WO2011036674A1 - A new process for the preparation of olmesartan medoxomil - Google Patents

A new process for the preparation of olmesartan medoxomil Download PDF

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Publication number
WO2011036674A1
WO2011036674A1 PCT/IN2009/000721 IN2009000721W WO2011036674A1 WO 2011036674 A1 WO2011036674 A1 WO 2011036674A1 IN 2009000721 W IN2009000721 W IN 2009000721W WO 2011036674 A1 WO2011036674 A1 WO 2011036674A1
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Prior art keywords
olmesartan
process according
olmesartan medoxomil
trityl
methyl
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PCT/IN2009/000721
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French (fr)
Inventor
Purna Chandra Ray
Anand Pandey
Premchand Patil
Ram Harakh Singh
Venkanna Gudla
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Inogent Laboratories Private Limited
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D257/04—Five-membered rings

Definitions

  • This invention in general relates to process for producing (5-methyl-2-oxo- l,3-dioxolen-4-yl)methyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(tetrazol-5- yl)phenyl]phenyl]methylimidaozle-5-carboxylate (olmesartan medoxomil). More particularly, the present invention provides a novel process for producing olmesartan medoxomil from alkaline salts of trityl olmesartan.
  • Olmesartan medoxomil described chemically as 2,3-dihydroxy-2-butenyl 4- ( 1 -hydroxy- 1 -methylethyl)-2-propyI- 1 -[p-(o- 1 H-tetrazol-5-phenyl)benzyl]imidazole- 5-carboxylate, cyclic 2,3-carbonate and structurally as given below, is an antihypertensive agent. It is a selective ATI subtype angiotensin II receptor antagonist. Olmesartan works by blocking the action of a substance in the body that causes blood vessels to tighten. As a result, olmesartan relaxes blood vessels thereby lowers blood pressure.
  • olmesartan medoxomil is prepared from trityl olmesartan medoxomil by hydrolysis employing 25% acetic acid at 60 °C to release triphenyl methanol.
  • the isolation of the desired compound from the mixture is very tedious as large amount of impurities are formed during the process.
  • US 5616599 discloses a process for the preparation of olmesartan medoxomil comprising -reacting ethyl-4-(l -hydroxyl- 1 -methylethyl)-2-propyl imidazole-5- carboxylate with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole using NaH as base in N,N-dimethyIformamide at 60°C to give ethyl-4-(l -hydroxyl- 1- methylethyl)-2-propyl- 1 -[[2' -[2-(triphenylmethyl)-2H-tetrazol-5-yl]biphenyl-4- yl]methyl]imidazole-5-carboxylate
  • the lithium intermediate so formed in the above process is difficult to handle and isolate as it involves use of hazardous reagents, formation of impurities and numerous extractive workup in the final stage.
  • US 200600069141 discloses a process for preparing olmesartan medoxomil comprising contacting trityl olmesartan medoxomil with an acid in a water miscible organic solvent, with or without water, to obtain a solution of olmesartan medoxomil and a precipitate of triphenyl carbinol followed by separating the precipitate of triphenyl carbinol from the solution of olmesartan medoxomil and contacting the solution of olmesartan medoxomil with a base to obtain a precipitate of olmesartan medoxomil.
  • Olmesartan medoxomil isolated from acidic conditions contains about 2.2% olmesartan acid impurity
  • WO 2007017135 A2 covers a one-pot process, comprising hydrolysis of the olmesartan ethyl ester, subsequent esterification with 4-chloromethyl-5-methyl-l,2- oxo-l,3-dioxolene, and deprotection of the trityl protection without any isolation during the process also in addition, it discloses a method of preparing olmesartan medoxomil, wherein the trityl olmesartan medoxomil is dissolved in acidic solution resulting in deprotection. The solution is neutralized and crude olmesartan medoxomil is precipitated, and requires careful recrystallizatio for purification, as the trityl alcohol is the potential impurity during this process.
