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WO2013042066A1 - Procédé de préparation d'azilsartan médoxomil - Google Patents

Procédé de préparation d'azilsartan médoxomil Download PDF

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Publication number
WO2013042066A1
WO2013042066A1 PCT/IB2012/055001 IB2012055001W WO2013042066A1 WO 2013042066 A1 WO2013042066 A1 WO 2013042066A1 IB 2012055001 W IB2012055001 W IB 2012055001W WO 2013042066 A1 WO2013042066 A1 WO 2013042066A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
process according
compound
azilsartan
alkyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IB2012/055001
Other languages
English (en)
Inventor
Prakash Bhimaji Kshirsagar
Anand Prakash Tiwari
Shyam Sunder Verma
Kaptan Singh
Mohan Prasad
Sudershan Kumar Arora
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Ranbaxy Laboratories Ltd
Original Assignee
Ranbaxy Laboratories Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Ltd filed Critical Ranbaxy Laboratories Ltd
Publication of WO2013042066A1 publication Critical patent/WO2013042066A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • the present invention relates to processes for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof.
  • Azilsartan medoxomil of Formula I is a prodrug of azilsartan of Formula II
  • Azilsartan medoxomil is an angiotensin II receptor blocker (ARB) indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive agents.
  • the present invention relates to processes for the preparation of azilsartan medoxomil or pharmaceutically acceptable salts thereof.
  • Figure 1 depicts the X-ray powder diffraction pattern (XRPD) of the azilsartan medoxomil obtained according to Example 3.
  • Figure 1A provides the table of values for the XRPD pattern depicted in Figure 1.
  • Figure 2 depicts the X-ray powder diffraction pattern (XRPD) of the azilsartan medoxomil obtained according to Example 4.
  • Figure 2A provides the table of values for the XRPD pattern depicted in Figure 2.
  • Figure 3 depicts the X-ray powder diffraction pattern (XRPD) of the azilsartan medoxomil obtained according to Example 5.
  • Figure 3 A provides the table of values for the XRPD pattern depicted in Figure 3.
  • One aspect of present invention provides a process for the preparation of compound of Formula III,
  • R is alkyl or aryl group, which comprises
  • Another aspect of present invention provides a process for the preparation of azilsartan medoxomil or a salt thereof, which comprises:
  • R is alkyl or aryl group
  • Another aspect of the present invention provides (2-ethoxy-l- ⁇ [2'-(5-oxo-4,5- dihydro- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl ⁇ - 1 H-benzimidazol-7-yl)-carboxyl-4- nitrophenyl sulfonateof Formula V.
  • Treatment of azilsartan with a compound of Formula RSO 2 X may be carried out in the presence of at least one base and solvent.
  • the compound of Formula RSO 2 X (wherein X is a halogen atom and R is alkyl or aryl group) may be selected from a group consisting of 4- nitrobenzenesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride or p- bromobenzenesulphonyl chloride, for example, 4-nitrobenzenesulfonyl chloride.
  • the at least one base may be organic or inorganic.
  • the organic base may be selected from agroup consisting of triethyl amine, diisopropyl ethyl amine, tri-n-butyl amine, 4- dimethylaminopyridine, pyrollidine or N-methyl morpholine, for example,
  • the solvent may be selected from group consisting of halogenated hydrocarbonsor aromatic hydrocarbons, for example, dichloromethane.
  • Treatment of azilsartan with a compound of Formula RSO2X (wherein X is a halogen atom and R is alkyl or aryl group) may be carried out at 0°C to 60°C, for example, at 5°C to 40°C. Treatment may be carried out for about 2hours to about 5 hours.
  • the compound of Formula III or Formula V may be isolated by filtration, distillation, decantation, vacuum drying, evaporation or a combination thereof.
  • Reaction of the compound of Formula III or Formula V with 4-(hydroxymethyl)-5- methyl-l,3-dioxol-2-one of Formula IV may be carried out in the presence of at least one base and solvent.
  • the base may be organic or inorganic.
  • the organic base may be selected from a group consisting of triethyl amine, diisopropyl ethyl amine, 4- dimethylaminopyridine, pyrollidine or N-methyl morpholine, for example, 4- dimethylaminopyridine.
