863031-21-4

Basic information

• Product Name: 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 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester
• Synonyms: 1H-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-, (5-Methyl-2-oxo-1,3-dioxol-4-yl)Methyl ester;Azilsaran medoxomil;(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-3-[[4-[2-(5-oxo-4H-1,2,4-+oxadiazol-3-yl)phenyl]phenyl]methyl]benzimidazole-4-carboxylate;1-[[2'-(2,5-Dihydro-5-oxo-1,2,4-oxadiazol-3-yl)[1,1'-biphenyl]-4-yl]methyl]-2-ethoxy-1H-benzim;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 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester;Azilsartan medoxomil;TAK 491;Azilsartan MedoxiMil
• CAS NO: 863031-21-4
• Molecular Formula: C₃₀H₂₄N₄O₈
• Molecular Weight: 568.53356
• EINECS: 1308068-626-2
• Product Categories: Inhibitors;Azilsartan Medoxomil
• Mol File: 863031-21-4.mol

Chemical Properties

• Appearance: /
• Density: 1.45
• Storage Temp.: Refrigerator
• Solubility: DMSO (Slightly), Methanol (Slightly, Heated, Sonicated)
• PKA: 6.99±0.20(Predicted)
• CAS DataBase Reference: 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 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester(CAS DataBase Reference)
• NIST Chemistry Reference: 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 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester(863031-21-4)
• EPA Substance Registry System: 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 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester(863031-21-4)

Safety Data

• Hazardous Substances Data: 863031-21-4(Hazardous Substances Data)

Usage

Uses

Used in Hypertension Treatment:
Azilsartan medoxomil is used as a long-acting angiotensin II receptor blocker (ARB) for lowering hypertension. It reduces blood pressure and decreases plasminogen activator inhibitor 1 (PAI-1) levels in the plasma, left ventricle, and aortic wall in a dose-dependent manner. It also inhibits the pressor response induced by angiotensin II in normotensive rats and improves glucose infusion, a marker of insulin sensitivity, in spontaneously hypertensive rats. Azilsartan medoxomil has been shown to have more potent antiproteinuric effects than other ARBs, such as olmesartan medoxomil, making it a valuable treatment option for hypertension.

Originator

Takeda (United States)

InChI:InChI:1S/C30H24N4O8/c1-3-38-28-31-23-10-6-9-22(27(35)39-16-24-17(2)40-30(37)41-24)25(23)34(28)15-18-11-13-19(14-12-18)20-7-4-5-8-21(20)26-32-29(36)42-33-26/h4-14H,3,15-16H2,1-2H3,(H,32,33,36)

Synthetic route

Carbonyldiimidazole (64269-79-0) + (5-methyl-2-oxo-2H-1,3-dioxol-4yl)methyl 2-ethoxy-1-[(4-(2-[N-hydroxy-carbamimidoyl]phenyl)phenyl)-methyl]-1H-1,3-benzodiazole-7-carboxylate (1449029-77-9) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
In dimethyl sulfoxide at 50℃; for 2h;	98.2%

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%

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(N'-{[(4-nitrophenoxy)carbonyl]oxy}carbamimidoyl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate (1449029-80-4) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
at 20 - 60℃; for 12h; Solvent; Temperature;	87%
With 2-methylpropyl acetate at 20 - 60℃; for 12h; Reagent/catalyst; Temperature;	87%

(5-methyl-2-oxo-2H-1,3-dioxol-4yl)methyl 2-ethoxy-1-[(4-(2-[N-hydroxy-carbamimidoyl]phenyl)phenyl)-methyl]-1H-1,3-benzodiazole-7-carboxylate (1449029-77-9) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
With di(succinimido) carbonate In ethyl acetate at 25 - 45℃; for 16h; Solvent; Reagent/catalyst; Temperature; Large scale;	82%
Multi-step reaction with 2 steps 1: triethylamine / dichloromethane / 1.5 h / 0 - 30 °C 2: 10 h / 20 - 115 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / dichloromethane; water / 1 h / 20 - 30 °C 2: 12 h / 20 - 60 °C View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / water; dichloromethane / 1 h / 20 - 30 °C 2: 2-methylpropyl acetate / 12 h / 20 - 60 °C View Scheme

