FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
"AN IMPROVED PROCESS FOR THE
PREPARATION OF AZILSARTAN MEDOXOMIL
OR PHARMACEUTICALLY ACCEPTABLE
SALTS THEREOF"
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED UNDER THE INDIAN COMPANIES ACT, 1956,
HAVING ITS REGISTERED OFFICE LOCATED AT
UNICHEM BHAVAR PRABHAT ESTATE, OFF S. V. ROAD,
JOGESHWARI (WEST), MUMBAI - 400 102,
MAHARASTRA, INDIA

FIELD OF THE INVENTION;
The present invention relates to an improved process for the preparation of azilsartan medoxomil or pharmaceutical!)' acceptable salts thereof.
BACKGROUND OF THE INVENTION:
Azilsartan medoxomil (CAS: 863031-21-4) is chemically known as (5-Methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-[[2'-(5-oxo-4,5-dihydro-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate.
Azilsartan medoxomil and salts thereof has the uses such as a strong and long lasting angiotensin II antagonistic activity and hypotensive action, and an insulin sensitizing activity, and which is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac diseases (cardiac hypertrophy, cardiac failure, cardiac infarction and the like), nephritis, stroke and the like and metabolic diseases such as diabetes and the like. Azilsartan medoxomil is the prodrug of 2-ethoxy-l-:([2'-(5-oxo-4, 5-dihydro-l, 2, 4-oxadiazol-3-yl) biphenyl-4-yl] methyl)- 1 H-benzimidazole-7 -carboxylic acid. Azilsartan medoxomil is approved as monoptassium salt (Azilsartan Kamedoxomil) for the treatment of hypertension and is marketed under the brand name Edarbi®.


US patent No. 5.583,141 disclosed Azilsartan and its physiologically acceptable esters and salts and also methods for preparing them. US patent No. 7,157.584 disclosed Azilsartan medoxomil and pharmaceuticaliy acceptable salts thereof.
US '584 disclosed processes for the preparation of Azilsartan medoxomil which comprises reacting Azilsartan disodium salt (11a) with (5-methyl-2-oxo-l, 3-dioxol-4-yl)methyl chloride herein after referred to as Medoxomil chloride in the presence of DMF and CHCI3 to produce Azilsartan medoxomil (I) as shown in scheme 1 below:


The major disadvantage with the above prior-art process is the use of chloroform as solvent which is carcinogenic in nature and also hazardous. This process also leads to the formation of N-alkylated impurity (Azilsartan N-medoxomil l1b) and N.O-dialkylatcd impurity (Azilsartan dimedoxomil IIc). Removal of these impurities in the final stage is very difficult and requires repeated crystallizations, which results in the low yield (about 14-22 %) of Azilsartan Medoxomil (I) and hence there is a need for improved process for the preparation of Azilsartan medoxomil.

US '584 disclosed another process for the preparation of Azilsartan medoxomil which comprises reacting Azilsartan ([[) with 2,4,6-trichlorobenzoyl chloride (VII) in presence of Triethyl amine (TRA) to produce Azilsartan mixed acid anhydride (IId), followed by reacting with 4-hydroxyrnethyl-5-rnethyl-l,3-dioxol-2-one herein after referred to as Medoxomil alcohol in the presence of N.N-dhnethylaminopyridinc to produce Azilsartan medoxomil (1) as shown in scheme 2 below:


The process depicted in scheme 2 requires the use of expensive 2, 4. 6-trichlorobenzoyl chloride, Number of reaction steps in the process is more. There is increase in reaction time. Hence there is a need for improved process for the preparation of Azilsartan medoxomil.
Many other prior art processes convert the Medoxomil chloride to Medoxomil alcohol and use Medoxomil alcohol for preparation of Azilsartan medoxomil or directly use commercially available Medoxomil alcohol which is expensive than medoxomil chloride.

