AN IMPROVED PROCESS FOR THE PREPARATION OF OLMESARTAN
MEDOXOMIL
Field of the Invention
This invention, in general relates to a process for producing (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). More particularly, the present invention provides an improved process for preparing Olmesartan medoxomil.
Background of the Invention Olmesartan medoxomil, described chemically as 2,3-dihydroxy-2-butenyl 4-(l-hydroxy- l-methylethyl)-2-propyl-l-[p-(o-lH-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. This lowers blood pressure.
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 in 25% acetic acid at 60 °C and triphenyl methanol is released. The drawback of this process the Isolation technique is very tedious and has not very good control for the impurities formation.
The product patent, US 5616599 discloses a process for the preparation of Olmesartan medoxomil comprising
-reacting ethyl-4-(l-hydroxyl-l-methylethyl)-2-propyl imidazole-5-carboxyIate with N- (triphenylmethyl)-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole using NaH as base in N,N- dimethylformamide at 60°C to give ethyl-4-(l-hydroxyl-l-methylethyl)-2-propyl-l-[[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-(l-hydroxyl-l-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- yl)methyl chloride using K2CO3 as base in N,N-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-1.
CPha NaH.
N = N
Br
HO
HO
N = N
CPh-,
N,N-d\metliylfonnam\de. 60 °C

LiOHHjO,
1.4-dioxane.
5-10°C
HO
Kc
HO
K2CO3
NrN-Dimethvlacetamide
O
.0
Li' T "N O
N = N
O
CPho
CPh,
O
O

75% Acetic acid

HO
O
N=N

OLMESARTAN MEDOXOMIL
Scheme-I
The final step in the aforementioned patent, involves use of hazardous reagents, formation of impurities and numerous extractive workup.
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.

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 appears to cover a one-pot process, comprising hydrolysis of the Olmesartan ethyl ester, the esterification with 4-chloromethyl-5-methyl-l,2-oxo-l,3- dioxolene, and the subsequent deprotection of the trityl protection without any Isolation during the process.
It also discloses a method of preparing Olmesartan medoxomil, where the trityl Olmesartan medoxomil is dissolved in acidic Solution which causes deprotection to occur. The Solution is neutralized and crude Olmesartan medoxomil is precipitated, which has to be carefully recrystallized to purify it, as the trityl alcohol is the potential impurity during this process.
W02007148344 A2 appears to cover process for hydrolysis of trityl olmesartan ester to obtain trityl Olmesartan dihydrate, which is esterified with 4-chloromethyl-5-methyl-2- 0X0-1,3-dioxolene in the presence of a base and catalyst to obtain Trityl Olmesartan medoxomil.
It Covers a process for the preparation of Olmesartan medoxomil which comprises:
i) contacting trityl Olmesartan medoxomil with an acid in water and water immiscible organic solvent
ii) separating aqueous and organic layers
iii) adjusting the pH of the aqueous layer with base
iv) extracting the resulting Solution of step iii) with water-miscible organic solvents and
v) isolating Olmesartan medoxomil.
A large quantity of acid is used and the isolation of Olmesartan medoxomil involves neutralization of large quantity of acidic Solution and exhaustive work up to isolate the material. The volume of the solvent used is high in the aforementioned process, which is not cost-effective. This process involved the large usage of hydrochloric acid (more then 6 volume) and neutralization of the same, requires large quantity of base. The handling of the large quantity of acid in the neutraHzation stage is not production friendly and invites safety risks too.
US 2006/0258727A1 appears to cover a process of preparing Olmesartan medoxomil containing less than about 0.1% of one or more of its impurities, OLM-Me, OLM-Cl and OLM-eliminate,
There is always a need to develop an efficient, robust, cost effective and environment- friendly process of olmesartan medoxomil. Surprisingly we found a process, where acid consumption as well as Isolation procedure is minimized. This provides for better control for the process related impurities also.
Summary of the Invention
According to the first aspect, the present invention provides a process for preparation of trityl Olmesartan medoxomil, comprising the steps of
a) alkylating 4-(l-Hydroxy-]-methyl)-2-propyl-lH-imidazole-5-carboxylic acid ethyl ester with N-(triphenylmethyl)-5-(4-bromomethyl biphenyl-2-yl) tetrazole in an organic solvent, presence of a base and a phase transfer catalyst to give trityl Olmesartan ethyl ester
b) hydrolysing the trityl Olmesartan ethyl ester in an organic solvent in presence of a base to give trityl Olmesartan acid, which is further treated with 4-chloromethyl-5-methyl-l,2- oxo-l,3-dioxolene to produce trityl Olmesartan medoxomil of formula (V).
In another aspect, the present invention involves the process of preparation of Olmesartan medoxomil by deprotecting trityl Olmesartan medoxomil of formula (V) in an organic solvent, by using less amount of acid and maintaining the reaction at low temperature to reduce the impurities formed during the process.
O
o
N-

