WO2011021224A2 - Procédé de préparation de (5-méthyl-2-oxo- 1,3-dioxolen-4-yl)méthyl-4-(1-hydroxy- 1 -méthyléthyl)-2-propyl- l-[4-[2-(tétrazol-5-yl)phényl]phényl]méthyl imidazole-5-carboxylate - Google Patents

Procédé de préparation de (5-méthyl-2-oxo- 1,3-dioxolen-4-yl)méthyl-4-(1-hydroxy- 1 -méthyléthyl)-2-propyl- l-[4-[2-(tétrazol-5-yl)phényl]phényl]méthyl imidazole-5-carboxylate Download PDF

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WO2011021224A2
WO2011021224A2 PCT/IN2010/000546 IN2010000546W WO2011021224A2 WO 2011021224 A2 WO2011021224 A2 WO 2011021224A2 IN 2010000546 W IN2010000546 W IN 2010000546W WO 2011021224 A2 WO2011021224 A2 WO 2011021224A2
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Prior art keywords
formula
compound
acid
acetone
olmesartan
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PCT/IN2010/000546
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WO2011021224A3 (fr
Inventor
Manne Satyanarayana Reddy
Chakilam Nagaraju
Srinivasan Thirumalai Rajan
Achampeta Kodanda Ramprasad
Karamala Rama Subba Reddy
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Msn Laboratories Limited
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Publication of WO2011021224A3 publication Critical patent/WO2011021224A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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 (5-methyl-2-oxo- 1 ,3 -dioxolen-4-yl)methyl4-(l -hydroxy- 1 -methylethyl)-2 -propyl- 1 -[4-[2- (tetrazol-5-yl) phenyl]phenyl]methyl imidazole-5-carboxylate compound of formula- 1 (commonly known as "olmesartan medoxomil”) through crystalline (5-methyl-2-oxo-l,3- dioxolen-4-yl)methyl4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(trityltetrazol-5-yl) phenyl]phenyl] methylimidazole-5-carboxylate compound of formula-8 (commonly known as "trityl olmesartan”).
  • Olmesartan medoxomil is a prodrug that is hydrolyzed to olmesartan during absorption from the gastrointestinal tract.
  • Olmesartan is a selective AT 1 subtype angiotensin II receptor antagonist.
  • Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin converting enzyme (ACE, kinase II).
  • ACE angiotensin converting enzyme
  • Olmesartan blocks the vasoconstrictor effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATj receptor in vascular smooth muscle.
  • Olmesartan medoxomil is marketed under the brand name of BENIC AR® in film-coated tablets of 5 mg, 20 mg and 40 mg for the treatment of hypertension in human. Background of the Invention:
  • Olmesartan medoxomil and process for its preparation was disclosed in US 5616599.
  • the disclosed process involves the condensation of ethyl 4-( 1 -hydroxy- 1 - methylethyl)-2-propylimidazole-5-carboxylate with 4-(2-trityltetrazole-5-yl)phenylbenzyl bromide in presence of sodium hydride in dimethylformamide to provide ethyl 4-(l- hydroxy-l-methylethyl)-2-propyl-l- ⁇ 4-[2-(trityltetrazol-5-yl)phenyl]phenyl ⁇ methyl imidazole -5-carboxylate.
  • the obtained ester is treated with lithium hydroxide in dioxane to provide the corresponding lithium carboxylate compound, which is then reacted with 4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene in presence of potassium carbonate in dimethylacetamide and the obtained trityl olmesartan was recrystallised from isopropyl ether.
  • trityl olmesartan was treated with an aqueous acetic acid to provide olmesartan medoxomil.
  • the purity of the obtained final compound was not satisfactory and required number of recrystallizations to get the desired purity.
  • the first aspect of the present invention is to provide a novel acetone solvate of trityl olmesartan, process for its preparation and its use in the preparation of highly pure olmesartan medoxomil compound of formula- 1.
  • the process for the preparation of novel acetone solvate of trityl olmesartan comprises of stirring the trityl olmesartan in acetone for a sufficient period of time and isolating the acetone solvate of trityl olmesartan.
  • the second aspect of the present invention is to provide a novel crystalline form of trityl olmesartan acetone solvate.
  • the novel crystalline form of the present invention is used to prepare highly pure olmesartan medoxomil compound of formula- 1.
