WO2011121592A1 - Process for irbesartan substantially free of dimmer impurity - Google Patents

Process for irbesartan substantially free of dimmer impurity Download PDF

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Publication number
WO2011121592A1
WO2011121592A1 PCT/IN2010/000199 IN2010000199W WO2011121592A1 WO 2011121592 A1 WO2011121592 A1 WO 2011121592A1 IN 2010000199 W IN2010000199 W IN 2010000199W WO 2011121592 A1 WO2011121592 A1 WO 2011121592A1
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Prior art keywords
methyl
biphenyl
tetrazol
butyl
diazaspiro
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PCT/IN2010/000199
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French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Rapolu Raji Reddy
Matta Ramakrishna Reddy
Bandi Vamsi Krishna
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Hetero Research Foundation
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Priority to PCT/IN2010/000199 priority Critical patent/WO2011121592A1/en
Publication of WO2011121592A1 publication Critical patent/WO2011121592A1/en

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    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C02F1/02—Treatment of water, waste water, or sewage by heating
    • C02F1/04—Treatment of water, waste water, or sewage by heating by distillation or evaporation
    • C02F1/14—Treatment of water, waste water, or sewage by heating by distillation or evaporation using solar energy
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C02F1/30—Treatment of water, waste water, or sewage by irradiation
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24S—SOLAR HEAT COLLECTORS; SOLAR HEAT SYSTEMS
    • F24S23/00—Arrangements for concentrating solar-rays for solar heat collectors
    • F24S23/70—Arrangements for concentrating solar-rays for solar heat collectors with reflectors
    • F24S23/77—Arrangements for concentrating solar-rays for solar heat collectors with reflectors with flat reflective plates
    • F—MECHANICAL ENGINEERING; LIGHTING; HEATING; WEAPONS; BLASTING
    • F24—HEATING; RANGES; VENTILATING
    • F24S—SOLAR HEAT COLLECTORS; SOLAR HEAT SYSTEMS
    • F24S25/00—Arrangement of stationary mountings or supports for solar heat collector modules
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C02F1/30—Treatment of water, waste water, or sewage by irradiation
    • C02F1/32—Treatment of water, waste water, or sewage by irradiation with ultraviolet light
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F1/00—Treatment of water, waste water, or sewage
    • C02F2001/007—Processes including a sedimentation step
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2201/00—Apparatus for treatment of water, waste water or sewage
    • C02F2201/008—Mobile apparatus and plants, e.g. mounted on a vehicle
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2209/00—Controlling or monitoring parameters in water treatment
    • C02F2209/003—Downstream control, i.e. outlet monitoring, e.g. to check the treating agents, such as halogens or ozone, leaving the process
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2209/00—Controlling or monitoring parameters in water treatment
    • C02F2209/02—Temperature
    • C—CHEMISTRY; METALLURGY
    • C02—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F—TREATMENT OF WATER, WASTE WATER, SEWAGE, OR SLUDGE
    • C02F2303/00—Specific treatment goals
    • C02F2303/04—Disinfection
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A20/00—Water conservation; Efficient water supply; Efficient water use
    • Y02A20/20—Controlling water pollution; Waste water treatment
    • Y02A20/208—Off-grid powered water treatment
    • Y02A20/212—Solar-powered wastewater sewage treatment, e.g. spray evaporation
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02E—REDUCTION OF GREENHOUSE GAS [GHG] EMISSIONS, RELATED TO ENERGY GENERATION, TRANSMISSION OR DISTRIBUTION
    • Y02E10/00—Energy generation through renewable energy sources
    • Y02E10/40—Solar thermal energy, e.g. solar towers
    • Y02E10/47—Mountings or tracking