U
N
Toluene, Concd HCl
-10to-l5°C

Olmesartan medoxomil
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 very much 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 olmesartan acid impurity is always less then 0.1% even in crude product.
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 is hydrolysed to obtain trityl Olmesartan acid, which is not isolated, but is in situ esterified with 4-chloromethyl- 5-methyl-2-oxo-l,3-dioxolene in organic solvent in presence of base to isolate trityl Olmesartan medoxomil.
The hydrolysis is carried out in presence of organic solvent selected from alcohols, such as methanol, ethanol, isopropyl alcohol, preferably isopropyl alcohol and the base selected from alkali hydroxides such as sodium hydroxide, potassium hydroxide, more preferably, potassium hydroxide.

O^OH
(Ph3)C
{Ph)3C'
IPA KOH/lPA

The esterification is carried out in organic solvent selected from ketones, more preferably acetone and the base is selected from alkali metal carbonates such as sodium carbonate or potassium carbonate, more preferably, potassium carbonate in presence of alkali iodide, which is selected from sodium iodide, lithium iodide, most preferably potassium iodide.
VO

Olmesartan medoxomil is prepared from trityl Olmesartan medoxomil 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, 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 ränge of -10 to 25 °C, 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:
(PhjjC

IPA KOH/iPA
1- -^O
O^OH

Vo V
Toliiene. Concd HCl
-10to-15°C

The Olmesartan acid impurity is not more then 0.1% in the crude product and the process waste is low in the present invention.
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.
EXAMPLE 1:
Preparation of ethv-4-(l-hvdroxv-l-methylethvl)-2-propvl-l-(4-f2-(tritvl tetrazole-5- yl) phenyll phenvU methylimidazole-S-carboxylate (III)
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 (40 g), potassium carbonate (50g)& tertiary butyl ammonium bromide (4 g) in acetone (800 ml) are refluxed for 14- 17 hr. The progress of the reaction is monitored by HPLC. After completion of the reaction, the solvents are distilled and water is added to the residual material. The material is filtered and dried to obtain ethy-4-(l-hydroxy-l-methylethyl)-2-propyl-l-{4- [2-(trityl tetrazole-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (120 g).Chromatographie purity 97%.
EXAMPLE 2:
Preparation of Trityl Olmesartan Medoxomil
Ethy-4-( 1 -hydroxy-1 -methylethyl)-2-propyl-1 - {4-[2-(trityltetrazole-5-yl)phenyl] phenyl} methylimidazole-5-carboxylate (100g) was suspended in isopropyl alcohol (400ml) and added potassium hydroxide (15g). The reaction mass is stirred. After completion of the reaction, isopropyl alcohol is distilled ander reduced pressure. The reaction residue is added to brine Solution and extracted with ethyl acetate, the ethyl acetate layer is washed with saturated sodium bicarbonate Solution. Distilled the ethyl acetate to obtain the residual material, to which, acetone (700ml), potassium carbonate (50g) and potassium iodide (5g) are added and the temperature is raised to 50-55°C. 4-chloromethyl-5-methyl- l,3-dioxol-2-one(30g) is added to the Solution in acetone at 50-55°C and monitored the reaction with TLC. After completion of the reaction, the reaction mass is cooled and filtered to remove the salts. The filtered acetone is recovered and the residue obtained is crystallized from methanol to give trityl Olmesartan Medoxomil (90 g). Chromatographie purity: 98%
EXAMPLE 3:
Preparation of Olmesartan medoxomil
Concentrated hydrochloric acid (55ml) is added to the Solution of trityl olmesartan medoxomil (100 g) in toluene (800 ml) at -10 to -15 °C and monitored the reaction with TLC. After completion of reaction, the reaction mass is filtered and washed with toluene. The residual material is suspended in dichloromethane and washed the dichloromethane suspension with sodium bicarbonate Solution. The solvent, dichlomethane is distilled under reduced pressure and the residue is crystallized with ethyl acetate to obtain the crude olmesartan medoxomil. The crude olmesartan medoxomil is purified with acetone to obtain pure olmesartan medoxomil (47 g). Chromatographie purity 99.58%.
EXAMPLE 4:
Preparation of ethv-4-(l-hvdroxv-l-methvlethvl)-2-propvl-l-(4-[2-(tritvl tetrazole-5- yl) phenyl] phenyl} methylimidazole-S-carboxylate (III)
N-(triphenylmethyl)-5-(4-bromomethyl biphenyl-2-yl) tetrazole (100 g), 4-(l-Hydroxy-l- methyl)-2-propyl-lH-imidazoIe-5-carboxylic acid ethyl ester(40 g), potassium carbonate (50g)& tertiary butyl ammonium bromide(4 g) in acetone (800 ml) were refluxed for 14- 17hr. The progress of reaction is monitored by HFLC. After completion of the reaction, the reaction mass is cooled and filtered to remove the salts. The filtrate is recovered and the residue obtained is crystallized in methanol to get ethy-4-(l-hydroxy-l-methylethyl)- 2-propyl-l-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (115 g). Chromatographie purity. 96%
EXAMPLE 5:
Preparation of Olmesartan medoxomil