  • the third aspect of the present invention is to provide a process for the preparation of crystalline form of trityl olmesartan acetone solvate, which comprises of reacting the 4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 -[4-[2-(trityltetrazol-5-yl) phenyl] phenyl]rnethylirnidazole-5-carboxylic acid compound of formula-6 with 4-chloromethyl-
  • the fourth aspect of the present invention is to provide a process for the preparation highly pure trityl olmesartan, which comprises of
  • the fifth aspect of the present invention is to provide an improved process for the preparation of highly pure olmesartan medoxomil compound of formula- 1, which comprises of the following steps,
  • the sixth aspect of the present invention is to provide an improved process for the preparation of olmesartan medoxomil compound of formula- 1, which comprises of the following steps;
  • the seventh aspect of the present invention is to provide an improved process for the preparation of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(trityltetrazol-5-yl) phenyl]phenyl]methylimidazole-5-carboxylic acid compound of formula-6, which comprises of reacting dimethyl-2-propyl[4-[2-(trityltetrazol-5-yl)phenyl]phenyl]methyl imidzole-4,5-dicarboxylate compound of formula-4 with Grignard reagent in a suitable solvent to provide the methyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(trityl tetrazol-5-yl)phenyl]phenyl] methylimidazole-5-carboxylate compound of formula-5, followed by its hydrolysis with a suitable base in a suitable solvent to provide the compound of formula-6, characterized in that the gr
  • the eighth aspect of the present invention is to provide one pot process for the preparation of 2-propyl-lH-imidazole-4,5-dicarboxylic acid compound of formula-9, which comprises of reacting the diaminomalenonitrile with trimethylorthobutyrate in a suitable alcoholic solvent to provide 2-propyl-lH-imidazole-4,5-dicarbonitrile compound of formula- 10, which on in-situ reaction with a suitable acid provides the compound of formula-9.
  • Figure-1 Illustrates the Powder X-ray diffractogram of trityl olmesartan acetone solvate Detailed Description of the Invention:
  • the first aspect of the present invention provides a novel acetone solvate of trityl olmesartan compound of formula-8.
  • novel acetone solvate of the present invention is used to prepare highly pure olmesartan medoxomil compound of formula- 1
  • the present invention provides a process for the preparation of trityl olmesartan acetone solvate, which comprises of stirring the trityl olmesartan in acetone for a sufficient period of time at a temperature from O to 35°C, preferably 0-5°C and isolating the acetone solvate of trityl olmesartan by filtration.
  • the second aspect of the present invention provides a novel crystalline form of trityl olmesartan acetone solvate.
  • the novel crystalline form of trityl olmesartan acetone solvate of the present invention here in designated as "crystalline form-M".
  • the crystalline form-M of trityl olmesartan of the present invention is characterized by its powder X-ray diffractogram having characteristics 2 theta peaks at 6.05, 10.22, 10.68, 12.04, 14.31, 15.76, 18.06, 19.28, 20.69, 21.36, 24.12, 29.02, 30.21 ⁇ 0.2 degrees 2 ⁇ .
  • the PXRD of crystalline form-M of the present invention is represented in figure- 1.
  • the reported/prior art processes for the preparation of olmesartan medoxomil involve a number of recrystallisations in a final stage to get the desired purity required for formulation.
  • novel acetone solvated form or crystalline form M of trityl olmesartan in the preparation of olmesartan avoids the number of recrystallisations in the final stage and also provides highly pure olmesartan medoxomil when compared to the prior art.
  • the third aspect of the present invention provides a process for the preparation of crystalline form-M of trityl olmesartan acetone solvated form, which comprises of reacting the 4-(l -hydroxy- l-methylethyl)-2-propyl-l- [4- [2-(trityltetrazol-5-yl)phenyl] phenyl]methylimidazole-5-carboxylic acid compound of formula-6 with 4-chloromethyl- 5-methyl-2-oxo-l,3-dioxolene compound of formula-7, in the presence of a suitable base selected from sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate, preferably sodium carbonate, in acetone and in presence or absence of a phase transfer catalyst selected from tetra butyl ammonium bromide, tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide, tetraoctyl ammonium bromide
  • the fourth aspect of the present invention provides a process for the preparation highly pure trityl olmesartan, which comprises of
  • trityl olmesartan acetone solvate in a suitable solvent selected from alcoholic solvents like methanol, ethanol, isopropanol, n-propanol and butanol; ester solvents like ethylacetate, methyl acetate, isopropylaceatate, ketone solvent like acetone; nitrile solvents like acetonitrile, hydrocarbon solvents like toluene, heptane, cyclohexane and hexane, and mixtures thereof,
  • the purification of trityl olmesartan comprising of a) Suspending the trityl olmesartan in a mixture of ethyl acetate and acetone,
  • the ratio of ethyl acetate and acetone employed for recrystallization is in the ratio of 1:99 to 99:1.