Definitions

  • the present invention provides a process for the preparation of irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH- tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one (or) 3- ((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one impurity.
  • U.S. Patent No. 5,270,317 discloses a variety of N-substituted heterocyclic derivatives and their salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. Among them, Irbesartan or 2-Butyl-3-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,3- diazaspiro[4.4]non-l-en-4-one, which has the formula (1):
  • Irbesartan is a potent, long-acting angiotensin II receptor antagonist that is especially useful in the treatment of cardiovascular ailments such as hypertension and heart failure, as well as in preventing disorders of central nervous system, glaucoma, diabetic retinopathy, and diabetic nephropathy.
  • Various processes for the preparation of irbesartan and related compounds are disclosed in U.S. Patent Nos. 5,270,317 and 5,629,331, and PCT Publication Nos. WO 2005/051943 and WO 2007/013101.
  • U.S. Patent No. 5,270,317 discloses a process for preparation of irbesartan is prepared by reaction of 2-n-Butyl-4- spirocylopentane-2-imidazolin-5-one with 4- bromomethyl-2-cyanobiphenyl in the presence of sodium hydroxide, followed by a column chromatography separation to 5 produce 1 -[(2'-cyanobiphenyl-4-yl)methyl]- 2-n-butyl-4-spirocyclopentane-2-imidazolin- 5-one, which by reaction with tributyltin azide and trityl chloride followed by deprotection with hydrochloric acid to produce irbesartan.
  • U.S. Patent No. 5,629,331 described a process for the preparation of irbesartan wherein 2-n-butyl3-[[2'-cyanobiphenyl-4-yl]methyl]-l,3-diazaspiro-[4.4]-non-en-4- one was treated with sodium azide in the presence of triethylamine hydrochloride in an inert polar aprotic solvent such as l-methylpyrrolidin-2-one at a temperature of 121 to 123°C.
  • an inert polar aprotic solvent such as l-methylpyrrolidin-2-one
  • WO 2005/051943 disclosed the process for transformation of aromatic nitrile to tetrazole protected irbesartan in the presence of protecting group, trialkyl tin halide, metal azide and phase transfer catalyst.
  • WO 2007/013101 describes a process for the preparation of irbesartan wherein 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]- 1 ,3-diazaspiro-[4.4]non-en-4- one is treated with sodium azide in the presence of triethylamine and acetic acid.
  • WO 2007/049293 disclosed the process for the preparation of irbesartan from aromatic nitrile derivative in the presence of trialkyltin azide and o-xylene.
  • WO2006/023889 disclosed a process for the preparation of irbesartan from aromatic nitrile derivative in the presence of triethylamine chlorhydrate, sodium azide and N-methylpyrrolidinone.
  • WO2007/054965 discloses a process for the preparation of irbesartan from aromatic nitrile derivative in the presence of trialkyltinhalide, sodium azide, diisopropylethyl amine and o-xylene.
  • WO 2006/001026, WO 2007/020659, WO 2005/1 13518 and WO 2007/0391 17 described the preparation of irbesartan by treatment of cyano compound with trialkyltin halide, metal azide in xylene.
  • WO 2009/072137 described a process for the preparation of highly pure irbesartan which comprises reacting l -[(2'-cyanobiphenyl-4-yl)methyl]2-n-butyl-4- spirocyclopentane-2-imidazolin-5-one with tributyltin azide in xylene or toluene and treating the reaction mass with hydrogen chloride in presence of ketonic solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone to obtain highly pure irbesartan.
  • ketonic solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone
  • the patent also disclosed a process for preparation of irbesartan substantially free of tin content can be prepared by stirring a solution or suspension of irbesartan containing tin content in a solvent selected from methanol, ethanol, acetone or water in the presence of sulfuric acid at a pH below 1.5 at least 20 minutes and isolating.
  • the common impurity of the irbesartan is 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3- diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l- en-4-one.