  • the inorganic base may be selected from alkali or alkaline metal hydroxides, alkali metal carbonates or bicarbonates, or alkaline metal carbonates or bicarbonates.
  • the at least one solvent may be selected from a group consisting of halogenated hydrocarbon, aromatic hydrocarbon or ethereal solvents, for example, dichloromethane.
  • Treatment of azilsartan sulfonic acid ester derivative with 4- (hydroxymethyl)-5-methyl-l,3-dioxol-2-one may be carried out at 20°C to 60°C, for example, at 30°C to 50°C. Treatment may be carried out for about lhour to about 4 hours.
  • the reaction mixture may be washed with hydrochloric acid solution.
  • the azilsartan medoxomil may be isolated by filtration, distillation, decantation, vacuum drying, evaporation or a combination thereof.
  • the azilsartan medoxomil may be crystallized using an organic solvent selected from water, ether, alcohol, aliphatic hydrocarbon, aromatic hydrocarbon or halogenated hydrocarbon, for example, water, ethanol or diisopropyl ether.
  • an organic solvent selected from water, ether, alcohol, aliphatic hydrocarbon, aromatic hydrocarbon or halogenated hydrocarbon, for example, water, ethanol or diisopropyl ether.
  • Powder Diffractometer in the range 3-40 degree 2 theta and under tube voltage and current of 45 Kv and 40 mA, respectively. Copper radiation of wavelength 1.54 angstrom and Xceletor detector was used.
  • Example 1 Preparation of (2-Ethoxy-l- (r2'-(5-Oxo-4.5-Dihydro-1.2.4-Oxadiazol-3- Yl Biphenyl-4-YllMethyl ⁇ - lH-Benzimidazol-7-Yl -Carboxyl-4-Nitrophenyl Sulfonate
  • Dichloromethane 50 mL was added to azilsartan (5 g) at 20°C to 30°C.
  • the reaction mixture was cooled to 0°C to 5°C.
  • 4-Dimethylaminopyridine(0.27 g) was added to the reaction mixture at 5°C.
  • Triethylamine (2.33 g) was slowly added to the reaction mixture at 5°C.
  • the temperature of the reaction mixture was raised to 40°C to 45°C and it was stirred for 2 hours.
  • the reaction mixture was cooled to 20°C to 30°C and was washed with saturated sodium bicarbonate solution (50 mL).
  • the reaction mixture was washed with 2N hydrochloric acid solution (25 mL).
  • the organic layer was recovered under vacuum at 25°C to 30°C.
  • the solution was recrystallized from diisopropylether (50 mL) to obtain the title compound.
  • Dichloromethane 50 mL was added to azilsartan (5 g) at 20°C to 30°C. The reaction mixture was cooled to 0°C to 5°C.4-Dimethylaminopyridine (0.27 g) was added to the reaction mixture at 5°C. Triethylamine (2.33 g) was slowly added to the reaction mixture at 5°C. A solution of 4-nitrobenzenesulfonyl chloride (2.91 g) in dichloromethane (25 mL) was slowly added to the reaction mixture at 0°C to 5°C. The temperature of the reaction mixture was raised to 20°C to 30°C and it was stirred for 1 hour.
  • Ethanol (15 mL) was added to azilsartan medoxomil (3.0 g) at 20°C to 30°C.
  • the reaction mixture was gradually heated to 50°C to obtain a clear solution.
  • Activated carbon was added to the reaction mixture at 50°C.
  • the reaction mixture was stirred for 30 minutes at 45°C to 50°C.
  • the reaction mixture was filtered through a celite bed at 50°C.
  • the reaction mixture was washed with ethanol (1.5 mL).
  • the filtrate was cooled to 20°C to 30°C.
  • the reaction mixture was stirred at 20°C to 30°C for 2 hours.
  • the solid product crystallized out, and was further stirred for 12 hours at 20°Cto 30°C.
  • the solid obtained was filtered at 20°C to 30°C and was washed with ethanol (1.5 mL). The solid obtained was dried in air for 30 minutes and dried under vacuum for 12 hours at 20°C to 30°C to obtain the title compound having an X-ray powder diffraction pattern as depicted in Figure 2.
  • Azilsartan medoxomil (3.0 g) was added to acetone (9.0 mL) and water (12.0 mL) at 20°Cto 30°C. The reaction mixture was maintained at 35°C for 2 hours. The reaction mixture was cooled to 0°C to 5°C and was stirred for 2 hours to 3 hours. The reaction mixture was filtered and washed with water (9 mL). The solid obtained was filtered and dried under vacuum at 40°C for 12 hours to obtain the title compound having an X-ray powder diffraction pattern as depicted in Figure 3.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des procédés de préparation d'azilsartan médoxomil ou de ses sels pharmaceutiquement acceptables.
PCT/IB2012/055001 2011-09-20 2012-09-20 Procédé de préparation d'azilsartan médoxomil Ceased WO2013042066A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2728/DEL/2011 2011-09-20
IN2728DE2011 2011-09-20