Ethy-4-( 1 -hydroxy-1 -methylethyl)-2-propyl-1 -{4-[2-(trityltetrazole-5-yl)phenyl] phenyl} methylimidazole-5-carboxylate (100g), product of Example 3 and potassium hydroxide (ISgm) is suspended in isopropyl alcohol (300ml). The progress of the reaction is monitored by TLC. After completion of reaction, isopropyl alcohol is distilled under reduced pressure. The reaction mixture is extracted with ethyl acetate and recovered to get the residual material, which is dissolved in acetone (700ml), potassium carbonate (50g) and potassium iodide (5g) are added to it. Acetone Solution of 4-chloromethyl-5- methyl-l,3-dioxol-2-one (35g) is added to it at reflux temperature. The progress of the reaction is monitored by TLC. After completion of reaction, the reaction mass is cooled and filtered to remove the salts. The mother Hquor is recovered and the residue obtained is dissolve in toluene (800ml), concentrated hydrochloric acid (50ml) is added at -10 to - 15 °C and the reaction is monitored with TLC. After completion of reaction, the reaction mass is filtered and washed with toluene. The residual material is suspended in dichloromethane and the dichloromethane suspension is washed with sodium bicarbonate Solution. Dichlomethane is distilled under reduced pressure and the residue is crystallized with acetone to obtain crude olmesartan medoxomil. The crude olmesartan medoxomil is purified with acetone to yield pure olmesartan medoxomil (49g). Chromatographie purity 99.67%
EXAMPLE 6:
Preparation of Trityl Olmesartan medoxomil
To dimethyl sulphoxide (500ml), N-(triphenylmethyl)-5-(4-bromomethyl biphenyl-2- yl) tetrazole (95 g) , 4-(l-methyl-l-methylethyl) -2-propyl-imidazole-5-ethyl carboxylate (50gm) and sodium hydroxide (30gm) is stirred at 25-30 °C for 12 hr. The progress of reaction is monitored by TLC. After completion of reaction, water (40ml) is added and the temperature is raised to 40-45°C. The progress of the reaction was monitored by TLC. After completion of reaction, 5-methy-2-oxo-l,3-dioxane-4yl) methyl chloride (55ml)was added slowly at 50-55°C and the progress of reaction is monitored by TLC. After completion of reaction, the reaction mass is cooled to 30-35 °C and in the process water (1500ml) is added, filtered and washed with water and dried. The dried material is purified with methanol and dried under vacuum at 40-45°C to yield 110 gm of the title Compound. Chromatographie purity: 98.5%
EXAMPLE 7:
Preparation of Olmesartan medoxomil
Concentrated hydrochloric acid (25ml) is added to the Solution of trityl olmesartan medoxomil (50gm)) in toluene (500 ml) at -10 to -15 °C and the reaction is monitored with TLC. After completion of reaction, the reaction mass is filtered and washed with toluene, The residual material is suspended in dichloromethane and washed the dichloromethane suspension with sodium bicarbonate Solution. Dichlomethane is distilled under reduced pressure and the residue is crystallized with ethyl acetate to obtain the crude olmesartan medoxomil. The crude olmesartan medoxomil is purified with acetone to yield pure olmesartan medoxomil (23 g). Chromatographie purity: 99.42%.
EXAMPLE 8:
Preparation of ethv-4-(l-hvdroxv-l-methvlethvl)-2-propvl-l-{4-[2-(tritvl tetrazole-5- yl) phenylj phenyl} methylimidazole-S-carboxylate (III)
To dimethyl sulphoxide (300ml), sodium hydroxide powder (20gm), 4-(l-methyl-l- methylethyl) -2-propyl-imidazole-5-ethyl carboxylate (40gm), N-(triphenylmethyl)-5-(4- bromomethyl biphenyl-2-yl) tetrazole (lOOgm) are added at 25-30 °C and stirred for 12- 15 hr. The progress of the reaction is monitored with TLC. After completion of the reaction, water (700ml) is added, filtered and washed with water (300ml) and dried at 45- 50°C for 12hr, to give 126 gm of the title Compound. Chromatographie purity: 93%
EXAMPLE 9;
Preparation of Trityl Olmesartan Medoxomil
To dimethyl sulphoxide (300ml), water (50 ml), sodium hydroxide powder (20gm) and ethy-4-(l-hydroxy-l-methylethyl)-2-propyl-l-{4-[2-(trityl tetrazole-5-yl) phenyl] phenyl} methylimidazole-5-carboxylate (100 g) is added at 20-25°C. The temperature of the reaction mass is raised to 40-45°C and the progress of reaction is monitored with TLC. 5-methy-2-oxo-l,3-dioxane-4yl) methyl chloride (60ml) is added slowly at 50- 55°C Over a period of 20 min and the reaction is monitored with TLC . After completion of reaction, water (1000ml) is added, filtered and washed with water, dried at 45-50°C for 12hr. The dried material is suspended in methanol, filtered, washed with methanol and dried under vacuum at 40-45°C to give 100 gm of the title Compound. Chromatographie purity: 98.8%
EXAMPLE 10:
Preparation of Olmesartan medoxomil
Concentrated hydrochloric acid (100ml) is added to the Solution of trityl olmesartan medoxomil (200gm)) in toluene (2000 ml) at -10 to -15 °C and monitored the reaction with TLC. After completion of reaction, filtered the reaction mass and washed with toluene. The residual material is suspended in ethyl acetate and washed the suspension with sodium bicarbonate Solution. The ethyl acetate is distilled under reduced pressure and the residual material is crystallized with ethyl acetate to obtain the crude olmesartan medoxomil. The crude olmesartan medoxomil is purified with acetone to yield pure olmesartan medoxomil (85 g). Chromatographie purity: 99.71%.