  • the trityl olmesartan obtained is having the purity greater than 98% by HPLC, preferably greater than 99% by HPLC.
  • the fifth aspect of the present invention provides a highly pure olmesartan medoxomil compound of formula- 1, which comprises of the following steps;
  • organic acid such as acetic acid, formic acid, benzoic acid, oxalic acid
  • oxoacids such as perchloric acid, chloric acid, chlorous acid, hypochlorous acid, sulfuric acid, sulfurous acid, p-toluene sulfonic acid, nitric acid, nitrous acid, phosphoric acid and carbonic
  • a suitable solvent selected from acetone or acetonitrile at a temperature range from 10 to 65°C to obtain a solution of olmesartan medoxomil with unwanted triphenol carbinol as a solid,
  • a suitable base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or its aqueous solution and ammonia ,
  • process for the preparation of olmesartan medoxomil compound of formula- 1 comprises of the following steps, a) treating the trityl olmesartan compound or its solvates with aqueous acetic acid at 40- 45°C to obtain a solution of olmesartan medoxomil with unwanted triphenol carbinol as a solid,
  • the sixth aspect of the present invention provides an improved process for the preparation of olmesartan medoxomil compound of formula- 1, which comprises of the following steps;
  • Formula-3 in the presence of a suitable alkali metal base such as potassium carbonate and in a suitable solvent like acetone or dimethyl formamide or mixtures thereof, preferably mixture of dimethylformamide and acetone provides the diester compound of formula-4,
  • the seventh aspect of the present invention provides an improved process for the preparation of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(trityltetrazol-5-yl) phenyl] phenyl]methylimidazole-5-carboxylic acid compound of formula-6, which comprises of the following steps; a) reacting the dimethyl-2-propyl[4-[2-(trityltetrazol-5-yl)phenyl]phenyl]methyl imidzole-4,5-dicarboxylate compound of formula-4,
  • a grignard reagent selected from methyl magnesium chloride or methylmagenesium bromide in a suitable solvent selected from toluene, tetrahydrofuran, followed by quenching the reaction mixture with a suitable aqueous acid, to provide methyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(trityltetrazol- 5-yl)phenyl]phenyl]methylimidazole-5-carboxylate compound of formula-5, characterized in that the addition of grignard reagent and maintenance of the reaction is carried out at the temperature of -30 to -50°C, preferably at -35°C to -38°C and quenching with an acid is carried out at a temperature of -5 to -10°C,
  • a suitable alkali metal base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide with or without water in a suitable solvent selected from ketone solvents like acetone; nitrile solvents like acetonitrile; alcoholic solvent selected from methanol, ethanol, isopropanol and butanol or mixtures thereof, followed by extracting the reaction mixture with a suitable hydrocarbon solvent selected from toluene, cylcohexane, heptane or hexane; ester solvents like ethyl acetate, methyl acetate or isopropyl acetate, to provide the compound of formula-6.
  • a suitable alkali metal base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, preferably sodium hydroxide with or without water in a suitable solvent selected from ketone solvents like acetone; nitrile solvents like acetonitrile; alcoholic solvent selected from
  • the said compound of formula-6 is used in the preparation of olmesartan medoxomil compound of formula- 1 provides the highly pure olmesartan medoxomil which is free of impurity at 1.13 RRT (Impurity-X).
  • Impurity-X 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-
  • the impurity X is not removable/washable by conventional purification methods and hence we the present inventors have tried to control the Impurity-X at the origin itself i.e., during Grignard reaction, by varying the process parameters. After conducting various experiments, it was concluded that the adding grignard reagent at a temperature of -30 to -50°C and maintaining the grignard reaction at a temperature range of -30 to -50 0 C, followed by extraction of the reaction mixture with a suitable solvent after the hydrolysis step removed/controlled the impurity-X in the final compound.