  • WO2007148344 A2 discloses a process for hydrolysis of trityl olmesartan ester to obtain trityl Olmesartan dihydrate, which is esterified with 4-chloromethyl-5- methyl-2-oxo-l,3-dioxolene in the presence of a base and catalyst to obtain trityl olmesartan medoxomil.
  • olmesartan medoxomil which comprising contacting trityl olmesartan medoxomil with an acid in water and water immiscible organic solvent, separating aqueous and organic layers, adjusting the pH of the aqueous layer with base, extracting the resulting solution with water-miscible organic solvents and isolating Olmesartan medoxomil.
  • US 20060258727A1 discloses an alternate process for preparing olmesartan medoxomil containing less than about 0.1% of one or more of its impurities, OLM- Me, OLM-C1 and OLM-eliminate.
  • the present invention provides a process for the preparation of trityl olmesartan medoxomil, comprising the steps of:
  • the final detritylation process involves using little quantity (-0.5T of batch size) of acid with water immiscible solvent to precipitate the product completely.
  • the crude product thus isolated by filtration is purified to get the pure olmesartan medoxomil.
  • the triphenyl methanol impurity is very much soluble and is not present in the final product.
  • the less quantity of acid used leads to less degradation of product to form the olmesartan medoxomil.
  • the olmesartan acid impurity in the final product is less then 0.1%.
  • trityl olmesartan ethyl ester III
  • trityl olmesartan calcium IV
  • X 4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene
  • V trityl olmesartan medoxomil
  • the hydrolysis is carried out in presence of an organic solvent selected from alcohols, such as methanol, ethanol, isopropyl alcohol, preferably isopropyl alcohol and the base selected such as lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide and lithium hydroxide, more preferably, potassium hydroxide.
  • an organic solvent selected from alcohols, such as methanol, ethanol, isopropyl alcohol, preferably isopropyl alcohol and the base selected such as lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide and lithium hydroxide, more preferably, potassium hydroxide.
  • the esterification is carried out in organic solvent selected from ketones, more preferably acetone and the base is selected from lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide and lithium hydroxide more preferably, potassium carbonate in presence of alkali iodide, which is selected from sodium iodide, lithium iodide, most preferably potassium iodide.
  • organic solvent selected from ketones, more preferably acetone and the base is selected from lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide and lithium hydroxide more preferably, potassium carbonate in presence of alkali iodide, which is selected from sodium iodide, lithium iodide, most preferably potassium iodide.
  • Olmesartan medoxomil is prepared from trityl Olmesartan medoxomil (V) in water/ water immiscible organic solvent in presence of minimum amount of acid and at low temperature to ambient temperature.
  • the organic solvent used is selected from aromatic hydrocarbons such as toluene or xylene, most preferably toluene.
  • the acid is selected from organic acids such as acetic acid, oxalic acid, formic acid, p-toluenesulfonic acid or inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, most preferably hydrochloric acid.
  • the olmesartan acid impurity is not more then 0.1% and the process waste is low in the present invention.
  • the invention also relates to a crystalline form of trityl olmesartan calcium based on which the following X-Ray diffraction pattern (in Fig. 1) has given as peaks at degrees 2 Theta: 10.486, 13.416, 18.394, 21.097, and 31.6.
