Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• the present invention relates to an improved process for the preparation of substantially pure compound of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol- 3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan) of Formula
• the present invention also provides an efficient, commercially viable and facile synthesis for the preparation of pure intermediates of Azilsartan using eco-friendly, cheaply available reagents and low boiling solvents.
• Azilsartan (I) is an angiotensin receptor II antagonist used in the treatment of hypertension.
• Angiotensin II causes vasoconstriction via an angiotensin II receptor on the cell membrane and elevates blood pressure.
• Azilsartan medoxomil i.e. (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-[[2'- (2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7- carboxylic acid is developed by Takeda pharmaceuticals and is marketed under the trade name Edarbi. It was approved by USFDA on 25 Feb, 2011 and EMEA on 7 Dec 2011 for the treatment of high blood pressure in adults.
• Azilsartan medoxomil and its salts thereof are imbibed with properties such as strong and long lasting angiotensin II antagonistic activity and hypotensive action which has an insulin sensitizing activity useful for the treatment of metabolic diseases such as diabetes and the like., and a useful agent for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac diseases, nephritis and stroke.
• Azilsartan medoxomil is the prodrug of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan).
• the amidoxime compound of formula III obtained by the above process contains about 50% of amide imputiy along with desired product, owing to the strong reaction conditions which impairs the quality and loss of yield.
• the pH adjustment with HC1 in the hydrolysis step of compound IV results in the formation of an undesired desethyl impurity of formula V due to acid sensitive nature of the ether linkage in the benzimidazole moiety of Azilsartan.
• Formula V According to another method disclosed in US'054 for the preparation of Azilsartan comprises by reacting ethoxycarboimidoyl biphenyl benzimidazole derivative of compound with ethyl chloroformate to give N-methoxycarbonyl ethoxycarboimidoyl biphenyl benzimidazole derivative, which is further converted to compound of formula IV and then to Azilsartan of formula I by hydrolysis.
• cyanobiphenyl aminobenzoate derivative compound reacts with hydroxylamine hydrochloride in presence of triethylamine subsequently followed by addition of ethyl chlorocarbonate results in the formation of compound of formula IV which is further hydrolyzed to obtain Azilsartan of formula I.
• This publication also discloses that use of a carbonyl source reduces the formation of the content of desethyl impurity during cyclization.
• the main objective of the present invention is to provide a simple, effective and industrially feasible process for the preparation of substantially pure 2-Ethoxy-l-[[2'- (2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7- carboxylic acid (Azilsartan) with good yields on commercial scale.
• the present invention relates to an improved process for the preparation of substantially pure 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl- 4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan) of the Formula I,
• the present invention relates to an improved process for the preparation of substantially pure 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl- 4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan) compound of Formula I.
• the reaction basically relates to the formation of compound of Formula I which includes reacting Methyl l-[(2'-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole- 7-carboxylate of formula II with hydroxylamine or its salts, preferably hydrochloride in presence of a suitable solvent and a phosphate salt to give compound of formula III.
• the solvent to be used include polar solvents such as dimethyl sulfoxide (DMSO), ⁇ , ⁇ -dimethyl formamide (DMF), ⁇ , ⁇ -dimethyl acetamide (DMAC), 1- methylpyrrolidone (NMP), 1, 1,3,3-tetramethylurea (TMU), 1,3-dimethylimidazolidin- 2-one (DMI), l,3-dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), hexamethylphosphoramide (HMPA), Acetonitrile (ACN), 1,4-dioxane, sulfolane, tetrahydrofuran (THF), water or mixtures thereof, or possibly mixtures with other solvents.
• polar solvents such as dimethyl sulfoxide (DMSO), ⁇ , ⁇ -dimethyl formamide (DMF), ⁇ , ⁇ -dimethyl acetamide (DMAC), 1- methylpyrrolidone (
• the phosphate salt is selected from monobasic and dibasic salts of ammonium, potassium, sodium such as dipotassium hydrogen phosphate, potassium dihydrogen phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, ammonium dihydrogen phosphate and so on, more preferably dipotassium hydrogen phosphate.
• the reaction is carried out at a temperature in the range of 70 to 90°C, preferably at a temperature in the range of 80 to 85°C.
• the reaction mixture is heated for a sufficiently long time in the range of 20 to 42 hours.
• Chlorinated solvents are selected from methylene dichloride, chloroform etc, preferably methylene dichloride and base is selected from an organic base such as triethylamine, tributylamine, N,N- diisopropylethyl amine etc., preferably triethylamine.
• Low boiling organic solvent in cyclization step is selected from acetone, ethyl acetate, isopropyl acetate, methanol, ethanol and so on, preferably ethyl acetate.
• Base is selected from carbonates, bicarbonates such as potassium carbonate, sodium carbonate, sodium bicarbonate etc., preferably potassium carbonate. Cyclization proceeds with ease in low boiling organic solvent in presence of a base. Usage of low boiling organic solvent results in the formation of desired compound with high yield and purity.
• Azilsartan obtained from the above step was treated with a mixture of organic solvents followed by an alcoholic solvent to provide substantially pure Azilsartan compound of formula I.
• the mixture of organic solvents may be polar protic, polar aprotic or non polar solvents selected from alcohols such as methanol, ethanol, butanol, IPA or ethers such as dioxane, THF or dipolar aprotic solvent such as DMF, DMAC, DMSO, NMP, sulfolane and chlorinated solvents such as methylene dichloride, chloroform and so on whereas one of the organic solvent in the mixture is selected from chlorinated solvent, preferably methylene dichloride.
• An alcoholic solvent is selected from methanol, ethanol, isopropanol, preferably methanol.
• Example-2 Preparation of Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4- oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (Formula-IV) :
• reaction mass was poured into water (200.0 mL), organic layer was separated and washed with 5% NaHC0 3 solution (150.0 mL) and then with water (150.0 mL). The organic layer was dried over sodium sulfate and distilled to obtain the crude material (optionally be isolated using cyclohexane solvent).
• ethyl acetate (750.0mL) and potassium carbonate (112.5g 0.814mol) were added and heated to reflux for 6 to 8 hours. The contents were cooled, filtered and wet solid was slurried in water.
• Example-3 Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)
• Example-4 Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)
• a mixture of 0.4N NaOH solution (633.33 mL) and Methyl 2-ethoxy-l-[[2'-(2,5- dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7- carboxylate (40.0g) were stirred at 50-55°C for period of 60min.
• reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (200.0mL). pH of the separated aqueous product layer was adjusted to 4.0 to 4.5 using acetic acid at 10-15°C. The obtained solid material was filtered and washed with water (lOO.OmL). This material was dried to obtain the title product.
• Example-5 Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)
• Example-6 Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)
• Example-7 Purification of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3- yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

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Citations (2)

• 2016
  • 2016-03-16 WO PCT/IB2016/051470 patent/WO2016147120A1/en not_active Ceased
  • 2016-03-16 IN IN1330CH2015 patent/IN2015CH01330A/en unknown

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