FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPECIFICATION.
(See sectionl0]


Title of the invention: "An improved process for the preparation of Irbesartan"

Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF IRBESARTAN
FIELD OF INVENTION:
The present invention relates to a novel and improved process for the preparation of Irbesartan, an angiotensin II receptor antagonist for the treatment of hypertension.
BACKGROUND OF THE INVENTION:
Irbesartan is a potent, long-acting angiotensin II receptor that is especially useful in the treatment of cardiovascular ailments such as hypertension and heart failure. The chemical name of Irbesartan is 2-(n-butyl)-3-[[2'-(tetrazol-5-yl)biphenyl-4-yl]-I,3-diazaspiro[4.4]non-l-en-4-one. Irbesartan is represented by following structure (Formula-I)

Formula-I
Bernhart et al in U.S.Pat.No.5, 270,317 first disclose the synthetic process of Irbesartan. From the multi step synthesis 4'-[(2-Butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyI]biphenyl-2-carbonitrile was obtained which was react with tri butyl tin azide in xylene at reflux temperature to give a product which was isolated in pure
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form by protection of tri phenyl methyl group and doing column chromatography then after de-protection of tri phenyl methyl group by using 4N hydrochloric acid in methanol and tetrahydrofuran solvent mixture. From safety point of view handling of tri butyl tin azide is not safe on large scale however it is costly too.
U.S.Pat.No.5, 629,331 described a process for the preparation of Irbesartan form A and form B. From the multi step synthesis 4'-[(2-Butyl-4-oxo-i,3-diazaspiro[4.4]non-l-en-3-yl)methyl]biphenyl-2-carbonitrile was obtained which was react with sodium azide and tri ethyl amine hydrochloride in N-Methylpyrrolidone at 123°C temperature followed by alkaline workup and isolation at pH 4.7 to 5.8 as crude product which is purified in isopropyl alcohol and water to get a pure compound in Form A and in ethanol and water in Form B. However the removal of solvent is quite difficult.
W.O. 2005/051943 describes a process for the preparation of Irbesartan, which is also in safety point of view not suitable on large scale. This patent described the reaction of 4,-[(2-Butyl-4-oxo-l, 3-diazaspiro [4.4] non-l-en-3-yl) methyl] biphenyl-2-carbonitrile with tri butyl tin chloride, sodium azide and tetra butyl ammonium bromide in toluene as a solvent at reflux temperature for 20hr to give a product which is isolated in pure form by protection of tri phenyl methyl group and then after de-protection of tri phenyl methyl group by using formic acid in methanol solvent medium. From safety point of view in situ generation of tri butyl tin azide is also not safe.
WO 2007/013101 also described a process for the preparation of Irbesartan, which is also having tedious workup. This patent described the reaction of 4'-[(2-Butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl]biphenyl-2-carbonitrile with triethyl amine, acetic acid and sodium azide n-butanol as a solvent at 115-120°C temperature for 24hr followed by alkaline workup and isolation at pH 2 to 3 as product. Here during
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workup three layers were obtained which is generally not easy to isolate the middle oily layer.
The prior art for preparation of Irbesartan having multi step synthesis, protection de-protection, column chromatography, use of costly and dangerous reagent, tedious work up. Therefore there is a need for an improved synthetic process having easy work up, cost effective and environmentally friendly process.
SUMMARY OF THE INVENTION
This invention is directed to various methods for preparing Irbesartan as recited in the claims appended hereto. The main purpose of the present invention is to provide a commercially viable process by using easily available raw material.
Another object of the present invention is to provide an industrially viable process Of Irbesartan without doing multi step synthesis and tedious workup procedure.
Yet another object of the invention is to provide a simple process of producing Irbesartan in pure form without doing protection, de-protection and purification by column chromatography.
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DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides a simple process of producing Irbesartan in pure form having easy work up, cost effective and environmentally friendly process.
The present invention uses methane sulfonic acid. p-Toluene sulfonic acid, sulfuric acid . or tri fluoro acetic acid; with sodium azide and triethyl amine. The solvent for the reaction is from different class like aliphatic hydrocarbons, ketone, esters, ether and alcohols. Hydrocarbon solvent likes heptane, toluene or xylene. Ketone solvent likes methyl iso butyl ketone, ester solvent like n-butyl acetate; ether solvent likes dioxane, and alchohol like n-butanol. And the temperature for the reaction in the range of 50°C to 140° C. Time required for the completion of the reaction in the range of 24 hr to 150 hr.
For the reaction preferred acid is sulfuric acid, preferred solvent is n-butanol, preferred temperature is 115°C to 120°C and preferred time for the completion is 120 hr. After completion of the reaction, the reaction mass is quenched by water and layer is separated and organic layer is concentration under reduced pressure to obtained solid residue and solvent is recovered. The isopropyl alcohol is added to the solid residue
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and stirred for 15 hr to obtained crude material. The crude is purified by ethanol: water (95:05).
EXAMPLE-1
To a round bottom flask charge 80 ml n-butanol and 10 gm 4,-[(2-Butyl-4-oxo-l, 3-diazaspiro [4.4] non-l-en-3-yl) methyl] biphenyl-2-carbonitrile (Formula-II), rinse with the 20 ml of n-butanol, followed by the addition of 22 ml triethyl amine and 2.8 ml sulfuric acid. 5.05 gm Sodium azide was charged to the reaction mass. Reaction mass was heated at 115°C to 120°C. After two days 1.68 gm sodium azide was again charged to the reaction mass and maintaining continue at 115°C to 120°C. After 3 days 1.68 gm sodium azide was again charged to the reaction mass and maintaining continue for five days. Completion of the reaction was monitored by HPLC. After completion of the reaction, reaction mass was cooled to room temperature and 150 ml water was charged to the reaction mass and stir for 20 min. Separate out the organic layer and aqueous layer was extracted with 50 ml x 3 n-butanol. Organic layer was treated with charcoal. After charcoalisation organic layer was removed under reduced pressure to obtained oily residue. The traces of solvent were removed by aziotrope distillation to obtained crude Irbesartan. This crude Irbesartan was purified by isopropyl alcohol and ethanol:water mixture to obtained pure Irbesartan having HPLC purity >99.5%.
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Dated this 24th day of July 2008

Signature:

To
The Controller of Patents
The patent Office,
At Mumbai

Name: Dr. Rajendra Agarwal
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