  • the innovators have optimized the process and surprisingly found that by using little quantity (-0.5T of batch size) of acid with water immiscible solvent, the product precipitated completely.
  • the crude product, thus isolated by filtration is purified to get the pure olmesartan medoxomil.
  • the triphenyl methanol impurity is highly soluble in water and is not present in the final product.
  • the less quantity of acid used leads to less degradation of product to form the olmesartan medoxomil.
  • Ethy-4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 - ⁇ 4-[2-(trityltetrazole-5- yl)phenyl] phenyl ⁇ methylimidazole-5-carboxylate (1 OOg) was suspended in isopropyl alcohol (800ml)and added potassium hydroxide (15g). Reaction mass was stirred, after completion of reaction, isopropyl alcohol was distilled under reduced pressure. The reaction residue is added brine solution and extracted with ethyl acetate, the ethyl acetate layer is washed with saturated sodium bicarbonate solution. Partially recovered the ethyl acetate and added Calcium chloride (20gm).
  • the trityl olmesartan Calcium salt (lOOgm), acetone (1000ml), potassium carbonate (50g) and potassium iodide (5g) is subjected for reflux then 4- chloromethyl-5-methyl-l,3-dioxol-2-one(30g) solution in acetone is added at 50- 55°C. After completion of reaction, reaction mass was cooled and filtered to remove the salts. Filtered acetone is recovered and thus residue obtained is dissolved in toluene and cone hydrochloric acid (55ml) is added at -10 to -15°C and monitored the reaction with TLC . After completion of reaction, filtered the reaction mass and wash with toluene.
  • the residual material is suspended in ethyl acetate and washed the resulted suspension with sodium bicarbonate solution.
  • the ethyl acetate is partially distilled under reduced pressure to obtain the crude olmesartan medoxomil.
  • the crude olmesartan medoxomil is purified with acetone to yield pure olmesartan medoxomil (45 g). Chromatographic purity 99.89%.
  • the trityl olmesartan Calcium salt (lOOgm), acetone (1000ml), potassium carbonate (50g) and potassium iodide (5g) is subjected for reflux then 4- chloromethyl-5 -methyl- 1, 3 -dioxol-2-one(40g) solution in acetone is added at 50- 55°C. After completion of reaction, reaction mass was cooled and filtered to remove the salts. Filtered acetone is recovered and thus residue obtained is dissolved in toluene and cone hydrochloric acid (55ml) is added at -10 to -15°C and monitored the reaction with TLC . After completion of reaction, filtered the reaction mass and wash with toluene.
  • the residual material is suspended in methylene dichloride and washed the resulted suspension with sodium bicarbonate solution.
  • the methylene dichloride is distilled under reduced pressure and residue crystallized with ethyl acetate to obtain the crude olmesartan medoxomil.
  • the crude olmesartan medoxomil is purified with acetone to yield pure olmesartan medoxomil (42 g). Chromatographic purity 99.79%.
  • the trityl olmesartan Calcium salt (200gm), acetone (1800ml), potassium carbonate (200g) and potassium iodide (lOg) is subjected for reflux then 4- chloromethyl-5 -methyl- 1, 3 -dioxol-2-one(80g) solution in acetone is added at 50- 55°C. After completion of reaction, reaction mass was cooled and filtered to remove the salts. Filtered acetone is recovered and thus residue obtained is dissolved in toluene and cone hydrochloric acid (55ml) is added at -10 to -15°C and monitored the reaction with TLC . After completion of reaction, filtered the reaction mass and wash with toluene.
  • the residual material is suspended in methylene dichloride and washed the resulted suspension with sodium bicarbonate solution.
  • the methylene dichloride is distilled under reduced pressure and residue crystallized with ethyl acetate to obtain the crude olmesartan medoxomil.
  • the crude olmesartan medoxomil is purified with acetone to yield pure olmesartan medoxomil (42 g). Chromatographic purity 99.75%.