  • the eighth aspect of the present invention provides one pot process for the preparation of 2-propyl-lH-imidazole-4,5-dicarboxylic acid compound of formula-9 with high yields and purity, which is a key intermediate in synthesis of olmesartan medoxomil compound of formula- 1
  • the compound of formula-9 can be converted into dialkyl 2-propyl-lH-imdazole- 4,5-dicarboyxlate compound of formula-2.
  • R is selected from C M alkyl
  • a suitable alcohol like methanol, ethanol or isopropanol in presence of a suitable acid catalyst selected thionyl chloride, sulfuric acid or by conventional methods known in the art.
  • the present invention further provides the usage of ammonia as a base to increase the basicity or decrease the acidity of the reaction mixture which is obtained after the deprotection of trityl group from trityl olmesartan followed by filtration of unwanted solid in presence or absence of a suitable solvent.
  • ammonia refers to the either ammonia gas or aqueous ammonia solution.
  • the term highly pure/high pure refers to the purity of the compound more than 99.50% by HPLC, preferably more than 99.85% by HPLC.
  • dimethyl-2-propyl(4-[2-(trityltetrazol-5-yl)phenyl]phenyl)methyl imidzole- 4,5-dicarboxylate compound of formula-4 can be prepared by the process of the present invention or by the methods known in the art.
  • Olmesartan medoxomil prepared by the present invention can be further micronized or milled to get the desired particle size. Analysis of particle size distribution of olmesartan medoxomil was carried out using Malvern Mastersizer 2000.
  • Example-1 Preparation of acetone solvated form of trityl olmesartan:
  • Example-2 Preparation of crystalline form M of trityl olmesartan:
  • reaction mixture 25-30 0 C.
  • the reaction mixture was heated to 40-45 0 C and stirred for 4 hours.
  • the reaction mixture was filtered through hyflow and washed with acetone. The filtrate was completely distilled off under reduced pressure at 50-55 0 C and then cooled to 25-35 0 C.
  • reaction mixture was cooled to 0-5 0 C and stirred for an hour.
  • the solid formed was filtered, washed and dried at 60-70 0 C to get crystalline form M of trityl olmesartan.
  • Example-3 Preparation of acetone solvate trityl olmesartan:
  • the reaction mixture was heated to 40-45 0 C and stirred for 4 hours.
  • the reaction mixture was cooled to 25-35°C and then to 0-5 0 C.
  • the reaction mixture was stirred for an hour at 0-5°C.
  • the solid was filtered, washed with acetone and dried at 50-60°C to get the title compound.
  • Example-5 Preparation of highly pure olmesartan medoxomil compound of formula- 1 from acetone solvate of trityl olmesartan:
  • Aqueous acetic acid (1200 ml acetic acid in 1800 of water) was added to acetone solvated form of trityl olmesartan (100 grams) at 25-35 0 C.
  • the reaction mixture was heated to 60-65 0 C and stirred for 15 minutes at 60-65 0 C.
  • the reaction mixture was cooled to 25-35°C and water (1500 ml) was added to it.
  • the reaction mixture was cooled to 5-10 0 C and stirred for 45 minutes.
  • the unwated triphenyl carbinol was filtered off and washed with aqueous acetic acid.
  • Methylene chloride 1000 ml was added to the above filtrate and stirred for 15 minutes at 25-3O 0 C.
  • the organic and aqueous layers were separated and extracted the aqueous layer with methylene chloride. Added a mixture of 5% solution of sodium chloride and sodium bicarbonate and separated the organic and aqueous layers. The organic layer was washed with 5% sodium chloride solution and solvent from the organic layer was distilled off under reduced pressure at below 65°C. The reaction mixture was cooled to 40 0 C and acetone (50 ml) to it. The reaction mixture was cooled to 0-5 0 C and stirred for 2 hours. The solid filtered, washed with chilled acetone and dried at 55 -65 0 C to get the high pure olmesartan medoxomil . .