Thus, there exists a need for an improved alternative preparative routes, which for example, involve fewer steps, use reagents that are less expensive and/or easier to handle, consume smaller amounts of reagents, provide a higher yield of product free from impurities i.e. N-alkylated impurity and N,0-dialkylated impurity, mentioned above in the description, have smaller and/or more eco-friendly waste products, and/or provide a product of higher purity.
OBJECTIVE OF THE INVENTION:
The main objective of the present invention is to provide an improved, simple and cost-effective process for the preparation of Azilsartan medoxomil (I) from Azilsartan (II) with high purity and good yield on commercial scale.
SUMMARY OF THE INVENTION:
Accordingly, the present invention provides an improved process for the preparation of Azilsartan medoxomil (I), which comprises combining Azilsartan (II) with medoxomil chloride in presence of solvent, metal oxide, optionally a base and optionally a catalyst.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides an improved process for the preparation of Azilsartan medoxomil (I).

The process of (he present invention comprises combining Azilsartan (II) with medoxomil chloride in presence of solvent, metal oxide, optionally a base and optionally a catalyst.
Prior art processes teach preparation of Aziisartan medoxomil (I) from medoxomil alcohol, because using medoxomil chloride for the preparation of Azilsartan medoxomil (I) leads to formation of Azilsartan N-medoxomil (l1b) and Azilsartan dimedoxomil (11c) impurities and isolation and/or removal of these impurities is very difficult and makes final product Azilsartan medoxomil (I) of poor quality. Also: the yield obtained by the prior art process is on the lower side (about 14-22%).
However it was surprisingly found that combining Azilsartan (II) with medoxomil chloride in the presence of solvent, metal oxide, optionally a base and optionally a catalyst gives the aziisartan medoxomil in good yield and quality. Improved yield and quality are some of the aspects of improved process described in the present invention. Novelty and inventive step of the present invention resides in optional use of base. It was surprisingly found that using metal oxide in the process for preparation of Azilsartan medoxomil (I) by reacting Azilsartan (II) with medoxomil chloride substantially reduced the formation of Azilsartan N-medoxomil (11b) and Azilsartan dimedoxomil (11c) impurities. Therefore this process leads to the formation of Azilsartan Medoxomil of superior quality which is substantially free from Azilsartan N-medoxomil (11b)

impurity and Azilsarlan dimedoxomil (IIe) impurity. As used here in the term ''substantially free'' means Azilsartan N-medoxomil (lib) impurity is present in 1% or less and Azilsartan dimedoxomil (IIe) impurity is present in 1% or less and both impurities are present in 1% or less.
Schematic representation of the process for preparation of Azilsartan medoxomil (J) from Azilsartan (II) and medoxomil chloride is shown in scheme 3 below:

Azilsartan prepared by any methods known in the prior art can be used for the preparation of Azilsartan medoxomil (I) by a process of the present invention. The process of the present invention comprises combining Azilsartan (II) with medoxomil chloride in presence of solvent. Solvent is selected from polar solvents selected from DMF, DMSO, Dimetylacetamide. Acetonitrile, Tetrahydrofuran or mixture thereof more preferably dimetylacetamide.
The process of the present invention can be carried out in presence or absence of base. A base is selected from organic base selected from amines selected from

triethylamine, diisopropylamine. diethylamine more preferably triethylamine or inorganic base selected from carbonates selected form sodium or potassium carbonate more preferably potassium carbonate. Use of the base in the process further improves yield.
Metal oxide which is added to the reaction mixture is selected from Silver oxide (Ag20), Cuprous oxide (Cu2O). Aluminium oxide (Al2O3), Zinc oxide (ZnO), more preferably Silver oxide (Ag20) or Cuprous oxide (C112O). The process of the present invention further supports recovery of metal oxide used and therefore reduces the cost.
The process of the present invention can be carried out in presence or absence of catalyst such as potassium iodide.
The reaction mixture containing essentially Azilsartan (II), medoxomil chloride, metal oxide and. optionally a base and catalyst is maintained at 40-l20°C more preferably 60-80°C to form the azilsartan medoxomil product. The product is isolated at acidic pH.
The crude Azilsartan Medoxomil was extracted using organic solvents such as ethyl acetate, MDC. This was further purified using organic solvents, preferably polar organic solvents such as Methanol. Ethanol. IPA. DMSO more preferably