  • the process of the invention ensures the preparation of irbesartan substantially free of 3-((2'-(l-((2'-(lH- tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non-l -en-4-one (or) 3-((2'-(2-((2'-(l H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5 -yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3 -diazaspiro [4.4]non- 1 - en-4-one impurity.
  • An object of the present invention is to provide a process for the preparation of irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3-diazaspiro[4.4]non- 1 - en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5- yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one impurity.
  • step (b) heating the contents obtained in step (a) at about reflux;
  • step (b) maintaining the solution obtained in step (b) at below room temperature; and d) isolating the irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non- 1 -en-4-one (or) 3-((2'-(2-((2'-( 1 H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non- 1 -en-4-one impurity.
  • step (b) heating the contents obtained in step (a) at about reflux;
  • step (b) maintaining the solution obtained in step (b) at below room temperature; and d) isolating the irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3- diazaspiro[4.4]non- 1 -en-4-one (or) 3-((2'-(2-((2'-( 1 H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3- diazaspiro[4.4]non- 1 -en-4-one impurity.
  • HPLC conditions for analysis are: Column : Zorbax SB Phenyl, 150 x 4.6 mm, 3.5 ⁇ .
  • Buffer (Solvent A) Mix 3.0 ml of orthophosphoric acid and 950 ml of water. Adjust pH to 3.2 with triethylamine.
  • Solvent B Acetonitrile: Buffer (90 : 10 v/v)
  • Preferable alcohol solvent used in step (a) may be selected from methanol, ethanol or isopropyl alcohol and more preferable alcohol solvent is methanol.
  • ketonic solvent used in step (a) may be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone and more preferable ketonic solvent is acetone.
  • the ratio of alcohol solvent and ketonic solvent may be 1 :2 to 2: 1 and more preferably the ratio is 1 : 1.
  • the maintenance in step (c) may preferably be carried out at about 0 to 10 C and more preferably at about 0 to 5 C.
  • Isolation of irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3- diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 - en-4-one impurity in step(c) may preferably be carried out by the methods known such as filtration or centrifugation.
  • the temperature of the reaction mass was raised to 80°C and maintained for 10 hours at 80°C.
  • the reaction mass was filtered and washed with ethyl acetate. The filtrate was distilled off completely under vacuum at below 40°C and co-distilled with methanol to obtain residue.
  • methanol 1000 ml
  • methanol hydrochloride 77%, 350 ml
  • temperature of the reaction mass was raised to 25 to 30°C.
  • the reaction mass was maintained for 3 hours at 25 to 30°C and the reaction mass was further cooled to 0°C, stirred for 30 minutes at 0°C.
  • the separated solid was filtered and washed with chilled methanol.
  • the filtrate was distilled off completely under vacuum at below 40°C and co-distilled with toluene to obtain residue.
  • To the residue was added toluene (500 ml) and water (300 ml) at 25 to 30°C.
  • the reaction mass was cooled to 0°C and pH of the reaction mass was adjusted to above 12.0 with sodium hydroxide solution (20%, 600 ml) at below 5°C.
  • the temperature of the reaction mass was raised to 25 to 30°C and stirred for 30 minutes at same temperature, layers were separated.
  • the aqueous layer was washed with toluene and added methylene chloride (1300 ml) at 0°C.
  • the pH of the reaction mass was adjusted to 2.5 to 3.0 with sulphuric acid solution (30%, 250 ml) at below 10°C.
  • the reaction mass was stirred for 15 minutes at 10°C, layers were separated and the total aqueous layer was extracted with methylene chloride. Combined the organic layers was added methanol (100 ml) and give the carbon treatment. Distilled off the solvent completely under vacuum at below 40°C and co-distilled with isopropyl alcohol to obtain residue.
  • isopropyl alcohol 1000 ml
  • the temperature of the reaction mass was raised to 80°C and then maintained for 30 minutes at 80°C.
  • the reaction mass was cooled to 0°C and maintained for 1 hour at 0°C, filtered.