  • Example-8 Preparation of 4-(l-hydroxy-l-methyIethyl)-2-propyl-l-[4-[2-(trityl tetrazol-5-yl) phenyl] phenyl] methylimidazole-5-carboxy Hc acid (formuIa-6):
  • Methyl magnesium chloride (186 ml) was added to a mixture of dimethyl- 2-propyl[4-[2-(trityltetrazol-5-yl)phenyl]phenyl]methylimidzole-4,5-dicarboxylate ( 100 grams) in toluene (600 ml) at -35 to -30°C and stirred for 3 hours. Aqueous acetic acid was added to the reaction mixture at below -5°C then stirred at 25-30°C. The layers were separated and extracted the aqueous layer with toluene. The organic layer washed with aqueous sodium chloride solution then the organic layer was distilled off under reduced pressure at below 55°C.
  • Aqueous acetic acid 120 ml acetic acid in 180 ml of water was added to trityl olmesartan (10 grams) obtained as per example-9 at 25-35°C.
  • the reaction mixture was heated to 60-65 0 C and stirred for 15 minutes at 60-65 0 C.
  • the reaction mixture was cooled to 25-35°C and water (150 ml) was added to it.
  • the reaction mixture was cooled to 5-10 0 C and stirred for 45 minutes.
  • the unwated triphenyl carbinol was filtered off and washed with aqueous acetic acid.
  • Methylene chloride 100 ml was added to the above filtrate and stirred for 15 minutes at 25-3O 0 C.
  • the organic and aqueous layers were separated and extracted the aqueous layer with methylene chloride. Added a mixture of 5% solution of sodium chloride and sodium bicarbonate and separated the organic and aqueous layers. The organic layer was washed with 5% sodium chloride solution and solvent from the organic layer was distilled off under reduced pressure at below 65 0 C. The reaction mixture was cooled to 40 0 C and acetone (50 ml) to it. The reaction mixture was further cooled to 0-5°C and stirred for 2 hours. The solid was filtered, washed with chilled acetone and dried at 55-65°C to get the high pure olmesartan medoxomil.
  • a mixture of dimethyl-2-propylimidazole-4,5-dicarboxylate compound of formula-2a (100 grams), 4-[2-(trityltetrazol-5-yl)phenyl]benzyl bromide compound of formula-3 (296 grams), potassium carbonate (119 grams) in dimethyl formamide (100 ml) and acetone (500 ml) was heated to reflux temperature.
  • the reaction mixture was stirred up to reaction completion and solvent was distilled off completely from the reaction mixture under reduced pressure at below 50°C.
  • the reaction mixture was cooled to 25-30 0 C, acetone (150 ml) and water (1000 ml) were added to it then stirred for 60 minutes.
  • the obtained solid was filtered, washed with water and then the wet solid was recrystallized from acetone to provide the title compound.
  • Example-12 Preparation of 4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(2-trityl tetrazol-5-yl)phenyl]phenyl] methyl imidazole-5-carboxylic acid (formula-6):
  • Methyl magnesium chloride (186 ml) was added to dimethyl-2-propyl-l-[4-(2-(2- trityltetrazol-5-yl)phenyl]phenyl)methyl imidazole-4,5-dicarboxylate (100 grams) in toluene (600 ml) at -25 to -30 0 C and stirred up to completion of the reaction at 0 to -5 0 C.
  • reaction mixture was quenched with aqueous acetic acid (15% solution) at below
  • Example-13 Preparation of trityl olmesartan (formuIa-8):
  • Tritylolmesartan (100 grams) was added to aqueous acetic acid (400 ml in 200 ml of water) at 40-45°C and stirred up to the completion of reaction at 40-45°C.
  • the reaction mixture was cooled to 25-30°C and water (600 ml) was added.
  • the reaction mixture was cooled to 0-5 0 C and stirred for 60 minutes.
  • the unwanted solid was filtered off and washed with aqueous acetic acid.
  • Acetone (100 ml) was added to the above filtrate, cooled to 15-20°C and basii ⁇ ed with aqueous ammonia.
  • the reaction mixture temperature was raised to 25-30°C and filtered, washed the solid with water.
  • the obtained solid was dissolved in methylene chloride (1500 ml) then washed with water. The solvent was distilled off completely and acetone (200 ml) was added to the obtained residue at 25-30°C. The reaction mixture was heated to reflux and stirred for 30 minutes. The reaction mixture was cooled to 25-30 0 C and stirred for an hour. The obtained solid was filtered, washed with acetone and then dried to get the title compound.
