carbamimidoyl)[biphenyl]-4-yl)methyl)-1H-benzoimidazole-7-carboxylate (1403474-75-8) → azilsartan (147403-03-0)

Conditions	Yield
With sodium ethanolate In tetrahydrofuran at 20℃; for 4h;	66 %Chromat.
With potassium tert-butylate In tetrahydrofuran at 20℃; for 4h; Product distribution / selectivity;	93 %Chromat.
Multi-step reaction with 2 steps 1: dibutylamine / 2 h / 110 - 115 °C 2: sodium hydroxide; water / 1.5 h / 70 - 75 °C View Scheme
Multi-step reaction with 2 steps 1: isopropyl alcohol / 80 °C 2: pyrographite; sodium hydroxide / water / 2 h / 55 °C View Scheme

ethyl 2-ethoxy-1-((2'-(N'-((ethoxycarbonyl)oxy)carbamimidoyl)[biphenyl]-4-yl)methyl)-1H-benzoimidazole-7-carboxylate (1403474-75-8) → ethyl ester of 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]-imidazole-7-carboxylic acid (1403474-70-3) + azilsartan (147403-03-0)

Conditions	Yield
With sodium ethanolate In dimethyl sulfoxide at 20℃; for 4h; Product distribution / selectivity;	A 39.3 %Chromat. B 55.3 %Chromat.

ethyl 1-[(2'-cyano-[1,1']-biphenyl-4-yl)methyl]-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (139481-41-7) → azilsartan (147403-03-0)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydroxylamine hydrochloride / dimethyl sulfoxide; water / 15 h / 90 °C 2: dimethyl sulfoxide; methanol / 2 h / 20 - 25 °C 3: sodium hydroxide; water / 3 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine; hydroxylamine hydrochloride / dimethyl sulfoxide / 12 h / 75 °C 2: 1,8-diazabicyclo[5.4.0]undec-7-ene / tetrahydrofuran / 2 h / 20 °C 3: sodium hydroxide / 75 °C View Scheme
Multi-step reaction with 4 steps 1: triethylamine; hydroxylamine / ethanol; water / 7 h 2: triethylamine / dichloromethane / 2 h / 20 °C 3: ethanol / 15 h / Reflux 4: sodium hydroxide / ethanol / 1.6 h / 73 - 75 °C View Scheme

ethyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (1397836-41-7) → azilsartan (147403-03-0)

Conditions	Yield
Multi-step reaction with 2 steps 1: dimethyl sulfoxide; methanol / 2 h / 20 - 25 °C 2: sodium hydroxide; water / 3 h / 50 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: ethanol / 15 h / Reflux 3: sodium hydroxide / ethanol / 1.6 h / 73 - 75 °C View Scheme
Multi-step reaction with 3 steps 1: triethylamine / dichloromethane / 2 h / 20 °C 2: ethanol / 15 h / Reflux 3: sodium hydroxide / ethanol / 1.6 h / 73 - 75 °C View Scheme

azilsartan (147403-03-0) → 1-[[2'-(carbamimidoyl)[1,1'-biphenyl]-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid

Conditions	Yield
With palladium on activated charcoal; ammonium formate; acetic acid In ethanol at 80℃; for 5h; Inert atmosphere;	96%

4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (91526-18-0) + azilsartan (147403-03-0) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Stage #1: 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one; azilsartan With dmap; potassium carbonate; p-toluenesulfonyl chloride In N,N-dimethyl acetamide at 10℃; for 3h; Stage #2: In N,N-dimethyl acetamide pH=5; Stage #3: In water; acetone at 35℃; for 2h;	95%
Stage #1: 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one; azilsartan With dmap; p-toluoylsulfonylchloride; potassium carbonate In ISOPROPYLAMIDE at -15 - 25℃; Stage #2: With hydrogenchloride In ISOPROPYLAMIDE; water for 0.5h; pH=4 - 5;	81%
With dmap; potassium carbonate; p-toluenesulfonyl chloride In N,N-dimethyl acetamide at 8 - 10℃; for 3h;	80.1%

3-(hydroxymethyl)-4-phenylfuroxan (135733-30-1) + azilsartan (147403-03-0) → 3-(4-phenyl-1,2,5-oxadiazole-2-oxide-3-)methyl-2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

Conditions	Yield
With dmap; triethylamine; p-toluenesulfonyl chloride In dichloromethane at 20℃; for 5h; Reagent/catalyst; Solvent; Temperature;	94%
With dmap; potassium carbonate; p-toluenesulfonyl chloride In N,N-dimethyl-formamide at 10℃; for 3h;