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Abstract

The present invention provides a process for the preparation of irbesartan substantially free of 3-((2'-(1-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-1H- tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (or) 3- ((2'-(2-((2'-(1H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one impurity.

Description

PROCESS FOR IRBESARTAN SUBSTANTIALLY FREE OF DIMMER
IMPURITY
Field of the Invention
The present invention provides a process for the preparation of irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH- tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one (or) 3- ((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one impurity.
Background of the Invention
U.S. Patent No. 5,270,317 discloses a variety of N-substituted heterocyclic derivatives and their salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. Among them, Irbesartan or 2-Butyl-3-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,3- diazaspiro[4.4]non-l-en-4-one, which has the formula (1):
Figure imgf000002_0001
Irbesartan is a potent, long-acting angiotensin II receptor antagonist that is especially useful in the treatment of cardiovascular ailments such as hypertension and heart failure, as well as in preventing disorders of central nervous system, glaucoma, diabetic retinopathy, and diabetic nephropathy. Various processes for the preparation of irbesartan and related compounds are disclosed in U.S. Patent Nos. 5,270,317 and 5,629,331, and PCT Publication Nos. WO 2005/051943 and WO 2007/013101.
U.S. Patent No. 5,270,317 discloses a process for preparation of irbesartan is prepared by reaction of 2-n-Butyl-4- spirocylopentane-2-imidazolin-5-one with 4- bromomethyl-2-cyanobiphenyl in the presence of sodium hydroxide, followed by a column chromatography separation to 5 produce 1 -[(2'-cyanobiphenyl-4-yl)methyl]- 2-n-butyl-4-spirocyclopentane-2-imidazolin- 5-one, which by reaction with tributyltin azide and trityl chloride followed by deprotection with hydrochloric acid to produce irbesartan.
U.S. Patent No. 5,629,331 described a process for the preparation of irbesartan wherein 2-n-butyl3-[[2'-cyanobiphenyl-4-yl]methyl]-l,3-diazaspiro-[4.4]-non-en-4- one was treated with sodium azide in the presence of triethylamine hydrochloride in an inert polar aprotic solvent such as l-methylpyrrolidin-2-one at a temperature of 121 to 123°C.
WO 2005/051943 disclosed the process for transformation of aromatic nitrile to tetrazole protected irbesartan in the presence of protecting group, trialkyl tin halide, metal azide and phase transfer catalyst.
WO 2007/013101 describes a process for the preparation of irbesartan wherein 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]- 1 ,3-diazaspiro-[4.4]non-en-4- one is treated with sodium azide in the presence of triethylamine and acetic acid.
WO 2007/049293 disclosed the process for the preparation of irbesartan from aromatic nitrile derivative in the presence of trialkyltin azide and o-xylene.
WO2006/023889 disclosed a process for the preparation of irbesartan from aromatic nitrile derivative in the presence of triethylamine chlorhydrate, sodium azide and N-methylpyrrolidinone.
WO2007/054965 discloses a process for the preparation of irbesartan from aromatic nitrile derivative in the presence of trialkyltinhalide, sodium azide, diisopropylethyl amine and o-xylene. WO 2006/001026, WO 2007/020659, WO 2005/1 13518 and WO 2007/0391 17 described the preparation of irbesartan by treatment of cyano compound with trialkyltin halide, metal azide in xylene.
WO 2009/072137 described a process for the preparation of highly pure irbesartan which comprises reacting l -[(2'-cyanobiphenyl-4-yl)methyl]2-n-butyl-4- spirocyclopentane-2-imidazolin-5-one with tributyltin azide in xylene or toluene and treating the reaction mass with hydrogen chloride in presence of ketonic solvent such as acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone to obtain highly pure irbesartan. The patent also disclosed a process for preparation of irbesartan substantially free of tin content can be prepared by stirring a solution or suspension of irbesartan containing tin content in a solvent selected from methanol, ethanol, acetone or water in the presence of sulfuric acid at a pH below 1.5 at least 20 minutes and isolating.
3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl- 4-yl)methyl)-2-butyl-l ,3-diazaspiro[4.4]non-l-en-4-one and 3-((2'-(2-((2*-(lH- tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- l ,3-diazaspiro[4.4]non-l-en-4-one are two principle impurities of irbesartan was disclosed in Acta Chim. Slov. 2009, 56, 559-565.
The common impurity of the irbesartan is 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3- diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l- en-4-one.
We have found a simple and effective process for the reduction of 3-((2'-(l- ((2'-(l H-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)- 2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3- diazaspiro[4.4]non-l-en-4-one impurity in the irbesartan. The process of the invention ensures the preparation of irbesartan substantially free of 3-((2'-(l-((2'-(lH- tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non-l -en-4-one (or) 3-((2'-(2-((2'-(l H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5 -yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3 -diazaspiro [4.4]non- 1 - en-4-one impurity.