We Claim:
1. A process for preparation of (5-methyl-2-oxo-l,3-dioxolen-4-yl)methyl-4-(l-hydroxy- l -methylethyl)-2-propyl-1 -[4-[2-(tetrazoI-5-yl)phenyI]phenyI]methyIimidaozIe-5- carboxylate (Olmesartan medoxomil) from trityl Olmesartan medoxomil in water immiscible organic solvent in presence of acid and at low temperature to ambient temperature.
-10 to -15 °C

wherein, the precipitated product is isolated by Filtration and washed with organic solvent.
2. The organic solvent used according to claim 1, is selected from aromatic hydrocarbons such as toluene or xylene, preferably toluene.

3. The acid according to claim 1, is selected from inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, most preferably hydrochloric acid.
4. A process according to claim 1, wherein reaction is carried out at a temperature in the ränge of -10 to 25 °C, most preferably below 0°C
5. A process according to claim 1, wherein Olmesartan acid impurity is not more then 0.1%.
6. The product thus obtained in Solution from the claim 1, is washed to obtain crude olmesartan medoxomil.
7. The crude product obtained from claim 6, is purified by recrystallization with organic solvents.
8. The process according to claim 7, wherein the organic solvents is selected from acetone and ethyl acetate.
9. The process according to claim 7, wherein the olmesartan obtained contains less then 0.05% of the olmesartan acid impurity.