WO2012139535A1 - A method of preparing 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-1h-benzo[d]imidazole-7-carboxylates and conversion thereof to azilsartan - Google Patents

A method of preparing 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-1h-benzo[d]imidazole-7-carboxylates and conversion thereof to azilsartan Download PDF

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Publication number
WO2012139535A1
WO2012139535A1 PCT/CZ2012/000030 CZ2012000030W WO2012139535A1 WO 2012139535 A1 WO2012139535 A1 WO 2012139535A1 CZ 2012000030 W CZ2012000030 W CZ 2012000030W WO 2012139535 A1 WO2012139535 A1 WO 2012139535A1
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formula
methyl
azilsartan
alkyl
solvent
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PCT/CZ2012/000030
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English (en)
French (fr)
Inventor
Stanislav Radl
Jan Stach
Original Assignee
Zentiva, K.S.
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Priority to HU1300733A priority Critical patent/HU230577B1/hu
Publication of WO2012139535A1 publication Critical patent/WO2012139535A1/en

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the invention relates to an improved method of preparing alkyl 2-ethoxy- l-((2'-(5-oxo-4,5- dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzo[i/]imidazole-7-carboxylates of formula I,
  • R is either a branched or unbranched Ci-C 4 alkyl, ArCH 2 , Ar 2 CH, or Ar 3 C, wherein Ar is a substituted or unsubstituted phenyl, and conversion thereof to azilsartan of formula II.
  • This compound is an efficient angiotensin II ATI receptor antagonist, which is used in the form of the prodrug azilsartan medoxomil of formula III in the treatment of hypertension.
  • Azilsartan of formula II is prepared, according to the published patents (US 5,583, 141 and EP 0 520 423) from the starting methyl l-((2'-cyanobiphenyl-4-yl)methyl)-2-ethoxy-lH- benzo[i ]imidazole-7-carboxylate of formula IVa.
  • This compound which is a well-known intermediate of synthesis of candesartan, is first converted, by reaction with hydroxylamine generated in situ from hydroxylamine hydrochloride, to methyl 2-ethoxy-l-((2'- ((hydroxyamino)iminomethyl)biphenyl-4-yl)methyl)-lH-benzo[ii
  • the invention relates to efficient, basically initiated cyclization of N-[(alkoxycarbonyl]- oxyjimidamides of formula VI,
  • This cyclization is carried out under more moderate conditions than the previously known thermal methods and minimizes production of impurities.
  • the compounds of formula VI are subsequently hydrolyzed to azilsartan of formula II or its salts.
  • the cyclization and hydrolysis can be done in one reaction step; such an arrangement makes the entire process more efficient.
  • the invention relates to an improved method of preparing alkyl 2-ethoxy- l -((2'-(5-oxo-4,5- dihydro-l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)-lH-benzo[c ]irnidazole-7-carboxylates of formula I,
  • R is either a branched or unbranched C 1 -C4 alkyl, ArC3 ⁇ 4, Ar 2 CH, or Ar 3 C, wherein Ar is a substituted or unsubstituted phenyl; in a preferable embodiment, R being methyl, ethyl or benzyl; in which method the corresponding alkoxycarbonyl derivatives of formula VI,
  • R' is a branched or unbranched, substituted or unsubstituted Ci-C 8 alkyl or substituted or unsubstituted phenyl, are cyclized by means of a base in a suitable solvent.
  • a suitable solvent may include a polar aprotic solvent selected from the group of dimethyl sulfoxide (DMSO), N,N-dimethyl formamide (DMF), N,N-dimethyl acetamide (DMAc), 1 - methyl pyrrolidone (NMP), 1 , 1 ,3,3-tetramethyl urea (TMU), 1 ,3 -dimethyl imidazolidin-2-one (DMI), l ,3-dimethyl-3 ,4,5,6-tetrahydro-2(lH)-pyrimidinone (DMPU), or hexamethyl phosphoramide (HMPA), preferably DMSO.
  • DMSO dimethyl sulfoxide
  • DMF N,N-di
  • the cyclization is carried out at a temperature in the range from_0 °C to the boiling point of the solvent used.
  • the present method is performed by processing the reaction mixture by dilution with water or by pouring of the reaction mixture into water, acidification and subsequent isolation of the insoluble product by filtration or centrifugation.
  • the purification method of the compounds of formula I, obtained by the present method is carried out by crystallization from suitable solvents, including alcohols, e.g. methanol, ethanol, isopropanol, esters of aliphatic acids, e.g. methyl acetate, ethyl acetate, isopropyl acetate, amides, e.g. yV,N-dimethyl formamide, N,N- dimethyl acetamide, 1 -methyl pyrrolidone, ethers, e.g. dioxan, 1 ,2-dimethoxyethane, 1 - methoxy-2-(2-methoxyethoxy)ethane, or mixtures of these solvents.
  • suitable solvents including alcohols, e.g. methanol,
  • Another object of the invention provides use of alkyl 2-ethoxy- l -((2'-(5-oxo-4,5-dihydro- l ,2,4-oxadiazol-3-yl)biphenyl-4-yl)methyl)- l H-benzo[i/]imidazole-7-carboxylates of formula I, wherein R is either a branched or unbranched C i -C 4 alkyl, ArC3 ⁇ 4, Ar 2 CH, or Ar 3 C, wherein Ar is a substituted or unsubstituted phenyl, for the preparation of azilsartan of formula II,
  • Another object provides a method of preparing azilsartan of formula II, consisting in basically initiated cyclization of the corresponding alkoxycarbonyl derivatives of formula VI
