FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
& THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
An Improved Process for the Preparation of Irbesartan


APPLICANT;
CALYX CHEMICALS AND PHARMACEUTICALS LTD. 2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India

Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed:


TITLE
AN IMPROVED PROCESS FOR THE PREPARATION OF IRBESARTAN
FIELD OF THE INVENTION:
The present invention relates to an improved and efficient process for preparing 2-n-Butyl-3-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4-one of formula I, which is also known by adopted name "Irbesartan". In particular, the present invention provides an improved process for the preparation of tetrazole moiety of Irbesartan.

Formula I
BACKGROUND OF THE INVENTION:
Irbesartan (2-n-Butyl-3-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,3-
diazaspiro[4.4]non-l-en-4-one), represented by formula-I is a non-peptide angiotensin-II antagonist (blocker). Angiotensin is an important participant in the rennin angiotensin-aldosterone system (RAAS) and has a strong influence on blood pressure. Irbesartan inhibits the action of angiotensin-II as its receptors and thus prevents the increase in blood pressure produced by the hormone-receptor interactions. It is therefore useful in the treatment of hypertension and heart failure.
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Tetrazolyl compounds such as Irbesartan disclosed in US patent no. 5,270,317, Candesartan disclosed in US patent no. 5,196,444, Losartan and its salts, disclosed in US patent no. 5,138,069 and Valsartan disclosed in US patent no. 5,399,578 belong to the class of non-peptide angiotensin-II receptor antagonists. These compounds are generally prepared by cyclization of aromatic nitriles to tetrazolyl compounds by use of trialkyltin azide.
EP 0454511 describes a process for the preparation of Irbesartan by the reaction of 2-n-butyl-3- [[2'-cyanobiphenyl-4-yl] methyl]-l, 3-diazaspiro[4. 4]non-l- en-4-one with tributyltin azide in xylene at reflux for 110 hrs. US patent no. 5,270,317 discloses reaction time of up to 210 hrs.
J. Med. Chem. (1993), 36, 3371-3380, discloses a process for the preparation of Irbesartan by heating cyano derivative with tributyltin azide in xylene under refluxed condition, after completion of reaction, reaction mass is extracted with IN sodium hydroxide solution. Acidified to pH ~5 using 3N HC1 & extracted the product with methylene dichloride. Residue obtained after removing methylene dichloride is recrystallized from 96% ethanol to give Irbesartan.
US 5,629,331 describes a process for the preparation of Irbesartan wherein the' precursor 2-n-butyl-3- [[2'-cyanobiphenyl-4-yl] methyl]-l, 3-diazaspiro[4. 4]non-l- en-4-one is treated with sodium azide in presence of triethylamine hydrochloride in a polar aprotic solvent such as DMF and NMP at temperature of 110-140 °C.
WO 2004/065383 also describes the synthesis of Irbesartan tritylate by reacting 2-(l-trityl-lH-tetrazol-5-yl)phenyIboronic acid with 2-butyl-3-(4'-bromobenzyl)-l,3-diazaspiro[4,4]non-l-en-4-one under Suzuki coupling conditions. The product so obtained is then submitted to acid conditions in order to hydrolyse the trityl group of the tetrazole ring in order to give Irbesartan. One negative aspect of said techniques is the
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use of a voluminous protecting group such as trityl, which very considerably increases the molecular weight of the intermediates, which is then dramatically diminished in the final hydrolysis that provides Irbesartan, thereby resulting in a process of low atomic efficiency. This further creates a considerable amount of residual products & increases the number of synthesis steps in the process.
WO 2007013101 describes yet another process for the preparation of Irbesartan wherin the tetrazole moiety of Irbesartan is formed by reacting 2-n-butyl-3- [[2'-cyanobiphenyl-4-yl] methyl]-l, 3-diazaspiro[4. 4]non-l- en-4-one with sodium azide, in presence of organic acid such as acetic acid and organic base such as triethyl amine using n-butyl actate, n-heptane, toluene or xylene as solvent at 115-120 °C for 24hrs.
The process described in WO 2007052301 and WO 2007049293 for the preparation of Irbesartan comprises the reaction of l-(2'-cyanobiphenyl-4-yi)methyl-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one with tributyltin azide in o-xylene at elevated temperatures. Even after 80 hrs of reaction, the yield of the product reported is only 78%.
IN 193265 describes the process for the preparation of Irbesartan which comprises reacting 2-n-butyl-3- [[2'-cyanobiphenyl-4-yl] methyl]-l, 3-diazaspiro[4. 4]non-l- en-4-one with sodium azide using an aliphatic amine selected from trialkyl amines such as triethylamine or tributylamine and acetic acid in a solvent such as anisole at 50-150 °C.
WO 2007054965 describes a process for the preparation of Irbesartan in which 2-n-butyl-3- [[2'-cyanobiphenyl-4-yl] methyl]-l, 3-diazaspiro[4. 4]non-l- en-4-one was treated with trialkyltin halide and metal azide in presence of a base like triethyl amine or isopropyl amine.
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EP 1918288 discloses the preparation of Irbesartan by reacting 2-n-butyl-3- [[21-cyanobiphenyl-4-yl] methyl]-!, 3-diazaspiro[4. 4]non-l- en-4-one with sodium azide and zinc halide in an organic solvent like THF, N,N-dimethylformamide or N,N-dimethyl acetamide.
Thus, most of the prior art processes use trialkyltin azide as a reagent which is not safe to handle and is costly. The reaction time is usually long, ranging from 36 hrs to 4 days. Also these processes involve tedious workup procedures e.g. a large number of steps which include the protection and subsequent deprotection, and isolation of intermediates as well as separations by column chromatography results in excessive production times, which in turn renders the process more costly and less eco-friendly, hence the processes are not suitable for commercial scale up.
Accordingly, there remains a need for a simple, commercially advantageous and industrially viable process.
The process of the present invention avoids the use of trialkyltin azide, reduces the reaction time, uses cost efficient raw materials and selective solvents which are recoverable and reusable, avoids any chromatographic purification method for intermediates or final product and provides final compound Irbesartan with high yield and with purity > 99.5%. Thus, the process of present invention is an improved, efficient and industrially viable process for the preparation of Irbesartan.
OBJECT OF THE INVENTION:
An object of the present invention is to provide an improved and efficient process for the preparation of Irbesartan of formula I, more particularly, for the preparation of tetrazole moiety of Irbesartan.
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Another object of the present invention is to provide an environment friendly process for the preparation of Irbesartan by avoiding the use of toxic trialkyltin azide.
Another object of the present invention is to provide a commercially feasible process for the preparation of Irbesartan by reducing reaction time.
Yet another object of the present invention is to provide an industrially viable process for producing Irbesartan of formula-I, employing cost efficient raw materials and selective solvent system wherein the solvents used in the process are recoverable and reusable.
Further object of the present invention is to provide an improved process for the preparation of Irbesartan, avoiding any chromatographic purification method for intermediates or final product and provide Irbesartan with high yield and with purity > 99.5%.
SUMMARY OF THE INVENTION:
According to an aspect of the present invention, there is provided an improved, efficient and commercially feasible process for the preparation of Irbesartan of formula I comprising the steps of,
a) condensation of a spiro-intermediate of formula II with a halomethyl-cyanobiphenyl of formula III in an organic solvent in presence of water and base to get a product 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4-one (herein after called as cyano-irbesartan) of formula IV
b) reacting cyano-irbesartan formula IV with sodium azide, triethylamine and triethylamine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 100-110 °C
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c) continue heating the reaction mixture at 100-110 °C for 12-18 hrs.
d) isolating the product 2-n-butyl-3-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,3-diazaspiro[4.4]non-l-en-4-one (herein after called as Irbesartan) of formula I by usual work-up procedure.
The process for the preparation of Irbesartan is as depicted in Scheme-1 below

