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 - Process for the Preparation of Irbesartan
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 the Invention
The present invention relates to novel process for preparation of pure cyano intermediate compound of Irbesartan and that use in the process for preparation of Irbesartan.
Background of the Invention
Irbesartan is chemically, 2-butyl-3-[[2'-(lH-tetrazol-5-yl) [1,1'-biphenyl]-4-yl]-l,3-diazaspiro[4,4]non-l-en-4-one and is represented by the Formula I

Irbesartan and its use in treating hypertension were first disclosed by Bemhart et al in U.S. Pat. No. 5,270,317 and assigned to Sanofi. The process for the preparation of irbesartan described in '317 patent involves the formation of tetrazole ring by a reaction of the cyano intermediate (Formula II) with tributyltin azide.

Irbesartan obtained by the process described in the '317 patent does not have satisfactory purity. Unacceptable amounts of impurities are formed along with Irbesartan. The yield of Irbesartan obtained is very poor and the process involves column chromatographic purifications. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.
U. S. Patent No. 5,270, 317 describes a process for preparation of Irbesartan which involves condensation of the spiro compound of Formula II with halo methyl- cyan biphenyl compound of

Formula III. This reaction is carried out in presence of N, N-dimethyl formamide as a solvent and sodium hydride as base.
U. S. Patent No. 6,162, 922 describes a process for preparation of Irbesartan which involves treating the spiro intermediate of Formula II with halo methyl- cyan biphenyl intermediate of Formula III in presence of a water immiscible solvent, a base and a phase transfer catalyst.

During above process impurity formation is very high that reduces overall yield. There is a need for an improved process for the preparation of Irbesartan that is economical and results in high purity of the product. Therefore, there is a need to develop an improved and commercially viable process of preparing pure Irbesartan which is suitable for large-scale preparation, in lesser reaction time, in terms of simplicity, purity and yield of the product.
Summary of the invention:
In one general aspect there is provided a process for the preparation of Irbesartan Formula I

In another aspect of the present invention provides a process for preparation of Irbesartan comprising, condensing compound of formula II and formula III to obtain compound of formula IV in presence of water, water miscible solvent and a base.


In another aspect of the present invention provides a process for preparation of Irbesartan comprising,
a. Refluxing compound of formula II and formula III in presence of a water miscible
solvent, a base and water;
b. Separating upper product layer without addition of any additional solvent;
c. optionally washing the product layer with saturated brine solution;
d. stirring the product layer with water;
e. filtering the compound of formula IV;
f. Recrystallising the product in the suitable solvent.
It is another object of the present invention provides a process for preparation of Irbesartan comprising recrystallising cyano Irbesartan, compound of formula IV in acetone.
Detailed Description of the Invention:
An embodiment of the present invention provides a process for the preparation of Irbesartan.
In another embodiment present invention provides a process for preparation of Irbesartan comprising, condensing compound of formula II and formula III to obtain compound of formula IV in presence of water, water miscible solvent and a base.

Embodiments of the process may include one or more of the following features. For example, the water miscible organic solvent may include one or more of water miscible lower alcohols, water miscible polar aprotic solvents and mixtures thereof. The lower alcohols may include one or more of methanol, ethanol, isopropanol and n-propanol. The polar aprotic solvent may include one or more of tetrahydrofuran, acetone, acetonitrile, 1, 4-dioxane, N, N-dimethylacetamide, and dimethylsulphoxide, more specifically acetone.

The base may include one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, potassium t-butoxide or mixtures thereof more specifically sodium hydroxide. The main advantage of the present invention is reduction of impurity from 5.0% to 0.5%.
In another embodiment the present invention provides a process for preparation of Irbesartan comprising,
a. Refluxing compound of formula II and formula III in presence of a water miscible solvent, a
base and optionally water;
b. Separating upper product layer without addition of any additional solvent;
c. optionally washing the product layer with saturated brine solution;
d. stirring the product layer with water;
e. filtering the compound of formula IV;
f. Recrystallising the product in the suitable solvent.
Embodiments of the Suitable solvent include MTBE, isopropanol and acetone.
prior art process involves reaction in one solvent, then removal of solvent after completion of the reaction, further extraction of product in water immiscible solvent, removal of that solvent also and finally crystallisation of product in any solvent.
Present inventors develop an advance work up process that is very smooth for isolation of cyano intermediate. There is no need for any solvent distillation. During solvent distillation there is a chance to increase impurity formation. But, work up process employed by present invention removed two types solvent distillation, also removed extraction of product in any water immiscible solvent. Process employed by present inventors involves crystallisation of product in water only. Then finally the product undergoes recrystallisation.
Thus, the process of the present invention has following advantages:
1. Impurity is less formed.
2. Easy isolation process.
3. Removal of two types of solvent distillation
4. Reduction of workup time.
5. Comparative quality and good yield is obtained.