methanol. Azilsartan Medoxomii formed is optionally converted to its pharmaceutically acceptable salts by methods known in the prior art.
In this process, it is surprisingly noticed that. Azilsartan's reactivity towards the Medoxomii chloride is enhanced, it was surprisingly found that in less than 4hrs, Azilsartan is completely converted to Azilsartan Medoxomii by reacting with Medoxomii chloride. It is aiso surprising to note that due to increase in reactivity of Azilsartan towards Medoxomii chloride, the formation of N-Medoxomil impurity (l1b) and dimcdoNomil impurity (l1c) is suppressed thereby giving Azilsartan Medoxomii with higher quality and yield. The impurities formed in this process are removed by purifying the Azilsartan medoxomii with organic solvent selected from polar organic solvents such as Methanol, ethanol, IPA, DMSO, more preferably by using methanol. This purification with methanol further enhanced the quality of the Azilsartan Medoxomii and makes azilsartan medoxomii substantially free of Azilsartan N-Medoxomil (11b) impurity and Azilsartan dimedoxomil (l1e) impurity.
The following examples are for illustrative purposes only and are not intended nor should they be interpreted to. limit the scope of the invention.
EXAMPLES:
Example I: Preparation of Azilsartan Medoxomii (I)

10 gm Azilsartan and 100 ml. dimetylacetamidc was charged in a Round Bottom Flask. Charge 6.1 ml TEA, 1.8 gm Potassium iodide and copper oxide 6.26 gm. The reaction mixture was stirred for 10-30 min and the temperature was allowed to increase up to 60-70°C. Charged the solution of Medoxomil chloride, in dimetylacetamide (20mL). to the reaction mixture, at 60-70°C. The reaction mixture was stirred al this temperature till the completion. Filtered off solids and recovered copper oxide. To the filtrate added 1000 mL saturated aqueous solution of ammonium chloride / EDTA solution, to adjust the pH of the solution between 5.0 - 5.5. Product extracted with ethyl acetate. Then distilled off ethyl acetate under reduced pressure, to obtain solid product. The solid product was suspended in 50ml of methanol, stirred for 2 hours and filtered off to give Azilsartan Medoxomil as solid product.
Weight of the product: 7.5 gm. Yield: 75 %, HPLC purity: 99 %. Azilsartan N-medoxomil (Mb) and Azilsartan dimedoxomil (l1e): Less than 1%.
Example 2: Preparation of Azilsartan Medoxomil (I)
1.0 gm Azilsartan and 5 mL dimethylsulphoxide was charged in a Round Bottom Flask. Charge 0.61 ml TEA, 0.18 gm Potassium iodide and silver oxide 1.02 gm. The reaction mixture was stirred for 10 min and the temperature was allowed to increase up to 50-60°C and maintained at about 10-30 min. Charge the solution of Medoxomil chloride in dimcthylsulphoxide (200mL) to the reaction mixture at 50-60°C. The reaction mixture was stirred at this temperature till the completion. Filtered of solids and recovered silver oxide. Filtrate quenched in 100 mL water.