(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) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
In water; acetone Reflux;	78%

(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2-ethoxy-1H-benzo[d]imidazol-7-carboxylate + 3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazol-5(4H)-one → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Stage #1: (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl-2-ethoxy-1H-benzo[d]imidazol-7-carboxylate In ethanol at 20℃; for 0.166667h; Stage #2: 3-(4'-(bromomethyl)-[1,1'-biphenyl]-2-yl)-1,2,4-oxadiazol-5(4H)-one With tetrabutylammomium bromide; potassium carbonate In ethanol at 40 - 50℃; for 10h; Reagent/catalyst; Temperature;	77.9%
With potassium carbonate; potassium iodide In dichloromethane Reflux;	72%

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 dicyclohexylamine salt → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Stage #1: 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 dicyclohexylamine salt at 23 - 28℃; for 0.5h; Stage #2: With 4-chloromethyl-5-methyl-1,3-dioxol-2-one; potassium iodide at 50℃; for 3h;	76%

1-[{2’-(2,5-dihydro-5-oxo-1,2,4-oxodiazol-3-yl)(1,1’-biphenyl)-4-yl}methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester potassium salt → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
In water at 50 - 55℃; for 2h;	55%

disodium 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate + 4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Stage #1: disodium 2-ethoxy-1-{[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate; 4-chloromethyl-5-methyl-1,3-dioxol-2-one In N,N-dimethyl-formamide at 20℃; for 12h; Stage #2: With hydrogenchloride In chloroform; water	14%

C32H21Cl3N4O6 + 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (91526-18-0) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
With dmap In dichloromethane at 20℃; for 4h;

4-chloromethyl-5-methyl-1,3-dioxol-2-one (80841-78-7) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: triethylamine; formic acid / acetonitrile / 10 - 65 °C 1.2: Reflux 2.1: dmap; potassium carbonate; p-toluoylsulfonylchloride / ISOPROPYLAMIDE / -15 - 25 °C 2.2: 0.5 h / pH 4 - 5 View Scheme

methyl 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxy-benzimidazole-7-carboxylate (139481-44-0) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Multi-step reaction with 4 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 4.1: dmap; potassium carbonate; p-toluoylsulfonylchloride / ISOPROPYLAMIDE / -15 - 25 °C 4.2: 0.5 h / pH 4 - 5 View Scheme
Multi-step reaction with 4 steps 1: hydroxylamine hydrochloride / dimethyl sulfoxide; water / 18 h / 90 °C 2: potassium carbonate / dimethyl sulfoxide / 4 h / 20 °C 3: sodium hydroxide; water / 3 h / 50 °C 4: potassium carbonate; p-toluenesulfonyl chloride; dmap / N,N-dimethyl acetamide / 3 h / 30 °C View Scheme
Multi-step reaction with 4 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 4: potassium carbonate; p-toluenesulfonyl chloride; dmap / N,N-dimethyl acetamide / 3 h / 30 °C View Scheme

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 medoxomil (863031-21-4)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide; water / 0.5 h / 50 - 55 °C 1.2: 0.5 h / 20 - 25 °C / pH 2 - 3 2.1: dmap; potassium carbonate; p-toluoylsulfonylchloride / ISOPROPYLAMIDE / -15 - 25 °C 2.2: 0.5 h / pH 4 - 5 View Scheme
Multi-step reaction with 2 steps 1: sodium hydroxide; water / 3 h / 50 °C 2: potassium carbonate; p-toluenesulfonyl chloride; dmap / N,N-dimethyl acetamide / 3 h / 30 °C View Scheme

methyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)-biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (147403-65-4) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Multi-step reaction with 3 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 3.1: dmap; potassium carbonate; p-toluoylsulfonylchloride / ISOPROPYLAMIDE / -15 - 25 °C 3.2: 0.5 h / pH 4 - 5 View Scheme
Multi-step reaction with 3 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / dimethyl sulfoxide / 4 h / 20 °C 2: sodium hydroxide; water / 3 h / 50 °C 3: potassium carbonate; p-toluenesulfonyl chloride; dmap / N,N-dimethyl acetamide / 3 h / 30 °C View Scheme
Multi-step reaction with 3 steps 1: potassium carbonate / dimethyl sulfoxide / 4 h / 20 °C 2: sodium hydroxide; water / 3 h / 50 °C 3: potassium carbonate; p-toluenesulfonyl chloride; dmap / N,N-dimethyl acetamide / 3 h / 30 °C View Scheme

ethyl 1-[(2'-cyano-[1,1']-biphenyl-4-yl)methyl]-2-ethoxy-1H-benzo[d]imidazole-7-carboxylate (139481-41-7) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Multi-step reaction with 4 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 4: potassium carbonate; p-toluenesulfonyl chloride; dmap / N,N-dimethyl acetamide / 3 h / 30 °C View Scheme

ethyl 2-ethoxy-1-((2′-(N′-hydroxycarbamimidoyl)biphenyl-4-yl)methyl)-1H-benzo[d]imidazole-7-carboxylate (1397836-41-7) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Multi-step reaction with 3 steps 1: dimethyl sulfoxide; methanol / 2 h / 20 - 25 °C 2: sodium hydroxide; water / 3 h / 50 °C 3: potassium carbonate; p-toluenesulfonyl chloride; dmap / N,N-dimethyl acetamide / 3 h / 30 °C View Scheme

4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (91526-18-0) + 4-Nitrobenzenesulfonyl chloride (98-74-8) + azilsartan (147403-03-0) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Stage #1: azilsartan With dmap; triethylamine In dichloromethane at 0 - 5℃; for 0.0833333h; Stage #2: 4-Nitrobenzenesulfonyl chloride In dichloromethane at 0 - 30℃; for 1h; Stage #3: 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one In N,N-dimethyl-formamide at 20 - 40℃; for 1h;	6.5 g

(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 (1427268-39-0) + 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one (91526-18-0) → Azilsartan medoxomil (863031-21-4)

Conditions	Yield
Stage #1: (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 In dichloromethane at 20 - 30℃; for 0.0833333h; Stage #2: 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one With dmap In dichloromethane at 20 - 45℃; for 2h;	5.1 g

Upstream product

• 80841-78-7 4-chloromethyl-5-methyl-1,3-dioxol-2-one 
• 91526-18-0 4-hydroxymethyl-5-methyl-[1,3]dioxol-2-one 
• 150058-27-8 2-ethoxy-1H-benzimidazole-7-carboxylic acid methyl ester 
• 114772-54-2 4'-(bromomethyl)-1,1'-biphenyl-2-carbonitrile 
• 64269-79-0 Carbonyldiimidazole 
• 1449029-77-9 (5-methyl-2-oxo-2H-1,3-dioxol-4yl)methyl 2-ethoxy-1-[(4-(2-[N-hydroxy-carbamimidoyl]phenyl)phenyl)-methyl]-1H-1,3-benzodiazole-7-carboxylate 
• 7693-46-1 4-Nitrophenyl chloroformate 
• 1403474-75-8 ethyl 2-ethoxy-1-((2'-(N'-((ethoxycarbonyl)oxy)carbamimidoyl)[biphenyl]-4-yl)methyl)-1H-benzoimidazole-7-carboxylate 
• 147403-03-0 azilsartan 
• 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 
• 1397836-41-7 2-ethoxy-3-[[2'-(N-hydroxycarbamimidoyl)biphenyl-4-yl]methyl]benzimidazole-4-carboxylic acid ethyl 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 
• 1449029-80-4 (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-{[2'-(N'-{[(4-nitrophenoxy)carbonyl]oxy}carbamimidoyl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylate 
• 1449029-78-0 (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl 2-ethoxy-1-[(2'-{N'-[(ethoxycarbonyl)oxy]carbamimidoyl}-biphenyl-4-yl)-methyl]-1H-benzimidazole-7-carboxylate 