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Abstract

This invention provides a new process for producing (5-methyl-2-oxo-1,3- dioxolen-4-yl)methyl-4-(1-hydroxy-1-methylethyl)-2-propyl-1-[4-[2-(tetrazol-5- yl)phenyl] phenyl] methylimidaozle-5-carboxylate (olmesartan medoxomil) from alkaline salts of trityl olmesartan more preferably calcium salts of trityl olmesartan.

Description

A NEW PROCESS FOR THE PREPARATION OF OLMESARTAN
MEDOXOMIL
Field of the Invention
This invention, in general relates to process for producing (5-methyl-2-oxo- l,3-dioxolen-4-yl)methyl-4-(l-hydroxy-l-methylethyl)-2-propyl-l-[4-[2-(tetrazol-5- yl)phenyl]phenyl]methylimidaozle-5-carboxylate (olmesartan medoxomil). More particularly, the present invention provides a novel process for producing olmesartan medoxomil from alkaline salts of trityl olmesartan.
Background of the Invention
Olmesartan medoxomil, described chemically as 2,3-dihydroxy-2-butenyl 4- ( 1 -hydroxy- 1 -methylethyl)-2-propyI- 1 -[p-(o- 1 H-tetrazol-5-phenyl)benzyl]imidazole- 5-carboxylate, cyclic 2,3-carbonate and structurally as given below, is an antihypertensive agent. It is a selective ATI subtype angiotensin II receptor antagonist. Olmesartan works by blocking the action of a substance in the body that causes blood vessels to tighten. As a result, olmesartan relaxes blood vessels thereby lowers blood pressure.
Figure imgf000002_0001
Olmesartan medoxomil
Various processes for the preparation of olmesartan medoxomil are known in prior art.
In J.Med.Chem., 1996, 39, 323-338 by Yanagisawa et al, olmesartan medoxomil is prepared from trityl olmesartan medoxomil by hydrolysis employing 25% acetic acid at 60 °C to release triphenyl methanol. The isolation of the desired compound from the mixture is very tedious as large amount of impurities are formed during the process.
The product patent, US 5616599 discloses a process for the preparation of olmesartan medoxomil comprising -reacting ethyl-4-(l -hydroxyl- 1 -methylethyl)-2-propyl imidazole-5- carboxylate with N-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole using NaH as base in N,N-dimethyIformamide at 60°C to give ethyl-4-(l -hydroxyl- 1- methylethyl)-2-propyl- 1 -[[2' -[2-(triphenylmethyl)-2H-tetrazol-5-yl]biphenyl-4- yl]methyl]imidazole-5-carboxylate
-the above product is hydrolysed with lithium hydroxide monohydrate as base in 1,4-dioxane at 5-10 °C to give lithium salt of 4-( 1 -hydroxyl- 1 -methylethyl)-2- propyl-l-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl]biphenyl-4-yl]methyl]imidazole- 5-carboxylic acid
-coupling the product of the previous step with 5-methyl-2-oxo-l,3-dioxolene-
4-yi)methyl chloride using K2C03 as base in Ν,Ν-dimethylacetamide at 50 °C to give trityl Olmesartan medoxomil
-Trityl Olmesartan medoxomil on deprotection using 75% acetic acid give Olmesartan medoxomil as given in scheme-I.
Figure imgf000004_0001
Figure imgf000004_0002
OLMESARTAN MEDOXOMIL
Scbeme-I
The lithium intermediate so formed in the above process is difficult to handle and isolate as it involves use of hazardous reagents, formation of impurities and numerous extractive workup in the final stage.
US 200600069141 discloses a process for preparing olmesartan medoxomil comprising contacting trityl olmesartan medoxomil with an acid in a water miscible organic solvent, with or without water, to obtain a solution of olmesartan medoxomil and a precipitate of triphenyl carbinol followed by separating the precipitate of triphenyl carbinol from the solution of olmesartan medoxomil and contacting the solution of olmesartan medoxomil with a base to obtain a precipitate of olmesartan medoxomil. Olmesartan medoxomil isolated from acidic conditions contains about 2.2% olmesartan acid impurity WO 2007017135 A2 covers a one-pot process, comprising hydrolysis of the olmesartan ethyl ester, subsequent esterification with 4-chloromethyl-5-methyl-l,2- oxo-l,3-dioxolene, and deprotection of the trityl protection without any isolation during the process also in addition, it discloses a method of preparing olmesartan medoxomil, wherein the trityl olmesartan medoxomil is dissolved in acidic solution resulting in deprotection. The solution is neutralized and crude olmesartan medoxomil is precipitated, and requires careful recrystallizatio for purification, as the trityl alcohol is the potential impurity during this process.
WO2007148344 A2 discloses a process for hydrolysis of trityl olmesartan ester to obtain trityl Olmesartan dihydrate, which is esterified with 4-chloromethyl-5- methyl-2-oxo-l,3-dioxolene in the presence of a base and catalyst to obtain trityl olmesartan medoxomil.
