FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION:
EFFICIENT PROCESS FOR PREPARATION OF IRBESARTAN
INTERMEDIATE
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra
(East), Mumbai - 400 051.
3. PREAMBLE TO THE DESCRIPTION
The present invention relates to an efficient process for the preparation of irbesartan intermediate.
The following specification particularly describes the invention and the manner in which it is to be performed.

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4. DESCRIPTION
The present invention relates to an efficient process for the preparation of a compound of formula II, a useful intermediate in the synthesis of irbesartan.
Irbesartan is a known angiotensin II receptor antagonist. Chemically irbesartan is, 2n-butyl-4-spirocyclopentane- 1 - [(2'-(tetrazol-5yl) biphenyl-4-yl) methyl]-2-imidazolin-5 one having structure as depicted in Formula I. Irbesartan is indicated for the treatment of cardiovascular diseases such as hypertension and heart failure. It is also useful in preventing disorders of central nervous system, glaucoma, diabetic retinopathy, and diabetic nephropathy.

U.S. Patent No. 5,270,317 discloses N-substituted heterocyclic derivatives including Irbesartan. The process disclosed in this patent involves the formation of trityl protected Irbesartan and deprotection of trityl group by hydrochloric acid in tetrahydrofuran and methanol. After evaporation of the solvents, the residue is taken up in water and ION sodium hydroxide to get pH 12. The aqueous phase is washed with ether, toluene and ether again. The aqueous phase is acidified to
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pH 2 by HCI acid and extracted with ethyl acetate. Evaporation of Ethyl acetate yielded Irbesartan
Journal of Medicinal Chemistry 1993, 36, 3371-3380, discloses a process for the preparation of Irbesartan by treating cyano derivative with tributyl tin azide in xylene under refluxed condition, after completion of reaction, reaction mass is extracted with I N sodium hydroxide solution. Acidified to pH -5 using 3 N HCI and extracted the- product with methylene chloride. Residue obtained after removing methylene chloride is crystallized from 96% ethanol to give Irbesartan.
U.S. Patent Nos. 6,800,761 and 7,008,959 directed to novel crystal habit of irbesartan and its process for the preparation.
Other methods of preparing irbesartan and its intermediate are disclosed in U.S. Patent Nos. 6,162,922; 7,019,148; U.S. Application No. 06/041147 and PCT Patent Applications WO 05/113518; WO 05/051928; WO 05/051929; WO 05/051943; WO 06/073376; WO 06/089927 and WO 07/020659.
The present invention provides an efficient process for preparation of a compound of formula II, a useful intermediate for the synthesis of irbesartan. The process of present invention avoids prior art use of hazardous and expensive reagents and the product is easy to isolate and handle thus making the process amenable for commercial scale use.
The present inventors have surprisingly found that when potassium hydroxide is crushed and used in powdered form in the process for preparation of compound of formula II, it results in good yield and significantly better quality of product.
In one general aspect there is provided a process for the preparation of a compound of formula II, an intermediate useful in the synthesis irbesartan. The process includes the steps of
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Formula II
a) condensing a compound of formula III,

Formula III
with a compound of formula IV,

in the presence of polar aprotic solvent and powder potassium hydroxide
b) isolation of compound of formula II from reaction mass thereof
The process includes condensation of 2-n-butyl-1,3-diazaspiro[4,4]non-1-ene-4-one hydrochloride (Formula III) with 4-bromomethyl-2'-cyanobiphenyl of (Formula IV) in the presence of polar aprotic solvents and powder potassium hydroxide. The Polar aprotic solvent may include one or more of N, N-dimethylformamide, N, N-dimethylacetamide, dimethylsulphoxide, N-methyl pyrrolidone,
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tetrahydrofuran or acetonitrile. The condensation reaction is carried out at a temperature of about 20° C to 40° C for about 4 to 6 hours. After completion of reaction, the reaction mixture is poured into water, filtered and dried to give 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl] methyl]-1, 3-diazaspiro-[4, 4] non-1 -ene-4-one (Formula II).
The compound of formula II thus obtained can be converted to irbesartan by processes known in the art.
The present invention is further illustrated by the following example which are provided merely to be 'exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
EXAMPLE
Preparation of 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl] methyl]-1, 3-diazaspiro-[4, 4] non-1 -ene-4-one (Formula II)
2-n-butyl-1,3-diazaspiro[4,4]non-1-ene-4-one hydrochloride of formula III (29 gm) and 4-bromomethyl-2'-cyanobiphenyl of formula IV (30 gm) was dissolved in dimethylsulfoxide (300 ml), and to this crushed potassium hydroxide powder (18 gm) was added and the reaction mixture was stirred at about 25-30° C for 4-5 hours. After completion of reaction, the mixture was poured into water, filtered and dried to get the title compound. Yield: 36.5 gm Purity: 93.56% By HPLC
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WE CLAIM:
1. A process for the preparation of a compound of formula II, an intermediate useful in the synthesis of irbesartan. The process includes the steps of

Formula II

a) condensing a compound of formula III,


H3C

Formula III
with a compound of formula IV,

in the presence of polar aprotic solvent and powder potassium hydroxide
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b) isolation of compound of formula II from reaction mass thereof
2. The process of claim 1, wherein the polar aprotic solvent comprises one or
more of dimethylsulphoxide, N, N-dimethylformamide, N, N-dimethylacetamide,
N-methyl pyrrolidone, tetrahydrofuran, and acetonitrile.
3. The process of claim 2, wherein polar aprotic solvent used is
dimethylsulphoxide.
4. The process of claim 1, wherein the reaction is carried out at a temperature of about 20-30° C.
5. The process of claim 1, wherein the reaction is carried out for about 4-6 hours.
Dated this 27TH day of April, 2007 For Wockhardt Limited

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