FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
A NOVEL PROCESS FOR PURIFICATION OF OLMESARTAN MEDOXOMIL
UNICHEM LABORATORIES LIMITED, A COMPANY
REGISTERED UNDER THE INDIAN COMPANY ACT, 1956, HAVING ITS REGISTERED OFFICE LOCATED AT
MAHALAXMI CHAMBERS, 2nd FLOOR,
22, BHULABHAIDESAI ROAD, MUMBAI-400 026.
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

A Novel process for purification of Olmesartan medoxomil.
Technical Field
The present invention relates to a simple and convenient process for making pure Olmesartan medoxomil.
Background of the Invention:
Olmesartan medoxomil is an angiotensin II receptor antagonist, used in the treatment of hypertension. The chemical name of Olmesartan medoxomil is 4-(l-Hydroxy-1-methyl ethyl)-2-propyl-l-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl)methyl]-l-H-imidazole-5-carboxylic acid (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl ester and is represented by the following chemical formula (I).

(I)
The Olmesartan medoxomil has been covered under US 5616599 (Apr 1997, Hiroaki Y, et al). The said patent also describes the synthesis of Olmesartan medoxomil involving (5-methy 1-2-oxo-l, 3-dioxolen-4-yl) methyl -4- (1 -hydroxy- l-methylethyl)-2-propyl

imidazole-5-carboxylate (II) and 4-[2-(trityl tetrazol-5-yl)-phenyl)] benzyl bromide (III) as the key intermediates.
,Br

^^ C(Ph)2
(III)

Example 61 of the '599 patent discloses preparation of olmesartan medoxomil via condensation of both the intermediates (II) and (III) in N,N-dimethylacetamide in presence of potassium carbonate at 60°C. After the reaction, the mass was diluted with ethyl acetate and the ethyl acetate was washed with water. The distillation of the solvent under reduced pressure gave the residue and the resulting residue was column chromatographed to get the amorphous solid. The solid thus obtained was crystallized from diisopropyl ether to get the pure trityl olmesartan medoxomil as represented by formula (IV). The trityl olmesartan medoxomil was detritylated in aqueous acetic acid. After evaporation of aqueous acetic acid, the residue was dissolved in toluene and again toluene was distilled to remove traces of water and acetic acid. The residue was again column chromatographed to get the Olmesartan medoxomil (I).

(IV)
Thus in the process described above olmesartan medoxomil was purified by column chromatography. The use of column chromatography is not feasible at commercial scale since it is very time consuming and the consumpt ion of the solvents is very large to produce small amount of the compound. WO 2007017135 A2 (Feb 2007, Zupancic Silvo, et al) describes a process for the preparation of olmesartan medoxomil, wherein the trityl olmesartan was detritylated in ethanol and ethyl acetate with cone. Hydrochloric acid. The olmesartan was obtained by extraction with ethyl acetate and crude olmesartan medoxomil thus obtained was crystallized in various solvent like 2-butanone, isobutanol, THF, methylene chloride, heptane, isopropanol, acetone and ethanol. However in these solvents reduction of olmesartan acid impurity is very minimum.
WO 2006/029057Al (Mar 2006, Hedvati, L. et al) discloses a process for the purification of olmesartan medoxomil, wherein the olmesartan medoxomil was prepared by detritylation of trityl olmesartan in acetone-water and sulphuric acid. The olmesartan medoxomil thus obtained was purified in aqueous acetone. The process involved mixing of water and organic solvent that cannot be reused. The process thus mentioned is not environment friendly.
US 2007/0105923Al (May 2007, Bobba K et al) also describes the purification of olmesartan. In the process disclosed the olmesartan medoxomil was purified by mixture of solvent like ethyl acetate and acetone or acetone and isopropyl alcohol. The said process also suffers the disadvantage of being environmentally unfriendly.

Thus in the synthesis of olmesartan medoxomil the main impurity identified is olmesartan acid since olmesartan medoxomil was obtained by detritylation of trityl olmesartan under acidic condition and under these condition medoxomil ester is very sensitive to hydrolysis and in this way olmesartan acid is formed like crude olmesartan medoxomil prepared by US 5616599 example 61b have 4.2 % olmesartan acid impurity. To remove this impurity to meet ICH guideline impurity level, where individual impurity should not be more than 0.1% several crystallizations are required.
Thus an alternative improved process for the preparation of pure olmesartan medoxomil is highly desired, which will substantially eliminate the shortcomings of the prior art such as selectively removal of the impurity of olmesartan acid, avoiding mixing of solvents or chromatographic purification steps and the like.
The present invention provides an improved process for the purification of olmesartan medoxomil, such that the final product obtained can meet the impurity guideline of ICH easily.
Object of the Invention:
The object of the present invention is to provide an improved process for the purification of olmesartan medoxomil.
Another object of the present invention is to provide an improved process for the purification of olmesartan medoxomil, wherein the olmesartan medoxomil so obtained has purity of greater than 99%.
Summary of the Invention:
According to the present invention there is provided a process for the purification of olmesartan medoxomil comprising the steps of
a) detritylation of trityl olmesartan with an aqueous acid;
b) extraction of the olmesartan medoxomil with water immiscible solvent to get crude olmesartan medoxomil;
c) purification of the crude olmesartan medoxomil.