In another embodiment the present invention provides a process for the preparation of Irbesartan comprising recrystallising cyano Irbesartan, compound of formula IV in acetone.
The present invention further illustrated in detail by the below examples which are however not limit to the scope of the invention.
EXAMPLE 1: Preparation of 2-n-butyl-3- [[2'-cvanobiphenvl-4-yl] methyl]-l, 3-diazaspiro- [4. 4] non-1- ene-4-one (Formula IV)
A mixture of 2-n-butyl-l, 3-diazaspiro [4.4] non-l-ene-4-one hydrochloride of Formula I (87 g), acetone (200 ml), water (200 ml) and 4'- bromomethyl [1, l'-biphenyl]-2-carbonitrile of Formula III (100 g) and sodium hydroxide (50.0gm) was stirred in 1 litter RBF. The mixture was heated at 40-45°C for 2-3 hrs. After completion of the reaction, the reaction mass was cooled at room temp and allowed to settle. The bottom aqueous layer is separated and the upper layer is washed with saturated brine solution. The product layer is stirred with water (250ml); the product is crystallized in water. The product was filtered and washed with water and then with methyl t-butyl ether to yield the crude cyano Irbesartan of Formula IV. Crude wet product is refluxed with acetone (150ml) till clear solution is obtained. Then the solution is stirred at 0°C for 2 hrs. Filtered the product and washed with acetone-water (1:1) Yield: 100 gm
EXAMPLE 2: 2-n-butyl-3- [r2' (tetrazol-5-vl) biphenvl-4-vllmethvil-l. 3-diazaspiro-r4. 41non- 1-ene-4-one (Irbesartan of Formula I)
A mixture of 2-n-butyl-3- [ [2'-cyanobiphenyl-4-yl] methyl] -1,3-diazaspiro- [4.4] non-l-ene-4-one of Formula IV as obtained in example 1 (100 g), triethylamine hydrochloride (140 g), and sodium azide (43 g) in toluene (250 ml) and xylene (1ml) was refluxed for 20 hrs. The reaction mixture was cooled to room temperature and to it was added aqueous sodium hydroxide solution (38g in 800ml water). The mixture was stirred at room temperature for 15 mm. The mixture was allowed to settle and then removed upper toluene layer. The product layer was washed with methyl t-butyl ether (150ml) and then stirred with the sodium nitrite solution (28gm in 100ml water). To the resulting aqueous phase was added 6N HC1 slowly to adjust the pH of the solution to about 4.8-5.3. After stirring at room temperature for 30 min, the crystals were filtered, washed with water (400 ml) and dried at 50 °C to

■
yield the compound of Formula I in 99.7% purity (100 g) which was purified, although this
purification is optional.
To this was added ethanol (96%, 1250 ml) and the resulting mixture was heated to reflux until the
product completely dissolved. The mixture was cooled to 15 °C and stirred at 15-20 °C for 30 min.
The separated crystals were filtered and washed with 96% ethanol and dried at 50 °C under reduced
pressure to yield Irbesartan.
Yield: 85 g HPLC Purity: 99.95%

We Claim:
1. A process for preparation of Irbesartan comprising,
a. Refluxing compound of formula II and formula III in presence of a water miscible solvent, a base and water;

b. Separating upper product layer without addition of any additional solvent;
c. optionally washing the product layer with saturated brine solution;
d. stirring the product layer with water;
e. filtering the compound of formula IV;
f. Recrystallising the product in the suitable solvent.
2. A water miscible solvent claimed in claim 1, selected from lower alcohols and water miscible polar aprotic solvents and mixtures thereof where the lower alcohols may include one or more of methanol, ethanol, isopropanol and n-propanol and the polar aprotic solvent may include one or more of tetrahydrofuran, acetone, acetonitrile, 1, 4-dioxane, N, N-dimethylacetamide, and dimethylsulphoxide, more specifically acetone.
3. A base claimed in claim 1, selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, potassium t-butoxide or mixtures thereof more specifically sodium hydroxide.
4. A suitable solvent claimed in claim 1, selected from methyl t-butyl ether, isopropanol acetonitrile and acetone.

5. A process for preparation of Irbesartan comprising recrystallising cyano Irbesartan, compound of formula IV in acetone.