A NEW PROCESS FOR THE PREPARATION OF OLMESARTAN
MEDOXOMIL
Field of the Invention This invention, in general relates to new process for producing (5-methyl-2-oxo-l,!-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 a new process for the preparation of Olmesartan medoxomil from alkaline salts of Trityl olmesartan.
Background of the Invention Olmesartan medoxomil, described chemically as 2,3-dihydroxy-2-butenyl 4-(l-hydrox; -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 prepjiration 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 Olmesartjm medoxomil by hydrolysis in 25% acetic acid at 60 °i 1 and triphenyl methanol is released. The drawback of this process the isolation techniqu i 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 Olmesartsn medoxomil comprising
-reacting ethyl-4-(l-hydroxyl-l-methylethyl)-2-propyl imidazole-5-carboxylate with >-(triphenylmethyl)-5-[4'-(bromomethyl)biphenyI-2-yl]tetrazole using NaH as base in 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-carboxyIate
-the above product is hydrolysed with lithium hydroxide monohydrate as base in 1 ,^ -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-^-yl)methyl chloride using KiCOs as base in N,N-dimethylacetamide at 50 °C to give tritj 1 Olmesaitan medoxomil
-Trityl Olmesartan medoxomil on deprotection using 75% acetic acid give Olmesartai medoxomil as given in scheme-1.


Isolation of lithium intennediate in the above process is difficult to handle and the fini .1 step in the aforementioned patent, involves use of hazardous reagents, formation c f 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 solven, with or without water, to obtain a solution of Olmesartan medoxomil and a precipitate c f triphenyl carbinol.

Separating the precipitate of triphenyl carbinol from the solution of Olmesartrn 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% Olmesartj n acid impurity
WO 2007017135 A2 appears to cover a one-pot process, comprising hydrolysis of tie Olmesartan ethyl ester, the esterification with 4-chloromethyl-5-methyl-1,2-oxo-1,;-dioxolene, and the subsequent deprotection of the trityl protection without any isolatia n 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 ta occur. The solution is neutralized and crude Olmesartan medoxomil is precipitatec, which has to be carefully recrystallized to purify it, as the trityl alcohol is the potentii 1 impurity during this process.
WO2007148344 A2 appears to cover process for hydrolysis of trityl olmesartan ester t)
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 Olmesartai
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 immiscibl;
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 involve; neutralization of large quantity of acidic solution and exhaustive work up to isolate th( material. The volume of the solvent used is high in the aforementioned process, which ii

not cost-effective. This process involved the large usage of hydrochloric acid (more thi n 6 volume) and neutralization of the same, requires large quantity of base. The handlii g of the large quantity of acid in the neutralization stage is not production friendly ai d invites safety risks too.
US 2006/0258727A1 appears to cover a process of preparing Olmesartan medoxoreil containing less than about 0.1% of one or more of its impurities, OLM-Me, OLM-Cl ai d OLM-eliminate,
There is always a need to develop an efficient, robust, cost effective and environment-friendly process of olmesartan medoxomil. The present invention overcome above prior art problems, especially when alkaline earth metal salts of trityl Olmesartan like Magnesium, Calcium and barium is used more preferably Calcium salt of trityl Olmesairtan. The process shows isolation of alkaline salts more preferably Calcium salt s much easier because of the divalent nature of the Calcium and also because of eas y crystallization.
One embodiment of this process is to minimize the multi-step extractive workups and t a minimize the impurities by using alkaline earth metals more preferably Calcium salts.
Another embodiment of this process, where acid consumption as well as isolation procedure is minimized. This provides for better control for the process related impuritit s also.
Summary of the Invention
According to the first aspect, the present invention provides a process for preparation c f trityl Olmesartan medoxomil, comprising the steps of:
a) Alkylating 4-(l-Hydroxy-l-methyl)-2-propyl-lH-imidazole-5-carboxylic acid ethjl ester with N-(triphenylmethyl)-5-(4-bromomethyl biphenyl-2-yl) tetrazole in an organi:

solvent, presence of a base and a phase transfer catalyst to give trityl Olmesartan eth ^^l
ester
b) Hydrolyzing the trityl Olmesartan ethyl ester with alkaline chlorides more preferab y
Calcium chloride in an organic solvent in presence of a base to give trityl olmesarti n
Calcium, which is further treated with 4-chloromethyl-5-methyl-l,2-oxo-I,3-dioxoleie
(X) to produce trityl olmesartan medoxomil of formula (V).

C. The innovators have optimized the final detritylation process and surprisingly foun 1 that by using little quantity (~().5T of batch size) of acid with water immiscible solven , the product precipitated completely. The crude product, thus isolated by filtration i> purified to get the pure olmesartan medoxomil. The triphenyl methanol impurity is ver' much soluble and is not present in the final product. The less quantity of acid used lead i to less degradation of product to form the olmesartan medoxomil. The olmesartan acii I impurity is always less then 0.1%.