The process for the preparation of olmesartan medoxomil which comprising contacting trityl olmesartan medoxomil with an acid in water and water immiscible organic solvent, separating aqueous and organic layers, adjusting the pH of the aqueous layer with base, extracting the resulting solution with water-miscible organic solvents and isolating Olmesartan medoxomil.
1 Existing process require a large quantity of acid during hydrolysis and further isolation to obtain olmesartan medoxomil involves neutralization of large quantity of acidic solution and exhaustive work up to isolate the material. In addition, the aforementioned process, employs large volume of the solvent, thereby making the process uneconomic. The large usage of hydrochloric acid (more then 6 volume) and neutralization of the same, requires large quantity of base. Moreover, the handling of the large quantity of acid during the neutralization stage is not amenable in large scale production and invites safety risks too.
US 20060258727A1 discloses an alternate process for preparing olmesartan medoxomil containing less than about 0.1% of one or more of its impurities, OLM- Me, OLM-C1 and OLM-eliminate.
In light of the foregoing discussion, there exists a need to develop an efficient, robust, cost effective and environment-friendly process for large scale production of olmesartan medoxomil. Further, the process should involve minimal use of acid and other solvents that is easier to handle during large scale production. Object and Summary of the Invention
It is a principal object of the present invention to provide a process for large scale production of olmesartan medoxomil.
It is another object of the present invention to provide a process for producing olmesartan medoxomil employing alkaline earth metal salts of trityl olmesartan like magnesium, calcium and barium, preferably calcium salt of trityl olmesartan.
It is a further object of the present invention to provide an economical process for producing olmesartan medoxomil, wherein the process involves minimal extractive workups and impurities employing alkaline earth metal salts of olmesartan medoxomil, preferably calcium salt.
It is yet another object of the present invention to provide a process for producing olmesartan medoxomil, wherein the process requires less amount of acid consumption as well as isolation procedure is minimized. This provides for better control for the process related impurities also.
According to the first aspect, the present invention provides a process for the preparation of trityl olmesartan medoxomil, comprising the steps of:
a) Alkylating 4-(l-Hydroxy-l-methyl)-2-propyl-lH-imidazole-5-carboxylic acid ethyl ester with N-(triphenylmethyl)-5-(4-bromomethyl biphenyl-2-yl) tetrazole in an organic solvent, in presence of a base and a phase transfer catalyst to give trityl olmesartan ethyl ester.
b) Hydrolyzing the trityl Olmesartan ethyl ester with alkaline chlorides more preferably calcium chloride in an organic solvent in presence of a base to give trityl olmesartan calcium, which is further treated with 4-chloromethyl-5-methyl-l,2-oxo- 1,3-dioxolene (X) to produce trityl olmesartan medoxomil of formula (V).
Figure imgf000007_0001
c). The final detritylation process involves using little quantity (-0.5T of batch size) of acid with water immiscible solvent to precipitate the product completely. The crude product thus isolated by filtration is purified to get the pure olmesartan medoxomil. The triphenyl methanol impurity is very much soluble and is not present in the final product. The less quantity of acid used leads to less degradation of product to form the olmesartan medoxomil. The olmesartan acid impurity in the final product is less then 0.1%.
Detailed description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description, of the invention and study of the included examples.
According to the present invention, trityl olmesartan ethyl ester (III) is hydrolyzed to obtain trityl olmesartan calcium (IV), which is isolated and esterified with 4-chloromethyl-5-methyl-2-oxo-l,3-dioxolene (X) in organic solvent in presence of base to isolate trityl olmesartan medoxomil (V).
The hydrolysis is carried out in presence of an organic solvent selected from alcohols, such as methanol, ethanol, isopropyl alcohol, preferably isopropyl alcohol and the base selected such as lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide and lithium hydroxide, more preferably, potassium hydroxide.
Figure imgf000008_0001