Downstream Products

• 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 
• 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 
• 147403-03-0 azilsartan 

Relevant articles and documents

Polymorphs and solvatomorphs of azilsartan medoxomil: Elucidation of solvent-induced construction and conformational diversity

Two polymorphs (AM-A and AM-B) of azilsartan medoxomil (AM) and four AM solvatomorphs with toluene (AM-TOL), 1,4-dioxane (AM-DIO), chloroform (AM-TCM) and N,N-dimethylacetamide (AM-DMA) have been prepared by the hydrolysis of azilsartan medoxomil potassium in aqueous-organic solutions. In the crystal structures of two polymorphs and three solvatomorphs (AM-TOL, AM-DIO and AM-TCM), two asymmetric AM molecules form the dimeric cycle-like structures via intermolecular N[sbnd]H?N hydrogen bonds in R22 (26) ring, while AM-DMA shows intramolecular N[sbnd]H?O hydrogen bond between AM and DMA molecules. The hydrogen bonds (C[sbnd]H?O or C[sbnd]H?N) and π···π (or C[sbnd]H···π) interactions are helpful to stabilize the conformational diversity of AM. The solvent-induced experiment shows that solvent molecules have great influence on the solvatomorph formation and DIO can form the most steady solvatomorph than other solvents. The thermal study demonstrates that toluene molecules in three solvatomorphs (AM-TOL, AM-DIO and AM-TCM) are the most difficult to remove from the cage. Our results illustrate that the solvent plays significant role in tuning the size of the cage and producing the conformational diversity of AM molecules.

METHOD FOR PREPARING AZILSARTAN WITH ENVIRONMENT-FRIENDLY SOLVENT, AND KEY INTERMEDIATE COMPOUNDS THEREOF

The present invention relates to a method for preparing azilsartan medoxomil, including synthesizing azilsartan dihexylamine salt as a key intermediate through an efficient one-pot reaction, and synthesizing azilsartan medoxomil by means of an ionic liquid and a eutectic solvent as eco-friendly solvents. According to the present invention, cyclization and hydrolysis are carried out continuously in preparing azilsartan medoxomil to reduce the reaction time and to save the cost. Particularly, azilsartan dihexylamine salt as a key intermediate is synthesized through a one-pot reaction, and an ionic liquid and a eutectic solvent are used as eco-friendly solvents, instead of an organic solvent, and thus the reactivity is increased so that the reaction may be performed at a temperature of less than 50°C. In this manner, production of lead-containing materials is reduced, and high-purity and highly competitive azilsartan medoxomil can be produced with high yield in a large amount.

Preparation method of azilsartan kamedoxomil hydrate

The invention provides a preparation method of azilsartan kamedoxomil hydrate. The preparation method at least comprises the following steps: (1) performing the chlorination; (2) performing the esterification; (3) forming azilsartan kamedoxomil; and (4) forming the azilsartan kamedoxomil hydrate. The preparation method has the characteristics of simple operation, high yield, high purity and good stability, and is suitable for industrialized production.

Novel preparation method of azilsartan medoxomil sylvite and its intermediate

The invention relates to a novel preparation method of azilsartan medoxomil sylvite and its intermediate. The method comprises the following steps: hydrolyzing a starting material VII to obtain an intermediate IX, then performing esterification with a side chain IV to obtain the intermediate X; reducing the other starting material VIII by hydroxylamine hydrochloride to obtain the intermediate XI, then performing esterification with ethyl chloroformate to obtain the intermediate XII, and closing ring to obtain the intermediate XIII; performing condensation of the intermediate X and the intermediate XIII to obtain the intermediate II, and finally performing reaction with potassium isooctanoate to obtain the azilsartan medoxomil sylvite. The method has the advantages of easy acquisition of raw materials, short synthesis route, less equipment investment, less by-product, low toxicity, little pollution, environment protection, and high product purity, and is suitable for industrial production.