Publications (1)

Publication Number Publication Date
WO2013042066A1 true WO2013042066A1 (fr) 2013-03-28

Family

ID=47222157

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2012/055001 Ceased WO2013042066A1 (fr) 2011-09-20 2012-09-20 Procédé de préparation d'azilsartan médoxomil

Country Status (1)

Country Link
WO (1) WO2013042066A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015051546A1 (fr) * 2013-10-12 2015-04-16 杭州领业医药科技有限公司 Formes cristallines de l'ester d'azilsartan et leur procédé de préparation
CN105949182A (zh) * 2013-10-12 2016-09-21 杭州领业医药科技有限公司 阿齐沙坦酯的晶型及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050187269A1 (en) * 2004-02-25 2005-08-25 Takeda Pharmaceutical Company Limited Benzimidazole derivative and use thereof
WO2012090043A1 (fr) * 2010-12-29 2012-07-05 Jubilant Life Sciences Limited Nouvelles formes à l'état solide d'azilsartan médoxomil et leur procédé de préparation
WO2012107814A1 (fr) * 2011-02-08 2012-08-16 Jubilant Life Sciences Limited Procédé amélioré pour la préparation d'azilsartan médoxomil

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050187269A1 (en) * 2004-02-25 2005-08-25 Takeda Pharmaceutical Company Limited Benzimidazole derivative and use thereof
US7157584B2 (en) 2004-02-25 2007-01-02 Takeda Pharmaceutical Company Limited Benzimidazole derivative and use thereof
US7572920B2 (en) 2004-02-25 2009-08-11 Takeda Pharmaceutical Company Limited Benzimidazole derivative and use as a II receptor antagonist
EP2119715A1 (fr) 2004-02-25 2009-11-18 Takeda Pharmaceutical Company Limited Dérivé de benzimidazole et son utilisation en tant qu'antagoniste de récepteur
WO2012090043A1 (fr) * 2010-12-29 2012-07-05 Jubilant Life Sciences Limited Nouvelles formes à l'état solide d'azilsartan médoxomil et leur procédé de préparation
WO2012107814A1 (fr) * 2011-02-08 2012-08-16 Jubilant Life Sciences Limited Procédé amélioré pour la préparation d'azilsartan médoxomil

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015051546A1 (fr) * 2013-10-12 2015-04-16 杭州领业医药科技有限公司 Formes cristallines de l'ester d'azilsartan et leur procédé de préparation
CN105949182A (zh) * 2013-10-12 2016-09-21 杭州领业医药科技有限公司 阿齐沙坦酯的晶型及其制备方法
CN105949183A (zh) * 2013-10-12 2016-09-21 杭州领业医药科技有限公司 阿齐沙坦酯的晶型及其制备方法
CN105949182B (zh) * 2013-10-12 2019-03-19 杭州领业医药科技有限公司 阿齐沙坦酯的晶型及其制备方法

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