An object of the present invention is to provide a process for the preparation of irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3-diazaspiro[4.4]non- 1 - en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5- yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one impurity.
Summary of the Invention
In an aspect, there is provided a process for the preparation of irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH- tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one (or) 3- ((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one impurity, which comprises: a) dissolving irbesartan containing 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3- diazaspiro[4.4]non-l-en-4-one impurity in a mixture of alcohol solvent and ketonic solvent in a ratio of 1 :3 to 3: 1 ;
b) heating the contents obtained in step (a) at about reflux;
c) maintaining the solution obtained in step (b) at below room temperature; and d) isolating the irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non- 1 -en-4-one (or) 3-((2'-(2-((2'-( 1 H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non- 1 -en-4-one impurity.
Detailed Description of the Invention
According to an aspect of the present invention there is provided a process for the preparation of irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3- diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l- en-4-one impurity, which comprises:
a) dissolving irbesartan containing 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1,3- diazaspiro[4.4]non-l-en-4-one impurity in a mixture of alcohol solvent and ketonic solvent in a ratio of 1 :3 to 3 : 1 ;
b) heating the contents obtained in step (a) at about reflux;
c) maintaining the solution obtained in step (b) at below room temperature; and d) isolating the irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3- diazaspiro[4.4]non- 1 -en-4-one (or) 3-((2'-(2-((2'-( 1 H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3- diazaspiro[4.4]non- 1 -en-4-one impurity.
The term "irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l- en-4-one impurity" refers to irbesartan having the content of either or both of 3-((2'- ( 1 -((2'-( 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one and 3-((2'-(2-((2'-(lH-tetrazol- 5 -yl)biphenyl-4-yl)methyl)-2H-tetrazol-5 -yl)biphenyl-4-yl)methyl)-2-butyl- 1,3- diazaspiro[4.4]non-l-en-4-one impurity in equal to or less than about 0.2% by weight, preferably equal to or less than about 0.1% by weight, more preferably equal to or less than about 0.05% by weight and still more preferably not detected. The contents of irbesartan and the impurities are determined by High performance liquid chromatography (HPLC).
HPLC conditions for analysis are: Column : Zorbax SB Phenyl, 150 x 4.6 mm, 3.5 μπι.
(Agilent Technologies, USA, part No. 863953-912)
Elution : Gradient (Solvent A : Solvent B)
Buffer (Solvent A) : Mix 3.0 ml of orthophosphoric acid and 950 ml of water. Adjust pH to 3.2 with triethylamine.
Solvent B : Acetonitrile: Buffer (90 : 10 v/v)
Flow rate 1.0 ml/minute.
Detector wavelength 220 nm
Injection volume 10 μΐ
Column oven temperature Acetonitrile
Run time 60 minutes.
Preferable alcohol solvent used in step (a) may be selected from methanol, ethanol or isopropyl alcohol and more preferable alcohol solvent is methanol.
Preferable ketonic solvent used in step (a) may be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone and more preferable ketonic solvent is acetone.
Preferably the ratio of alcohol solvent and ketonic solvent may be 1 :2 to 2: 1 and more preferably the ratio is 1 : 1.
The maintenance in step (c) may preferably be carried out at about 0 to 10 C and more preferably at about 0 to 5 C.
Isolation of irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l ,3- diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 - en-4-one impurity in step(c) may preferably be carried out by the methods known such as filtration or centrifugation.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitations on the scope or spirit of the invention.
Examples
Preparation of irbesartan (Reference example) 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one hydrochloride (100 gm), ethyl acetate (1000 ml) and potassium carbonate (200 gm) are added at 25 to 30°C, and stirred to obtain a solution. To the solution was added potassium carbonate (200 gm), 5-[4'-(bromomethyl)biphenyl-2-yl]-l-trityl-lH-tetrazole (260 gm) and tetra butyl ammonium bromide (5 gm) at 25 to 30°C. The temperature of the reaction mass was raised to 80°C and maintained for 10 hours at 80°C. The reaction mass was filtered and washed with ethyl acetate. The filtrate was distilled off completely under vacuum at below 40°C and co-distilled with methanol to obtain residue. To the residue was added methanol (1000 ml) at 25 to 30°C and the reaction mass was cooled to 0°C. To the reaction mass was added slowly methanol hydrochloride (7%, 350 ml) and temperature of the reaction mass was raised to 25 to 