FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention-: AN IMPROVED PROCESS FOR THE PREPARATION OF
AZILSARTAN MEDOXOMIL
2. Applicant(s)
(a) NAME: ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road.
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention and the manner in which is to be performed:

Field of invention
The present invention relates to an improved and industrially advantageous process for the preparation of Ailsartan medoxomil of formula (I) in high yield and purity.

Background of the invention
Azilsartan medoxomil 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-oxadiazo]-3-yl)biphenyI-4-yl]methyl}-lH-benzimidazole-7-carboxylate.Azi]sartan medoxomil is in a group of drugs called angiotensin 11 receptor antagonists. Angioatensin 11 causes vasoconstriction via an angiotensin II receptor on the cell membrane and elevates blood pressure. Therefore, an angiotensin II receptor antagonist can be an effective therapeutic drug for circulatory diseases such as hypertension and the like. Azilsartan medoxomil keeps blood vessels from narrowing, which lowers blood pressure and improves blood flow. The current pharmaceutical product containing this drug is being sold by Takeda using the trade name Edarbi in the form of tablets.
Azilsartan medoxomil and related compounds were first time disclosed in US 5243054.
The process disclosed in US 5243054 is schematically describes as below.


US5243054 discloses process for the preparation of Azilsartan in which ring closure reaction of compound of formula II is disclosed in presence of xylene to obtain compound of formula III. The yield of compound of formula III obtained is relatively less and results in elevated level of impurities. These impurities are difficult to remove from final Azilsartan. The process involves column chromatographic purifications. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfavorable.
Therefore there is a need of an improved process for the preparation of Azilsartan that is economical and suitable in terms of lesser reaction temperature and time, in terms of simplicity, purity and yield of the product.
Azilsartan obtained by present invention can be converted to Azilsartan medoxomil potassium.
Object of the invention:
It is an object of present invention to provide an improved and industrially advantageous process for the preparation of Ailsartan medoxomil of formula (I) in high yield and purity.


A further object of the present invention is to provide a process for preparation of Azilsartan comprising, ring closure reaction of compound of formula II to obtain compound of formula III in presence of n-butanol.

Detailed description of the invention
Accordingly, present invention provides an improved and industrially advantageous process for the preparation of Ailsartan medoxomil of formula (I) in high yield and purity.


Present invention provides a process for preparation of Azilsartan comprising, ring closure reaction of compound of formula II to obtain compound of formula III in presence of n-butanol. Hydrolysis of formula III gives Azilsartan with high yield and purity.

Azilsartan obtained by present invention can be converted to Azilsartan medoxomil potassium.
Literature process involves use of O-xylene in ring closer reaction of compound of formula II; which results in number of impurities, affecting the final quality of compound. The reaction is very sluggish and yield is very low.
When the reaction of ring closure is done using n-butanol, it provides multiple advantages in terms of yield, level of impurity, better process control and operation simplicity.
Advantages of using n-butanol as compared to 0-Xylene are depicted below.
Table-l

Prior art process Process of Present invention
Batch no: I II III I II III
Purity 79.83 75.75 76.74 98.01 97.96 97.65
Any other impurity 19.58 16.67 15.25 0.38 0.28 0.30
Reaction temperature 115-125OC I00-110OC
Reaction time 3-4 hrs 3-4 hrs
% Yield 60-70 % 70-80 %

Thus, the process of the present invention has following advantages:
1. Formation of impurity is very less.
2. It eliminates the requirement of chromatographic purification method and provides a process which is economical and industrially applicable.
3. The process is simple and easy to handle and does not require special handling care or critical temperature conditions.

Claims
1. A process for preparation of Azilsartan comprising, ring closure reaction of compound represented by the following formula II to obtain compound of formula III in presence of n-butanol.

2. The process according to claim 1 where in the compound of formula III is hydrolyse to obtain Azilsartan.