N,N-dimethyl acetamide (127-19-5) + 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (91526-18-0) + azilsartan (147403-03-0) → (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester of 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid dimethylacetamide (1417575-99-5)

Conditions	Yield
With dmap; potassium carbonate; p-toluenesulfonyl chloride at 30℃; for 3h; Cooling;	86.4%

4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) + azilsartan (147403-03-0) → C35H28N4O11

Conditions	Yield
With sodium carbonate; sodium iodide In N,N-dimethyl acetamide at 35℃; for 3h; Reagent/catalyst; Solvent;	85.9%

4-bromomethyl-1,3-dioxa-5-methylcyclopentene-2-one (80715-22-6) + azilsartan (147403-03-0) → C35H28N4O11

Conditions	Yield
With potassium carbonate In N,N-dimethyl-formamide at 60℃; for 6h;	83%

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl iodide (80841-79-8) + azilsartan (147403-03-0) → C35H28N4O11

Conditions	Yield
With sodium carbonate In tetrahydrofuran at 70 - 80℃; for 6h; Reagent/catalyst; Solvent;	78.4%

azilsartan (147403-03-0) → 2-oxo-3-((2’-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid

Conditions	Yield
With hydrogenchloride In ethanol; water at 20℃; for 3h; pH=2;	60%
With hydrogen bromide In ethanol at 78 - 85℃; for 1h;

tetrahydrofuran (109-99-9) + 2-methylimidazole (693-98-1) + azilsartan (147403-03-0) → C25H20N4O5*C4H6N2*C4H8O

Conditions	Yield
In water at 20℃; for 2h;	45%

azilsartan (147403-03-0) + 2-oxo-4-hydroxymethyl-3-methyl-1,2,5-oxadiazol (183537-57-7) → 4-(3-methyl-1,2,5-oxadiazole-2-oxide-3-)methyl-2-ethoxy-1-{[2’-(5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate

Conditions	Yield
With dmap; potassium carbonate; p-toluenesulfonyl chloride In N,N-dimethyl-formamide at 20℃; for 3h;	44.4%
With dmap; potassium carbonate; p-toluenesulfonyl chloride In N,N-dimethyl-formamide at 20℃; for 3h;	44.4%

2-methylimidazole (693-98-1) + acetone (67-64-1) + azilsartan (147403-03-0) → C25H20N4O5*C4H6N2*C3H6O

Conditions	Yield
In water at 20℃; for 2h;	44%

Upstream product

• 147403-52-9 methyl 2-ethoxy-1-((2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]-imidazole-7-carboxylate 
• 139481-44-0 methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylate 
• 541-41-3 chloroformic acid ethyl ester 
• 147403-65-4 methyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate 
• 1403477-45-1 methyl 2-ethoxy-1-((2'-(N'-(methoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate 
• 1403474-75-8 ethyl 2-ethoxy-1-((2'-(N'-((ethoxycarbonyl)oxy)carbamimidoyl)[biphenyl]-4-yl)methyl)-1H-benzoimidazole-7-carboxylate 
• 1403477-44-0 methyl 2-ethoxy-1-((2'-(N'-(phenoxycarbonyloxy)carbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate 
• 147404-82-8 2-ethoxy-1-[[2'-[N'((ethoxycarbonyl)oxy)carbamimidoyl][1,1-biphenyl]-4-yl]methyl]-1H-benzimidazole-7-carboxylic acid methyl ester 
• 616-38-6 carbonic acid dimethyl ester 
• 1403474-70-3 ethyl ester of 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]-imidazole-7-carboxylic acid 
• 1397836-41-7 2-ethoxy-3-[[2'-(N-hydroxycarbamimidoyl)biphenyl-4-yl]methyl]benzimidazole-4-carboxylic acid ethyl ester 
• 863031-21-4 Azilsartan medoxomil 
• 114772-54-2 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile 
• 1397836-41-7 ethyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate 

Downstream Products

• 863031-21-4 Azilsartan medoxomil 
• 1309776-70-2 choline 1-[[2'-(4,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-2-ethoxy-1H-benzimidazol-7-carboxylate 
• 1309776-68-8 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxyl acid ethanolamine salt 
• 1417576-00-1 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-oxo-3-((2’-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylate 
• 1417576-01-2 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-((2′-(4-ethyl-5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate 
• 1427268-39-0 (2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazol-7-yl)-carboxyl-4-nitrophenyl sulfonate 
• 1417575-99-5 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester of 1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid dimethylacetamide 

Relevant articles and documents

Liquid chromatography/tandem mass spectrometry study of forced degradation of azilsartan medoxomil potassium