Another object of the invention is a process for the purification of olmesartan medoxomil by dissolving crude olmesartan medoxomil in a water immiscible solvent preferably in ethyl acetate and adjusting the pH preferably in the range of 7.25 to 8.0 of the mixture with a base, preferably sodium bicarbonate.
According to another object of the present invention there is provided an improved process for the purification of olmesartan medoxomil, wherein the purification is carried out by dissolving crude olmesartan medoxomil in solvent and adjusting the pH of the reaction mixture to basic.
Detailed description of the Invention:
The present invention relates to a simple, environmentally friendly and commercially viable process for the purification of olmesartan medoxomil, wherein the olmesartan medoxomil obtained can meet the impurity guideline of ICH easily.
The said process according to present invention comprises the steps of detritylation of trityl olmesartan in aqueous acid, extraction of olmesartan medoxomil with water immiscible solvent and distillation of the solvent to obtain crude olmesartan medoxomil, and purification of the crude olmesartan medoxomil.
The said acid used in the detritylation step is any inorganic or organic acid selected from the group consisting of acetic acid, sulphuric acid, p-toluene sulphonic acid, formic acid, hydrochloric acid, methane sulphonic acid, preferably the acid used is acetic acid. The said detritylation reaction is carried out at the temperature in the range of 5°C to reflux temperature of the solvent; preferably at 25 °C - 60°C; especially at 35 °C - 40°C. The reaction time vary from 2.0 to 8.0 hours depending upon the temperature used for the detritylation and completed in 5.0 to 6.0 hours when reaction was carried out at 35 to 40°C.

The said detritylation step is followed by addition of water to the reaction mass and recovery of precipitated triphenyl carbinol by filtration. The filtrate thus obtained is made saturated with the addition of sodium chloride. The saturated solution thus obtained can be extracted with water immiscible solvents and the crude olmesartan medoxomil is obtained by the distillation of the solvents used.
The water immiscible solvents used for extraction is selected from the group consisting of ethyl acetate, methylene chloride, toluene , preferably the solvent used for extraction is ethyl acetate.
After distillation of the solvent, the crude olmesartan medoxomil obtained is purified by dissolving the said crude olmesartan medoxomil in a water immiscible solvent and adjusting the pH of the reaction mass to basic using a base. The pH of the reaction mass is adjusted to a range of 7.0 to 8.0, most preferably at 7.25 to 7.5.
The said base used for adjusting the pH of the reaction mass is any inorganic or organic base selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate or triethylamine, preferably the base used is sodium bicarbonate. The said water immiscible solvents used for dissolving the crude olmesartan medoxomil is selected from the group consisting of ethyl acetate, toluene, methylene chloride preferably the solvent used is ethyl acetate.
Further after the pH adjustment layer is separated and aqueous layer is again extracted with the solvent. Both the organic layers are combined and washed with water. The organic layer thus obtained is dried over a desiccating agent and the dried layer is concentrated to half of its original volume i.e. concentrated partially, it can be concentrated completely also. The mixture thus obtained is cooled and stirred at room temperature to complete crystallization. The olmesartan medoxomil thus obtained can be recovered by filtration or extraction, preferably by filtration. The crystal thus obtained can be dried in an oven. The olmesartan medoxomil thus obtained was analyzed by HPLC and meets in impurity specification as per ICH.
Thus the process according to present invention provides a simple, environmentally friendly method for the purification of olmesartan medoxomil, which avoids the chromatographic purification steps making it industrially feasible and the final product obtained is substantially free from impurity of olmesartan acid. The olmesartan