30°C. The reaction mass was maintained for 3 hours at 25 to 30°C and the reaction mass was further cooled to 0°C, stirred for 30 minutes at 0°C. The separated solid was filtered and washed with chilled methanol. The filtrate was distilled off completely under vacuum at below 40°C and co-distilled with toluene to obtain residue. To the residue was added toluene (500 ml) and water (300 ml) at 25 to 30°C. The reaction mass was cooled to 0°C and pH of the reaction mass was adjusted to above 12.0 with sodium hydroxide solution (20%, 600 ml) at below 5°C. The temperature of the reaction mass was raised to 25 to 30°C and stirred for 30 minutes at same temperature, layers were separated. The aqueous layer was washed with toluene and added methylene chloride (1300 ml) at 0°C. The pH of the reaction mass was adjusted to 2.5 to 3.0 with sulphuric acid solution (30%, 250 ml) at below 10°C. The reaction mass was stirred for 15 minutes at 10°C, layers were separated and the total aqueous layer was extracted with methylene chloride. Combined the organic layers was added methanol (100 ml) and give the carbon treatment. Distilled off the solvent completely under vacuum at below 40°C and co-distilled with isopropyl alcohol to obtain residue. To the residue was added isopropyl alcohol (1000 ml) at 40°C and the temperature of the reaction mass was raised to 80°C and then maintained for 30 minutes at 80°C. The reaction mass was cooled to 0°C and maintained for 1 hour at 0°C, filtered. The solid obtained was washed with isopropyl alcohol and dried at 50°C for 6 hours to obtain 135 gm of irbesartan containing 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 - en-4-one and 3-((2'-(2-((2*-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5- yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one impurity. Irbesartan: 99.2%;
The combined contents of 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH- tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one and 3- ((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one impurity (dimmer impurity): 0.7%.
Example 1 :
Process for the purification of irbesartan
Irbesartan containing 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)- lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl- 4-yl)methyl)-2 -butyl- l,3-diazaspiro[4.4]non-l-en-4-one impurity (10 gm) as obtained in reference example was dissolved in methanol (50 ml) and acetone (50 ml) at room temperature. The contents were heated to reflux to obtain clear solution and the solution was cooled to room temperature, stirred for 1 hour at room temperature. The solution was further cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C, filtered. The solid obtained was washed with in a mixture of chilled methanol and chilled acetone and then dried at 50 to 55°C for 4 hours to obtain 8.0 gm of irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one (or) 3-((2'-(2- ((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)- 2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one impurity. Irbesartan: 99.9%;
The combined contents of dimmer impurity: 0.07%. Example 2:
Process for the purification of irbesartan
Irbesartan containing 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl- 4-yl)methyl)-2 -butyl- l ,3-diazaspiro[4.4]non-l-en-4-one impurity (10 gm) was dissolved in methanol (100 ml) and acetone (100 ml) at room temperature. The contents were heated to reflux to obtain clear solution and the solution was cooled to room temperature, stirred for 1 hour at room temperature. The solution was further cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C, filtered. The solid obtained was washed with in a mixture of chilled methanol and chilled acetone and then dried at 50 to 55°C for 4 hours to obtain 7.5 gm of irbesartan substantially free of 3-((2'-(l-((2'- (lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2- butyl- l,3-diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl-l,3- diazaspiro[4.4]non-l-en-4-one impurity.
Irbesartan: 99.94%;
The combined contents of dimmer impurity: Not detected.
Example 3 :
Process for the purification of irbesartan
Irbesartan containing 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3-diazaspiro[4.4]non- 1 -en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2H-tetrazol-5-yl)biphenyl- 4-yl)methyl)-2-butyl-l,3-diazaspiro[4.4]non-l-en-4-one impurity (10 gm) was dissolved in ethanol (50 ml) and acetone (50 ml) at room temperature. The contents were heated to reflux to obtain clear solution and the solution was cooled to room temperature, stirred for 1 hour at room temperature. The solution was further cooled to 0 to 5°C and stirred for 1 hour at 0 to 5°C, filtered. The solid obtained was washed with in a mixture of chilled ethanol and chilled acetone and then dried at 50 to 55 C for 4 hours to obtain 7.2 gm of irbesartan substantially free of 3-((2'-(l-((2'-(lH- tetrazol-5-yl)biphenyl-4-yl)methyl)-lH-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3 -diazaspiro [4.4] non- 1 -en-4-one (or) 3 -((2'-(2-((2'-( 1 H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2 -butyl- 1 ,3-diazaspiro[4.4]non- 1 - en-4-one impurity.
Irbesartan: 99.8%;
The combined contents of dimmer impurity: 0.1%.