Rationale Azilsartan medoxomil potassium (AZM) is a new antihypertensive drug introduced in the year 2011. The presence of degradation products not only affects the quality, but also the safety aspects of the drug. Thus, it is essential to develop an efficient analytical method which could be useful to selectively separate and identify the degradation products of azilsartan medoxomil potassium. Methods AZM was subjected to forced degradation under hydrolytic (acid, base and neutral), oxidative, photolytic and thermal stress conditions. Separation of the drug and degradation products was achieved by a liquid chromatography (LC) method using an Acquity UPLC C18 CSH column with mobile phase consisting of 0.02% trifluoroacetic acid and acetonitrile using a gradient method. Identification and characterization of the degradation products was carried out using LC/electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-QTOFMS). Results A total of five degradation products (DP 1 to DP 5) were formed under various stress conditions and their structures were proposed with the help of tandem mass spectrometry (MS/MS) experiments and accurate mass data. A common degradation product (DP 4) was observed under all the degradation conditions. DP 1, DP 2 and DP 5 were observed under acid hydrolytic conditions whereas DP 3 was observed under alkaline conditions. Conclusions AZM was found to degrade under hydrolytic, oxidative and photolytic stress conditions. The structures of all the degradation products were proposed. The degradation pathway for the formation of degradation products was also hypothesized. A selective method was developed to quantify the drug in the presence of degradation products which is useful to monitor the quality of AZM.

AZILSARTAN ALKYL ESTER, METHOD FOR PRODUCING AZILSARTAN METHYL ESTER, AND METHOD FOR PRODUCING AZILSARTAN

PROBLEM TO BE SOLVED: To provide azilsartan alkyl ester to be an intermediate of azilsartan, and a method for producing azilsartan methyl ester having a novel crystal form, and a method for producing high-purity azilsartan from an obtained compound. SOLUTION: The present invention provides a method for producing high-purity azilsartan alkyl ester and/or azilsartan methyl ester by crystallizing azilsartan alkyl ester and/or azilsartan methyl ester in acetone or a solvent mixture of acetone and alcohol. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2021,JPOandINPIT

Synthesis technology for continuously preparing azilsartan in micro-channel reactor

The invention discloses a synthesis technology for continuously preparing azilsartan in a micro-channel reactor. The technology comprises the following steps: (1) adding SM-1, an aqueous hydroxylaminesolution and triethylamine into anhydrous ethanol, and performing a reaction to obtain an intermediate TAK1; (2) preparing a homogeneous solution A from the TAK1, triethylamine and dioxane; (3) preparing a homogeneous solution B from solid phosgene and dioxane; (4) dissolving sodium hydroxide in water to prepare a homogeneous solution C; (5) respectively pumping the homogeneous solution A and thehomogeneous solution B into a microstructure mixer I in a micro-channel reaction device at the same time, performing mixing, and introducing the obtained mixed solution into a microstructure reactorI; (6) respectively pumping the homogeneous solution C and the effluent of the microstructure reactor I into a microstructure mixer II in the micro-channel reaction device at the same time while step(5) is carried out, performing mixing, and introducing the obtained mixed solution into a microstructure reactor II; and (7) collecting the effluent of the microstructure reactor II to obtain the product azilsartan.

Azilsartan synthesis process

The invention provides an azilsartan synthesis process which is characterized by comprising the following steps: dissolving hydroxylamine hydrochloride into dimethyl sulfoxide, adding sodium bicarbonate at 20-25 DEG C, increasing the temperature to 45-55 DEG C, performing stirring for 45-60 minutes, further adding AQST-SM, increasing the temperature to 80-85 DEG C, and performing a temperature-keeping reaction for 20-22 hours so as to obtain AQST-1; dissolving the AQST-1 into tetrahydrofuran, dropping DBU (diazabicyclo) at 20-25 DEG C, further adding carbonyl diazole, and performing a reactionfor 1.5-2.5 hours at 20-25 DEG C so as to obtain AQST-3; mixing the AQST-3 with a sodium hydroxide solution, increasing the temperature to 70-75 DEG C, and performing a temperature-keeping reaction for 1-2 hours so as to obtain a crude product of AQST; and adding methanol into the crude product of AQST, increasing the temperature to 60-65 DEG C, performing pulping for 45-50 minutes, reducing thetemperature to the room temperature, performing filtering, bleaching filter cakes by using methanol, performing suction filtration till dryness, and performing vacuum drying, so as to obtain an AQST product. By adopting the azilsartan synthesis process provided by the invention, the AQST product is prepared, the yield is high, the content of AQST is high, the content of impurities is low, the quality of the AQST product is remarkably improved, and the azilsartan synthesis process is well applied to production of high-quality azilsartan tablets.