  • Preferable solvents that can be used in the method of preparing azilsartan of formula II include a dipolar aprotic solvent, most preferably DMSO or NMP.
  • Bases used include at least two molar equivalents of an alkali metal alcoholate R"OM, wherein R" is a branched or unbranched C 1 -C8 alkyl and M is an alkali metal.
  • the cyclization and conversion to the salt of azilsartan are carried out at a temperature from 0°C to the boiling point of the mixture, preferably at a temperature of 20 to 25°C.
  • Another embodiment includes carrying the method of preparing azilsartan of formula II, consisting in basically initiated cyclization of the corresponding alkoxycarbonyl derivatives of formula VI, out in one reaction step, i.e., performing the basically initiated cyclization of alkoxycarbonyl derivatives of formula VI by stirring a solution of the starting compounds in a suitable solvent, preferably in a dipolar aprotic solvent, most preferably in DMSO, in the presence of at least two molar equivalents of an alkali metal alcoholate R"OM, wherein R" is a branched or unbranched C 1 -C8 alkyl and M is an alkali metal, at a temperature in the range from 0°C to the boiling point of the solvent used, preferably at a temperature of 0°C to 50°C, most preferably at the room temperature.
  • the method of purification the compounds of formula II is carried out by crystallization from suitable solvents, including alcohols, e.g. methanol, ethanol, isopropanol, esters of aliphatic acids, e.g. methyl acetate, ethyl acetate, isopropyl acetate, amides, e.g. N,7V-dimefhyl formamide, /V-dimefhyl acetamide, 1 -methyl pyrrolidone, ethers, e.g. dioxan, 1 ,2- dimethoxyethane, l -methoxy-2-(2-methoxyethoxy)ethane, or mixtures of these solvents.
  • suitable solvents including alcohols, e.g. methanol, ethanol, isopropanol, esters of aliphatic acids, e.g. methyl acetate, ethyl acetate, isopropyl acetate,
  • R is a branched or unbranched Ci-C 4 alkyl, ArCH 2 , Ar 2 CH, or Ar 3 C, wherein Ar is a substituted or unsubstituted phenyl and R' is a branched or unbranched substituted or unsubstituted C ⁇ -C $ alkyl or a substituted or unsubstituted phenyl.
  • These starting substances are readily obtainable by reaction of the starting amidoximes of formula V with the corresponding alkyl chloroformate under conventional conditions, as previously described for the reaction of the amidoxime (Va) with alkyl chloroformates having, as R', methyl, ethyl, or 3-ethylhexyl.
  • compounds of formula V are formed under the above mentioned conditions. If the reaction was performed in alcohols, in particular in methanol or ethanol, the corresponding compounds of formula (V) were even the main products of the reaction. If the secondary products of formula V are contained as minority ones, they can be easily removed from the reaction mixture with regard to their considerable basicity either during the processing, which consists in pouring into water and subsequent acidification, or they can be removed by washing of the product with diluted acids on a filter, or by dissolution in a suitable solvent and shaking with diluted acids. A considerable reduction of formation of substances of formula V is achieved when weaker bases are used, e.g. potash. The reaction occurs at the room temperature, but it can also be performed at an elevated temperature.
  • alkali metal alcoholates are used in suitable solvents, e.g. in DMSO, NMP, THF, and other solvents, it is not only the cyclization to the corresponding esters of formula I that occurs, but the corresponding alkali metal salts of azilsartan are also produced, which are directly converted to azilsartan by processing with acidification.
  • basically initiated cyclization of N-[(alkoxycarbonyl]-oxy]imidamides of formula VI can be directly carried out to azilsartan, thus achieving shortening of the reaction sequence by one reaction step.
  • the use of t-BuOK in DMSO, NMP, or other solvents is the most - preferable, thus obtaining high yields of azilsartan as after reacting at the room temperature for several hours.
  • the reaction mixture was poured into a separation funnel containing water (150 ml) and the mixture was extracted with ethyl acetate (5 x 100 ml). The extract was dried with MgS0 4 and, after evaporation, 12.7 g of a solid yellowish substance were obtained. The evaporation residue was dissolved in DMSO (200 ml) and t- BuOK (8 g, 71.3 mmol) was added under stirring and cooling and the mixture was stirred at the room temperature for 5 h. Then, the reaction mixture was poured into water (750 ml) and the resulting solution was acidified with 5 % HCl. The separated product was aspirated, washed with water and air-dried.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
PCT/CZ2012/000030 2011-04-11 2012-04-04 A method of preparing 2-ethoxy-1-((2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl- 4-yl)methyl)-1h-benzo[d]imidazole-7-carboxylates and conversion thereof to azilsartan WO2012139535A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
HU1300733A HU230577B1 (hu) 2011-04-11 2012-04-04 Eljárás 2-etoxi-1-((2'-(5-oxo-4,5-dihidro-1,2,4-oxadiazol-3-il)-bifenil-4-il)-metil)-1H-benzol[d]imidazol7-karboxilátok előállítására és ezek átalakítása azilsartanná