medoxomil obtained via process according to present invention has purity of greater than 99%, preferably 99.63%; and has less than 0.3% olmesartan acid, preferably less than 0.1%, especially about 0.017% of olmesartan acid as impurity.
Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the spirit or scope of the present invention as defined.
Examples: The following examples are described for illustration only and are not intend to limit the scope of the invention or appended claims.
Example 1: Olmesartan medoxomil:
Charge 10.0 gm (0.01 mole) of trityl olmesartan in a 0.5 L of round bottom flask equipped with thermometer pocket and overhead stirrer. Charge 37.50 ml acetic acid and 12.50 ml water and stir for 6 hrs at 35°C-40°C. Progress of the reaction was monitored by HPLC. After completion of the reaction charge 100.0 ml of water and cool to 10-15°C. Filter the precipitated trityl alcohol and wash with 25.0 ml water. The filtrate thus obtained was saturated with 25.0 gm sodium chloride and extracted with 200.0 ml ethyl acetate, The mother liquor was again extracted with 50.0 ml ethyl acetate, Both the organic layer were combined. The ethyl acetate layer thus obtained was distilled out under reduced pressure at 40 °C -45°C to get crude olmesartan medoxomil 20.0gm
Example 2: Purification of Olmesartan medoxomil:
Charge 150ml of ethyl acetate into 20.0 gm of crude olmesartan medoxomil obtained in examplel in a round bottom flask equipped with thermometer pocket and overhead stirrer. To the solution thus obtained charge 150.0 ml water and adjust pH of the mixture to 7.28-7.50 using sodium bicarbonate at 10 -15°C. Separate the layers and aqueous layer

was again extracted with 100 ml ethyl acetate. Combine ethyl acetate layers and wash with 75.0 ml water. Dry the layer over anhydrous sodium sulphate and distill out under reduced pressure to a volume of approx 100.0 ml at 40 -45°C. Stir the mass for 4-5 hrs to complete crystallization. The crystal thus obtained was recovered by filtration and washed with 10.0 ml ethyl acetate. It was dried to get 5.6 gm olmesartan medoxomil. Yield: 80.0% Purity: 99.63% Olmesartan acid 0.017%.
“
“ We Claim,

1. A process for the purification of olmesartan medoxomil of formula I,
H3C CH,
OH--C

o

(I)
which comprises the steps of
a. Detritylation of trityl olmesartan with an aqueous acid;
b. Extraction of the olmesartan medoxomil with a water immiscible
solvent to get crude olmesartan medoxomil, and
c. Purification of the crude olmesartan medoxomil.
2. A process of claim la, wherein the acid used in step a) is selected from the group consisting of acetic acid, sulphuric acid, p-toluene sulphonic acid, formic acid, hydrochloric acid, methane sulphonic acid, preferably acetic acid.
3. A process of claim 1 a), wherein the detritylation is carried out at a temperature range of 5°C to about reflux temperature of the solvent, preferably at 25 °C to 60 °C, more preferably at 35 °C to 40 °C
4. A process of claim 1 a), wherein the detritylation reaction is completed in 2.0 to 8.0 hours preferably in 5.0 to 6.0 hours.
5. A process of claim 1 b), wherein the said water immiscible solvent is selected from the group consisting of ethyl acetate, methylene chloride, toluene preferably ethyl acetate.
6. A process of claim 1 c), wherein it comprises purification of the olmesartan medoxomil by dissolving the said crude olmesartan medoxomil in a water immiscible solvent and adjusting the pH of the mixture with a base.

7. A process of claim 6, wherein the said base is an inorganic or organic base selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium carbonate and triethylamine, preferably it is sodium bicarbonate.
8. A process as claimed in claim 6, wherein the water immiscible solvent used for dissolving the crude olmesartan medoxomil is preferably ethyl acetate

9. A process as claimed in claim 6, wherein the pH of the mixture is adjusted in the range of 7.0 to 8.0, preferably in the range of 7.25 to 7.50 after adding water to the mass.
10. A process as claimed in claim 6, wherein the layer is separated after pH adjustment and washed with water and olmesartan medoxomil is obtained by partial or complete concentration of the solvent used.
11. A process as claimed in claim 6, wherein the olmesartan medoxomil is obtained by filtration when solvent is partially concentrated.

12. A process for the purification of olmesartan medoxomil by dissolving crude olmesartan medoxomil in a water immiscible solvent preferably in ethyl acetate and adjusting the pH preferably in the range of 7.25 to 7.50 of the mixture with a base, preferably sodium bicarbonate.
13. A process for the preparation of compounds of formula (I) substantially as herein described and illustrated with reference to the accompanying examples.

Abstract:
The present invention relates to a novel process for the purification of olmesartan medoxomil. The process according to present invention comprises the steps of detritylation of trityl olmesartan; extraction of olmesartan medoxomil and purification via pH adjustment with a base.