MANUFACTURING METHOD OF AZILSARTAN FINE CRYSTAL

PROBLEM TO BE SOLVED: To provide a manufacturing method of Azilsartan fine crystal industrially. SOLUTION: A manufacturing method of fine particle powder of Azilsartan crystal form A shown in a general formula (I) includes a step separating crystal of Azilsartan by dropping acid water solution at 0-60°C after adding alcohol and water in alkalinity process liquid after hydrolysis of Azilsartan ester shown in a general formula (IV) or Azilsartan ester amine salt shown in a general formula (V) corresponding to it or Azilsartan ester salt shown in a general formula (VI). SELECTED DRAWING: None COPYRIGHT: (C)2020,JPOandINPIT

High-purity, small-particle-diameter and low-solvent-residue azilsartan bulk drug and preparation method thereof

The present invention discloses a high-purity, small-particle-diameter and low-solvent-residue azilsartan bulk drug and a preparation method thereof. The purity of the azilsartan bulk drug is more than or equal to 99.9%; the particle size of D90 is less than or equal to 20 [mu]m; and the solvent residue is less than or equal to 500 ppm. The present invention also discloses a high-purity intermediate used for preparing the azilsartan bulk drug and a preparation method thereof, wherein the purity of the intermediate is more than or equal to 99.9%.

Novel preparation method of azilsartan

The invention relates to a novel preparation method of azilsartan with relatively high yield and relatively high purity. A multi-refining or column chromatography method is not needed, in addition, the final yield reduction can not be caused. According to the preparation route provided by the application, the contents of an impurity A and an impurity B can be effectively reduced, the refining frequency is reduced, and the yield is also increased.

A method for preparing [...]

The invention relates to an azilsartan (a hypertension treating medicine) preparation method, and belongs to the field of medicines. The method has the beneficial effects that a compound 1 serves as an initial raw material of the reaction, the azilsartan is prepared through three reaction steps of hydroxylammonium chloride addition, ethyl chloroformate acylation and cyclization hydrolysis under the alkali action, and the cyclization and hydrolysis reaction steps of the prior art are combined into one step, so that conventional 4-5 steps are reduced to three steps, and the reaction time is shortened; and the yield is increased, the content of ethyoxyl-removing impurities is greatly reduced, experimental operations are simplified, the cost is lowered, the azilsartan with high purity is obtained, the high performance liquid chromatography (HPLC) purity is more than 99.5%, and the ethyoxyl and amide-removing impurities are all less than 0.1%.

Method for simply and conveniently synthesizing azilsartan

The invention relates to the field of medicine, and discloses a method for simply and conveniently synthesizing azilsartan. According to the method, 1-[(2'-(hydroxyl guanyl)[1,1-biphenyl]-4-radical) methyl]-2-ethoxylated-1H-benzimidazole-7-methyl formate is mixed with a carbonylation reagent, water serves as a solvent, and reaction is performed at 25 DEG C to obtain O-acylation intermediate; the O-acylation intermediate is mixed with an alkaline reagent, water serves as a solvent, reflux reaction is carried out at 100 DEG C, filtration is carried out, 1mol/L of diluted hydrochloric acid is used for adjusting the pH value to 3-4, suction filtration is carried out, and the solvent is recrystallized to obtain the azilsartan. The method for simply and conveniently synthesizing the azilsartan has the advantages that two steps of reactions of cyclization and hydrolyzation are combined into one step under the alkali action, the azilsartan is obtained with two steps in an aqueous phase, the synthesis steps are reduced, the operation is simple and convenient, and the water is used as the solvent, so that method has very high industrial application value.

Method for greenly and efficiently synthesizing azilsartan in water phase

The invention relates to a method for greenly and efficiently synthesizing azilsartan in water phase, belonging to the field of medicines. The method comprises the following steps: by taking water asa solvent and 1-[(2'-hydroxyamidino)[1,1-biphenyl]-4-yl]-2-ethoxyl-1H-benzimidazole-7-methyl formate and carbonylation reagent as starting raw materials, performing one-step reaction under base interaction to synthesize azilsartan. Esterification, cyclization and hydrolysis reactions are simplified into one step, so that the reaction time is extremely shortened, the reaction yield is increased, and the purity of the product is high. By taking water as a reactive solvent, the defects of the prior art that an organic solvent is high in toxicity, production is insafe and the like can be overcome,and a simple and efficient green synthesis method is provided for synthesis of azilsartan.