The esterification is carried out in organic solvent selected from ketones, more preferably acetone and the base is selected from lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide and lithium hydroxide more preferably, potassium carbonate in presence of alkali iodide, which is selected from sodium iodide, lithium iodide, most preferably potassium iodide.
Figure imgf000008_0002
Olmesartan medoxomil is prepared from trityl Olmesartan medoxomil (V) in water/ water immiscible organic solvent in presence of minimum amount of acid and at low temperature to ambient temperature.
The organic solvent used is selected from aromatic hydrocarbons such as toluene or xylene, most preferably toluene.
The acid is selected from organic acids such as acetic acid, oxalic acid, formic acid, p-toluenesulfonic acid or inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, most preferably hydrochloric acid.
The reaction is carried out at a temperature in the range of -10 to 25 °CS most preferably below 0 °C. Thus, in accordance with the present invention, the preparation of Olmesartan medoxomil follows the steps as given in the scheme below:
Figure imgf000009_0001
The olmesartan acid impurity is not more then 0.1% and the process waste is low in the present invention.
The invention also relates to a crystalline form of trityl olmesartan calcium based on which the following X-Ray diffraction pattern (in Fig. 1) has given as peaks at degrees 2 Theta: 10.486, 13.416, 18.394, 21.097, and 31.6.
The innovators have optimized the process and surprisingly found that by using little quantity (-0.5T of batch size) of acid with water immiscible solvent, the product precipitated completely. The crude product, thus isolated by filtration is purified to get the pure olmesartan medoxomil. The triphenyl methanol impurity is highly soluble in water and is not present in the final product. The less quantity of acid used leads to less degradation of product to form the olmesartan medoxomil.
The invention is further explained in detail in the following examples which is provided by way of illustrations only and should not be construed to limit the scope of the invention. EXAMPLES:
Experiment-1: Preparation of ethy-4-(l-hydroxy-l-methyIethyl)-2-propyl-l-{4- [2-(trityl tetrazole-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate
N-(triphenylmethyl)-5-(4-bromomethyl biphenyl-2-yl) tetrazole (100 g), 4-(l-
Hydroxy-l-methyl)-2-propyl-lH-imidazole-5-carboxylic acid ethyl ester(45g), potassium carbonate (50g) & tetrbutyl ammonium bromide (4 g) in acetone (800 ml) were refluxed for 14-17hr. Progress of reaction was monitor by HPLC. After completion of reaction, distilled the solvents and added water to the residual material. Filtered the material and dried to obtain ethy-4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- l-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (120 g).Chromatographic purity 97%.
Experiment-2: Preparation of Trityl Olmesartan Calcium
Ethy-4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 - {4-[2-(trityltetrazole-5- yl)phenyl] phenyl} methylimidazole-5-carboxylate (1 OOg) was suspended in isopropyl alcohol (800ml)and added potassium hydroxide (15g). Reaction mass was stirred, after completion of reaction, isopropyl alcohol was distilled under reduced pressure. The reaction residue is added brine solution and extracted with ethyl acetate, the ethyl acetate layer is washed with saturated sodium bicarbonate solution. Partially recovered the ethyl acetate and added Calcium chloride (20gm). The reaction mass is stirred over night, the precipitated material is filtered and washed with ethyl acetate. After drying the 89 gm Trityl Olmesartan Calcium obtained as white powder, purity 98% by HPLC. X-Ray diffraction pattern (in Fig. 1) given as peaks at degrees 2Theta: 10.486, 13.416, 18.394, 21.097, and 31.6.
Experiment-3: Preparation of Trityl Olmesartan Calcium
Ethy-4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 - {4- [2-(trityltetrazole-5- yl)phenyl] phenyl} methylimidazole-5-carboxylate (50g) was suspended in isopropyl alcohol (300ml) and added potassium hydroxide (8g). Reaction mass was stirred, after completion of reaction, isopropyl alcohol was distilled under reduced pressure. The reaction residue is added brine solution and extracted with ethyl acetate, the ethyl acetate layer is washed with saturated sodium bicarbonate solution. Partially recovered the ethyl acetate and added Calcium chloride (20gm). The reaction mass is stirred over night, the precipitated material is filtered and washed with ethyl acetate. After drying the 46 gm Trityl Olmesartan Calcium obtained as white powder, purity 97% by HPLC.