Applications Claiming Priority (2)

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CZ20110208A CZ303505B6 (cs) 2011-04-11 2011-04-11 Zpusob výroby 2-ethoxy-1-((2´-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)bifenyl-4-yl)methyl)-1H-benzo[d]imidazol-7-karboxylátu a jejich prevedení na azilsartan
CZPV2011-208 2011-04-11

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Cited By (7)

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CN103044412A (zh) * 2012-12-26 2013-04-17 华润赛科药业有限责任公司 一种阿齐沙坦的多晶型及其制备方法
CN103254188A (zh) * 2013-05-22 2013-08-21 黄冈鲁班药业有限公司 一种阿齐沙坦衍生物及其制备方法
CN103588764A (zh) * 2013-11-11 2014-02-19 浙江永宁药业股份有限公司 阿齐沙坦酯或其盐的合成方法及其中间体
CN103601723A (zh) * 2013-11-19 2014-02-26 合肥远志医药科技开发有限公司 一种阿齐沙坦的工业化生产方法
CN104072491A (zh) * 2013-03-29 2014-10-01 天津药物研究院 一种阿齐沙坦衍生化合物及其制备方法和应用
US20140371279A1 (en) * 2011-09-30 2014-12-18 Sunshine Lake Pharma Co., Ltd. Crystalline forms of azilsartan and preparation and uses thereof
WO2016058563A1 (en) * 2014-10-15 2016-04-21 Zentiva, K.S. A process for preparing highly pure azilsartan

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140371279A1 (en) * 2011-09-30 2014-12-18 Sunshine Lake Pharma Co., Ltd. Crystalline forms of azilsartan and preparation and uses thereof
US9174973B2 (en) * 2011-09-30 2015-11-03 Sunshine Lake Pharma Co., Ltd. Crystalline forms of azilsartan and preparation and uses thereof
CN103044412A (zh) * 2012-12-26 2013-04-17 华润赛科药业有限责任公司 一种阿齐沙坦的多晶型及其制备方法
CN103044412B (zh) * 2012-12-26 2016-04-06 华润赛科药业有限责任公司 一种阿齐沙坦的多晶型及其制备方法
CN104072491A (zh) * 2013-03-29 2014-10-01 天津药物研究院 一种阿齐沙坦衍生化合物及其制备方法和应用
CN103254188A (zh) * 2013-05-22 2013-08-21 黄冈鲁班药业有限公司 一种阿齐沙坦衍生物及其制备方法
CN103588764A (zh) * 2013-11-11 2014-02-19 浙江永宁药业股份有限公司 阿齐沙坦酯或其盐的合成方法及其中间体
CN103601723A (zh) * 2013-11-19 2014-02-26 合肥远志医药科技开发有限公司 一种阿齐沙坦的工业化生产方法
CN103601723B (zh) * 2013-11-19 2016-04-27 合肥远志医药科技开发有限公司 一种阿齐沙坦的工业化生产方法
WO2016058563A1 (en) * 2014-10-15 2016-04-21 Zentiva, K.S. A process for preparing highly pure azilsartan

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HU230577B1 (hu) 2017-01-30
CZ2011208A3 (cs) 2012-10-24
CZ303505B6 (cs) 2012-10-24
HUP1300733A2 (en) 2014-03-28

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