Adjusted pH of the reliction mass between 5 and 6 using 10% aqueous solution of HCl. Azilsartan Medoxomil (1.1 gm) was obtained as a solid product. Weight of the product: 1.1 g. Yield: 98.21 %, HPLC purity: 75.55 %.
Example 3: Preparation of Azilsartan Medoxomil (I)
10 gm Azilsartan and 100 mL dimetylacetamide was charged in a Round Bottom Flask. Charge 1.8 gm Potassium iodide and 6.26 gm copper oxide. The reaction mixture was stirred for 10-30 min and the temperature was allowed to increase up to 60-70°C. Charge the solution of Medoxomil chloride in dimetylacetamide (20mL) to the reaction mixture at 60-70oC. The reaction mixture was stirred at this temperature for 6 hrs. filter of solids and recovered copper oxide. To the filtrate add 1000 mL saturated aqueous solution of ammonium chloride / EDTA solution, till the pH of the solution attain between 5.0 - 5.5. Product extracted with ethyl acetate. Distill off ethyl acetate under reduced pressure to obtain Azilsartan Medoxomil as a solid product. This solid product was suspended in 50mI of methanol, stirred for 2 hours and filtered off to give Azilsartan Medoxomil as solid product.
Weight of the product: 6 gm. Yield: 48 %, HPLC purity: 97 %. Azilsartan N-medoxomil (l1b) and Azilsartan dimedoxomil (l1c): Less than \%,
Example 4: Preparation of Azilsartan Medoxomil potassium salt (la).
5 gm Azilsartan Medoxomil and 25 mL acetone was charged in Round bottom flask. Reaction mixture cooled lo 0-5°C. Solution of potassium 2-ethyl hexanoate

in acelone was added to the reaction mass at 0-5°C. Stirring was further continued for 2 hrs at 0-5°C. Filter solids and washed with acetone. Weight of the product: 3.8 gm. Yield: 71 %. HPLC purity: 99.19%. Azilsartan N-medoxomil (lib) and Azilsarian dimedoxomil (llc): Not detected.

CLAIMS:
We Claim:
1. An improved process for the preparation of Azilsarlan Medoxomil (i) comprising combining Azilsarlan (II) with Medoxomil chloride in the presence of solvent, metal oxide, optionally a base and optionally a catalyst.
2. The process for the preparation of Azilsarlan Medoxomil (I) as claimed in claim 1. wherein solvent is selected from polar solvents selected from Dimethylformamide. Dimethyl sulfoxide. Dimetylacelamide, Acetonitrile, Tetrahydrofuran or mixture thereof move preferably Dimeiylacelamide.

3. The process for the preparation of Azilsartan Medoxomil (I) as claimed in claim 1. wherein metal oxide is selected from Silver oxide (Ag2O). Cuprous oxide (Cu2O), Aluminum oxide (Al2O3). Zinc oxide (ZnO), more preferably Silver oxide (Ag2O) or Cuprous oxide (Cu2O).
4. The process for the preparation of Azilsartan Medoxomil (f) as claimed in claim 1. wherein the base is selected from organic base selected from amines selected from Irieihylamine. diisopropylamine, diethyl amine, more preferably trieihylamine or inorganic base selected from alkali carbonates selected form sodium or potassium carbonate more preferably potassium carbonate.
5. The process for the preparation of Azilsarlan Medoxomil (I) as claimed in claim I. wherein the catalyst is potassium iodide.

6. The process lor the preparation of Azilsartan Medoxomil (J) as claimed in claim I. wherein reaction is carried out at 40 to 120°C more preferably a! 60-80oC.
7. The process for the preparation of Azilsartan Medoxomil (I) as claimed in claim ]. further comprises purifying Azilsartan Medoxomil (1) with organic solvent selected from polar organic solvents selected from Methanol. Rthanol. IPA. DMSO more preferably methanol.
8. The process for the preparation of Azilsartan Medoxomil ([) as claimed in claim I. wherein Azilsartan N-medoxomil (lib) impurity is present in 1% or less, Azilsartan dimedoxomil (lie) impurity is present in 1% or less and both impurities are present in 1% or less.
9. The process for the preparation of Azilsartan Medoxomil (I) as claimed in claim i, wherein Azilsartan Medoxomil is optionally convened to its pharmaceutical!)' acceptable salts.