Experiment-4: Preparation of Trityl Olmesartan Calcium
Ethy-4-(l -hydroxy- l-methylethyl)-2-propyl-l -{4-[2-(trityltetrazole-5- yl)phenyl] phenyl} methylimidazole-5-carboxylate (500g) was suspended in isopropyl alcohol (2500mland added potassium hydroxide (80g). Reaction mass was stirred, after completion of reaction, isopropyl alcohol was distilled under reduced pressure. The reaction residue is added brine solution and extracted with ethyl acetate, the ethyl acetate layer is washed with saturated sodium bicarbonate solution. Partially recovered the ethyl acetate and added Calcium chloride (lOOgm). The reaction mass is stirred over night, the precipitated material is filtered and washed with ethyl acetate. After drying the 475 gm Trityl Olmesartan Calcium obtained as white powder, purity 97.5% by HPLC.
Experiment-5: Preparation of Trityl Olmesartan Calcium
Ethy-4-(l -hydroxy- 1 -methylethyl)-2 -propyl- 1 - {4-[2-(trityltetrazole-5- yl)phenyl] phenyl} methylimidazole-5-carboxylate (500g) was suspended in isopropyl alcohol (2500mland added potassium hydroxide (80g). Reaction mass was stirred, after completion of reaction, isopropyl alcohol was distilled under reduced pressure. The residual mass is diluted with ethyl acetate and Calcium chloride (lOOgm) is added. The reaction mass is stirred for lOhr, the precipitated material is filtered and washed with ethyl acetate. After drying the 475 gm Trityl Olmesartan Calcium obtained as white powder, purity 97.5% by HPLC.
Experiment-6: Preparation of Olmesartan medoxomil
The trityl olmesartan Calcium salt (lOOgm), acetone (1000ml), potassium carbonate (50g) and potassium iodide (5g) is subjected for reflux then 4- chloromethyl-5-methyl-l,3-dioxol-2-one(30g) solution in acetone is added at 50- 55°C. After completion of reaction, reaction mass was cooled and filtered to remove the salts. Filtered acetone is recovered and thus residue obtained is dissolved in toluene and cone hydrochloric acid (55ml) is added at -10 to -15°C and monitored the reaction with TLC . After completion of reaction, filtered the reaction mass and wash with toluene. The residual material is suspended in ethyl acetate and washed the resulted suspension with sodium bicarbonate solution. The ethyl acetate is partially distilled under reduced pressure to obtain the crude olmesartan medoxomil. The crude olmesartan medoxomil is purified with acetone to yield pure olmesartan medoxomil (45 g). Chromatographic purity 99.89%.
Experiment-7: Preparation of Olmesartan medoxomil
The trityl olmesartan Calcium salt (lOOgm), acetone (1000ml), potassium carbonate (50g) and potassium iodide (5g) is subjected for reflux then 4- chloromethyl-5 -methyl- 1, 3 -dioxol-2-one(40g) solution in acetone is added at 50- 55°C. After completion of reaction, reaction mass was cooled and filtered to remove the salts. Filtered acetone is recovered and thus residue obtained is dissolved in toluene and cone hydrochloric acid (55ml) is added at -10 to -15°C and monitored the reaction with TLC . After completion of reaction, filtered the reaction mass and wash with toluene. The residual material is suspended in methylene dichloride and washed the resulted suspension with sodium bicarbonate solution. The methylene dichloride is distilled under reduced pressure and residue crystallized with ethyl acetate to obtain the crude olmesartan medoxomil. The crude olmesartan medoxomil is purified with acetone to yield pure olmesartan medoxomil (42 g). Chromatographic purity 99.79%.
Experiment-8: Preparation of Olmesartan medoxomil
The trityl olmesartan Calcium salt (200gm), acetone (1800ml), potassium carbonate (200g) and potassium iodide (lOg) is subjected for reflux then 4- chloromethyl-5 -methyl- 1, 3 -dioxol-2-one(80g) solution in acetone is added at 50- 55°C. After completion of reaction, reaction mass was cooled and filtered to remove the salts. Filtered acetone is recovered and thus residue obtained is dissolved in toluene and cone hydrochloric acid (55ml) is added at -10 to -15°C and monitored the reaction with TLC . After completion of reaction, filtered the reaction mass and wash with toluene. The residual material is suspended in methylene dichloride and washed the resulted suspension with sodium bicarbonate solution. The methylene dichloride is distilled under reduced pressure and residue crystallized with ethyl acetate to obtain the crude olmesartan medoxomil. The crude olmesartan medoxomil is purified with acetone to yield pure olmesartan medoxomil (42 g). Chromatographic purity 99.75%.