A method for preparing arab League Qi Shatan ester (by machine translation)

The invention relates to a method of synthesizing arab League Qi Shatan ester, the method to the 4 [...] -bromo methyl-2-cyano biphenyl as the raw material and then by the hydroxylamine compound II is prepared by cyclization; to 2-ethoxylbenzimidazole-7-carboxylic acid as raw materials to carry out the esterification reaction to make compound V, then utilize the compound prepared with compound II arab League Qi Shatan ester V reaction. The method of the present invention the synthetic route is short, the operation is simple, high yield, at the same time reduces the raw material 4 the [...] -bromomethyl-2-cyanobiphenyl consumption, the cost is reduced. (by machine translation)

arab League Qi Shatan ester or its salt synthetic method and intermediates thereof, and method for synthesizing intermediate (by machine translation)

The invention relates to the field of medicines and in particular relates to a synthesis method for azilsartan medoxomil or salt thereof, an intermediate of the azilsartan medoxomil or the salt thereof and a synthesis method for the intermediate. According to the novel method for the azilsartan medoxomil or the salt thereof, the problems of low synthesized azilsartan medoxomil yield and large number of byproducts are solved. Furthermore, the invention further provides a synthesis intermediate of the azilsartan medoxomil or the salt thereof and two preparation methods. In a synthesis process, an alcohol fragment of the azilsartan medoxomil is introduced at first, so that a part of the azilsartan medoxomil is formed, and a cyclization structure fragment is synthesized; therefore, the problem that the yield is reduced because of side reaction caused by active hydrogen in a carbonyldimidazole structure of an azilsartan acid structure is solved in a reaction process; the reaction yield is greatly improved, so that a finished product is easier to purify; the synthesis method is particularly suitable for industrial production.

PROCESS FOR THE PREPARATION OF AZILSARTAN MEDOXOMIL OR PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF

The present invention relates to a process for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof.

Commercial synthesis of azilsartan kamedoxomil: An angiotensin II receptor blocker

A commercially viable process for the preparation of azilsartan kamedoxomil, an angiotensin II receptor blocker, has been developed. The present work describes the novel synthesis of azilsartan medoxomil from amidoxime methyl ester. The present work also describes the improved synthesis of amidoxime methyl ester and azilsartan kamedoxomil. This process features a high overall yield (36%) with 99.52% HPLC purity.

NOVEL POLYMORPHS OF AZILSARTAN MEDOXOMIL

The present invention provides a novel amorphous Form of azilsartan acid, process for its preparation and pharmaceutical compositions comprising it. The present invention also provides novel crystalline Forms of azilsartan medoxomil, processes for their preparations and pharmaceutical compositions comprising them. The present invention further provides a novel amorphous Form of azilsartan medoxomil potassium, process for its preparation and pharmaceutical compositions comprising it. The present invention further provides a novel process for the preparation of azilsartan medoxomil potassium crystalline Form II.

NOVEL PROCESS FOR PREPARATION OF AZILSARTAN MEDOXOMIL

The present invention provides novel process for preparation of azilsartan medoxomil (II) comprising coupling of azilsartan (I) and 4-(hydroxymethyl)-5-methyl-1,3-dioxol-2-one (VII) in presence of carbonyl compound, R3COR4, wherein substituents R3 and R4 represent a heterocyclic ring selected from imidazole, benzimidazole, triazole; or in presence of carbodiimides and base wherein carbodiimide is selected from dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-[3-(dimethyl-amino) propyl]-N'- ethylcarbodiimide. The present invention further provides novel Form I of azilsartan kamedoxomil.