  • Example-15 Purification of olmesartan medoxomil (formula-1):
  • Example-16 Purification of trityl olmesartan (formula-8):

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Abstract

La présente invention concerne un procédé amélioré pour la préparation d'un composé (5-méthyl-2-oxo- 1,3-dioxolen-4-yl)méthyl-4-(1-hydroxy- 1 -méthyléthyl)-2-propyl- l-[4-[2-(tétrazol-5-yl)phényl]phényl]méthyl imidazole-5-carboxylate de formule 1 par l'intermédiaire de (5-méthyl-2-oxo-l,3-dioxolen-4-yl)méthyl 4-(l-hydroxy-1-méthyléthyl)-2-propyl- 1 -[4-[2-(trityltétrazol-5-yl)phényl]phényl] méthylimidazole -5-carboxylate cristallin.
PCT/IN2010/000546 2009-08-19 2010-08-18 Procédé de préparation de (5-méthyl-2-oxo- 1,3-dioxolen-4-yl)méthyl-4-(1-hydroxy- 1 -méthyléthyl)-2-propyl- l-[4-[2-(tétrazol-5-yl)phényl]phényl]méthyl imidazole-5-carboxylate WO2011021224A2 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IN1975/CHE/2009 2009-08-19
IN1975CH2009 2009-08-19
IN3174CH2009 2009-12-24
IN3174/CHE/2009 2009-12-24

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014234354A (ja) * 2013-05-31 2014-12-15 株式会社トクヤマ オルメサルタンメドキソミルの製造方法
CZ305129B6 (cs) * 2010-11-24 2015-05-13 Zentiva, K.S. (5-Methyl-2-oxo-1,3-dioxol-4-ylmethyl)-4-(1-hydroxy-1-methyl-propyl)-2-propyl-1-[2´-(1H-tetrazol-5-yl)bifenyl-4-yl-methyl]imidazol-5-karboxylát jako nečistota olmesartan medoxomilu a způsob jeho přípravy
CN106083833A (zh) * 2016-06-30 2016-11-09 浙江华海药业股份有限公司 一种三苯甲基奥美沙坦酯的纯化方法
CN108047208A (zh) * 2018-01-12 2018-05-18 浙江华海药业股份有限公司 一种降低氯沙坦二聚物杂质的方法
CN112321575A (zh) * 2020-11-18 2021-02-05 福建天泉药业股份有限公司 一种适合工业化生产的奥美沙坦酯精制方法
CN112778209A (zh) * 2019-11-04 2021-05-11 宜昌东阳光长江药业股份有限公司 一种二酸的制备方法
CN115583940A (zh) * 2021-07-05 2023-01-10 润都制药(荆门)有限公司 一种制备洛沙坦钾关键中间体的方法

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JP2014234354A (ja) * 2013-05-31 2014-12-15 株式会社トクヤマ オルメサルタンメドキソミルの製造方法
CN106083833A (zh) * 2016-06-30 2016-11-09 浙江华海药业股份有限公司 一种三苯甲基奥美沙坦酯的纯化方法
CN108047208A (zh) * 2018-01-12 2018-05-18 浙江华海药业股份有限公司 一种降低氯沙坦二聚物杂质的方法
CN108047208B (zh) * 2018-01-12 2022-03-22 浙江华海药业股份有限公司 一种降低氯沙坦二聚物杂质的方法
CN112778209A (zh) * 2019-11-04 2021-05-11 宜昌东阳光长江药业股份有限公司 一种二酸的制备方法
CN112778209B (zh) * 2019-11-04 2024-05-14 宜昌东阳光长江药业股份有限公司 一种二酸的制备方法
CN112321575A (zh) * 2020-11-18 2021-02-05 福建天泉药业股份有限公司 一种适合工业化生产的奥美沙坦酯精制方法
CN112321575B (zh) * 2020-11-18 2023-07-21 福建天泉药业股份有限公司 一种适合工业化生产的奥美沙坦酯精制方法
CN115583940A (zh) * 2021-07-05 2023-01-10 润都制药(荆门)有限公司 一种制备洛沙坦钾关键中间体的方法

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