Claims

We Claim:
1. A process for the preparation of (5-methyl-2-oxo-l,3-dioxolen-4- yl)methyl-4-( 1 -hydroxy- 1 -methylethyl)-2-propyl- 1 - [4- [2-(tetrazol-5- yl)phenyl]phenyl] methylimidaozle-5-carboxylate (olmesartan medoxomil (VI)) from alkaline earth metal salts of trityl olmesartan, process comprising reacting alkaline earth metal salts of trityl olmesartan and 4-chloromethyl-5-methyl-2-oxo-l,3- dioxolene (formula X) in water miscible organic solvent in the presence of base followed by extraction in water immiscible solvent and treatment with an acid to obtain a precipitate, where in the precipitated product is isolated by filtration, washing and slurring to obtain olmesartan medoxomil.
Figure imgf000013_0001
Olmesartan medoxomil
2. The process according to claim 1, wherein the crystalline forms of the trityl olmesartan calcium is characterized by X-Ray diffraction pattern (in Fig. 1) given as peaks at degrees 2Theta: 10.486, 13.416, 18.394, 21.097, and 31.6.
3. The process according to claim 1, wherein the alkaline earth metal is selected from magnesium, calcium and barium to form trityl olmesartan calcium (IV), trityl olmesartan magnesium and trityl olmesartan barium.
4. The process according to claim 1, wherein the organic solvent is selected from acetone, acetonitrile, methyl isobutyl ketone and ethyl methyl ketone.
5. The process according to claim 1, wherein the base is selected from lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide and lithium hydroxide.
6. A process according to claim 1, wherein the detritylation reaction is carried out with acid in the presence of immiscible solvents at a temperature in the range of -10 to 30°C.
7. A process according to claim 6, wherein Alteration of olmesartan medoxomil is carried out after detritylation.
8. The process according to claim 1, wherein the olmesartan acid impurity in the final product is not more then 0.3%.
9. A process according to claim 8, wherein the resultant product is purified by recrystallization employing an organic solvent.
10. A process according to claim 9, wherein the olmesartan Medoxomil (VI) obtained contains less then 0.1% of the olmesartan acid impurity.
PCT/IN2009/000721 2009-09-24 2009-12-15 A new process for the preparation of olmesartan medoxomil WO2011036674A1 (en)

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Publication number Priority date Publication date Assignee Title
CN103214469A (en) * 2013-04-29 2013-07-24 孙威 Olmesartan medoxomil compound and preparation method thereof
CN103304550A (en) * 2012-03-16 2013-09-18 湖南欧亚生物有限公司 Preparation method of Olmesartan Medoxomil
CN103435602A (en) * 2013-07-31 2013-12-11 山东省医学科学院药物研究所 Preparation method of olmesartan medoxomil
CN103951659A (en) * 2014-04-11 2014-07-30 烟台万润药业有限公司 Olmesartan Medoxomi I with low solvent residue
CN109081833A (en) * 2018-09-25 2018-12-25 廊坊市泽康医药科技有限公司 A kind of preparation method of olmesartan medoxomil intermediate
CN107311990B (en) * 2017-07-25 2021-09-03 浙江华海致诚药业有限公司 Preparation method of olmesartan medoxomil

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WO2002006279A1 (en) * 2000-07-17 2002-01-24 Oxigene Inc Efficient method of synthesizing combretastatin a-4 prodrugs
WO2008076862A2 (en) * 2006-12-18 2008-06-26 Novartis Ag 1-substituted imidazole derivatives and their use as aldosterone synthase inhibitors
EP2036904A1 (en) * 2007-08-08 2009-03-18 LEK Pharmaceuticals D.D. A process for the preparation of olmesartan medoxomil

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WO2002006279A1 (en) * 2000-07-17 2002-01-24 Oxigene Inc Efficient method of synthesizing combretastatin a-4 prodrugs
WO2008076862A2 (en) * 2006-12-18 2008-06-26 Novartis Ag 1-substituted imidazole derivatives and their use as aldosterone synthase inhibitors
EP2036904A1 (en) * 2007-08-08 2009-03-18 LEK Pharmaceuticals D.D. A process for the preparation of olmesartan medoxomil

Cited By (7)

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Publication number Priority date Publication date Assignee Title
CN103304550A (en) * 2012-03-16 2013-09-18 湖南欧亚生物有限公司 Preparation method of Olmesartan Medoxomil
CN103304550B (en) * 2012-03-16 2016-01-27 湖南欧亚生物有限公司 A kind of preparation method of olmesartan medoxomill
CN103214469A (en) * 2013-04-29 2013-07-24 孙威 Olmesartan medoxomil compound and preparation method thereof
CN103435602A (en) * 2013-07-31 2013-12-11 山东省医学科学院药物研究所 Preparation method of olmesartan medoxomil
CN103951659A (en) * 2014-04-11 2014-07-30 烟台万润药业有限公司 Olmesartan Medoxomi I with low solvent residue
CN107311990B (en) * 2017-07-25 2021-09-03 浙江华海致诚药业有限公司 Preparation method of olmesartan medoxomil
CN109081833A (en) * 2018-09-25 2018-12-25 廊坊市泽康医药科技有限公司 A kind of preparation method of olmesartan medoxomil intermediate

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