Claims

We claim:
1. A process for the preparation of irbesartan substantially free of 3-((2'-(l-((2'-(lH- tetrazol-5 -yl)biphenyl-4-yl)methyl)- 1 H-tetrazol-5 -yl)biphenyl-4-yl)methyl)-2- butyl-l,3-diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)-2H-tetrazol-5 -yl)biphenyl-4-yl)methyl)-2-butyl- 1,3- diazaspiro[4.4]non-l-en-4-one impurity, which comprises:
a) dissolving irbesartan containing 3-((2'-(l-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non- 1 -en-4-one (or) 3-((2'-(2-((2'-( 1 H-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non-l-en-4-one impurity in a mixture of alcohol solvent and ketonic solvent in a ratio of 1 :3 to 3 : 1 ;
b) heating the contents obtained in step (a) at about reflux;
c) maintaining the solution obtained in step (b) at below room temperature; and d) isolating the irbesartan substantially free of 3-((2'-(l-((2'-(lH-tetrazol-5- yl)biphenyl-4-yl)methyl)- 1 H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non-l-en-4-one (or) 3-((2'-(2-((2'-(lH-tetrazol-5-yl)biphenyl-4- yl)methyl)-2H-tetrazol-5-yl)biphenyl-4-yl)methyl)-2-butyl- 1 ,3- diazaspiro[4.4]non- 1 -en-4-one impurity.
2. The process according to claim 1, wherein the alcohol solvent used in step (a) is a solvent or mixture of solvents selected from methanol, ethanol or isopropyl alcohol.
3. The process according to claim 2, wherein the alcohol solvent is methanol.
4. The process according to claim 1, wherein the ketonic solvent used in step (a) is a solvent or mixture of solvents selected from acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone.
5. The process according to claim 4, wherein the ketonic solvent is acetone.
6. The process according to claim 1, wherein the ratio of alcohol solvent and ketonic solvent is 1 :2 to 2: 1.
7. The process according to claim 6, wherein the ratio of alcohol solvent and ketonic solvent is 1 : 1. The process according to claim 1, wherein the maintenance in step (c) is carried out at about 0 to 10°C.
The process according to claim 8, wherein the maintenance is carried out at about 0 to 5°C.
PCT/IN2010/000199 2010-03-29 2010-03-29 Process for irbesartan substantially free of dimmer impurity WO2011121592A1 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0387390A1 (en) * 1989-02-23 1990-09-19 Jitsuo Inagaki Method and apparatus for purifying drinking water by solar light and heat
DE9404428U1 (en) * 1994-03-16 1994-09-29 Schwarzer Klemens Prof Dr Solar sterilizer
DE19714810A1 (en) * 1997-04-10 1998-10-15 Samland Thomas Dipl Math Disinfection of drinking water comprises concentration of UV radiation by mirrors or lenses and direction through transparent material
WO2000030981A1 (en) * 1998-11-25 2000-06-02 Sang Kwan Han Water purification method and device

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0387390A1 (en) * 1989-02-23 1990-09-19 Jitsuo Inagaki Method and apparatus for purifying drinking water by solar light and heat
DE9404428U1 (en) * 1994-03-16 1994-09-29 Schwarzer Klemens Prof Dr Solar sterilizer
DE19714810A1 (en) * 1997-04-10 1998-10-15 Samland Thomas Dipl Math Disinfection of drinking water comprises concentration of UV radiation by mirrors or lenses and direction through transparent material
WO2000030981A1 (en) * 1998-11-25 2000-06-02 Sang Kwan Han Water purification method and device

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ACRA,A: "Disinfection of Oral Rehydration Solutions by Sunlight", THE LANCET, vol. 2, 1980, pages 1257 - 1258
LAURIE F.CASLAKE ET AL.: "Disinfection of contaminated water by using solar irradiation", APPLIED AND ENVIRONMENTAL MICROBIOLOGY, February 2004 (2004-02-01), pages 1145 - 1150

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