Detailed description of the Invention
While this specification concludes with claims particularly pointing out and distinct y claiming that, which is regarded as the invention, it is anticipated that the invention a n be more readily understood through reading the following detailed description of tl e invention and study of the included examples.
According to the present invention, trityl olmesartan ethyl ester (III) is hydrolyzed i o obtain Trityl Olmesartan Calcium (IV), which is isolated and esterified with -^-chloromethyl-5-methyl-2-oxo-l,3-dioxolene (X) in organic solvent in presence of base l3 isolate trityl olmesartan medoxomil (V).
The hydrolysis is carried out in presence of organic solvent selected from alcohols, sue i as methanol, ethanol, isopropyl alcohol, preferably isopropyl alcohol and the basj selected from alkali hydroxides such as sodium hydroxide, potassium hydroxide, moij preferably, potassium hydroxide.

The esterification is canied out in organic solvent selected from ketones, mor; preferably acetone and the base is selected from alkali metal carbonates such as sodiun i carbonate or potassium carbonate, more preferably, potassium carbonate in presence o' alkali iodide, which is selected from sodium iodide, lithium iodide, most preferabl; potassium iodide.


Olmesartan medoxomil is prepared from trityl Olmesartan medoxomil (V) in wate/ water immiscible organic solvent in presence of minimum amount of acid and at lo^ v temperature to ambient temperature.
The organic solvent used is selected from aromatic hydrocarbons such as toluene cr 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 °C, most preferabl;' below 0 °C.
Thus, in accordance with the present invention, the preparation of Olmesartan medoxomi follows the steps as given in the scheme below:


The Olmesartan acid impurity is not more then 0.1% and the process waste is low in th;
present invention.
The invention also relates to a crystalline form of Trityl Olmesartan Calcium based o a
which the following X-Ray diffraction pattern (in Fig. 1) has given as peaks at degrees
2Theta: 10.486, 13.416, 18.394, 21.097, and 31.6.
The innovators have optimized the process and surprisingly found that by using litth
quantity (~0.5T of batch size) of acid with water immiscible solvent, the product
precipitaited completely. The crude product, thus isolated by filtration is purified to g( t
the pure olmesartan medoxomil. The triphenyl methanol impurity is highly soluble ii
water and is not present in the final product. The less quantity of acid used leads to les 3
degradation of product to form the olmesartan medoxomil.

The invention is further explained in detail in the following examples which is provide d by way of illustrations only and should not be construed to limit the scope of tie invention.
EXAMPLES;
Experiment-1: Preparation of ethy-4-(l-hydroxy-l-methylethyl)-2-propyl-l-{4-[2-(trityl tetrazole-5-yI) phenyl] phenyl} methylimidazole-S-carboxylate
N-(triphenylmethyl)-5-(4-bromomethyl biphenyl-2-yl) tetrazole (100 g), 4-(l-Hydroxy- -methyl)-2-propyl-lH-imidazole-5-carboxylic acid ethyl ester(45g), potassium carbonae (50g)& tetrbutyl ammonium bromide (4 g) in acetone (800 ml) were refluxed for 1' -17hr.Progress of reaction was monitor by HPLC. After completion of reaction, distilkd the solvents and added water to the residual material. Filtered the material and dried o obtain ethy-4-(l-hydroxy-1-methylethyl)-2-propyl-l-{4-[2-(trityl tetrazole-5-yl) pheny ] phenyl} methylimidazole-5-carboxylate (120 g).Chromatographic purity 97%.
Experiment-2: Preparation of Trityl Olmesartan Calcium
Ethy-4-(l-hydroxy-1 -methylethyl)-2-propyl-1 -{4-[2-(trityltetrazole-5-yl)phenyl] pheny}
methylimidazole-5-carboxylate (lOOg) was suspended in isopropyl alcohol (800ml)ani added potassium hydroxide (15g). Reaction mass was stirred, after completion (f reaction, isopropyl alcohol was distilled under reduced pressure. The reaction residue : s added brine solution and extracted with ethyl acetate, the ethyl acetate layer is washe 1 with saturated sodium bicarbonate solution. Partially recovered the ethyl acetate anl added Calcium chloride (20gm). The reaction mass is stirred over night, the precipitate 1 material is filtered and washed with ethyl acetate. After drying the 89 gm Trit; i Olmesaitan Calcium obtained as white powder, purity 98% by HPLC. X-Ray diffraction pattem (in Fig. 1) given as peaks at degrees 2Theta: 10.486, 13.416, 18.394, 21.097, anl 31.6.
Experiment-3: Preparation of Trityl Olmesartan Calcium
Ethy-4-(l-hydroxy-l-methylethyl)-2-propyl-l-{4-[2-(trityltetrazole-5-yl)phenyl] phenyl}
methylimidazole-5-carboxylate (50g) was suspended in isopropyl alcohol (300ml) ani added potassium hydroxide (8g). Reaction mass was stirred, after completion of reactioi,

isopropyl alcohol was distilled under reduced pressure. The reaction residue is add