H3C
Formula I (Irbesartan)

Scheme-I
In particular, the present invention provides an improved process for the preparation of tetrazole moiety of Irbesartan by reacting cyano-irbesartan of formula IV
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H,C

Formula IV
with sodium azide, triethylamine and triethylamine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 100-110 °C for 12-18 hrs.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an economical and a high yielding process for the industrial production of 2-n-butyl-3 - [[2' -(1 H-tetrazol-5-yl)[1,1' -biphenyl] -4-yl]methyl] -l,3-diazaspiro[4.4]non-l-en-4-one of formula I employing readily available raw materials and reagents.
The present invention relates to an improved process for the preparation of Irbesartan of formula I comprising the steps of,
a) condensation of a spiro-intermediate of formula II with a halomethyl-cyanobiphenyl compound of formula III in an organic solvent in presence of water and base to get a product cyano-irbesartan of formula IV
b) reacting cyano-irbesartan of formula IV with sodium azide, triethylamine and triethylamine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 100-110 °C
c) continue heating the reaction mixture at 100-110 °C for 12-18 hrs.
d) isolating the product Irbesartan of formula I by usual work-up procedure.
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The process for the preparation of Irbesartan is as depicted in Scheme-1

Scheme-I
The condensation of a spiro-intermediate of formula II with a halomethyl-cyanobiphenyl compound of formula III is carried out by the well known prior art process.
More particularly, the present invention is related to the process for the preparation of tetrazole moiety of Irbesartan which comprises,
a) reacting cyano-irbesartan of formula IV
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with sodium azide, triethylamine and triethylamine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 100-110 °C
b) continue heating the reaction mixture at 100-110 °C for 12-18 hrs.
c) isolating the product Irbesartan of formula I by usual work-up procedure.
Cyano-irbesartan of formula IV is obtained by the condensation of a spiro-intermediate of formula II with a halomethyl-cyanobiphenyl compound of formula III by the well known prior art process, as depicted in scheme-1 above.
In an embodiment of the present invention, cyano-irbesartan of formula IV is reacted with sodium azide, triethylamine and triethylamine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones. The organic solvent is selected from toluene, mono, di or tri-substituted benzenes, xylenes, ethers or ketons, preferably halobenzenes such as chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, anisole, diphenyl ether or methyl isobutyl ketone, more preferably halobenzenes such as chlorobenzene or 1,2-dichlorobenzene.
In another embodiment of the present invention the amount of organic solvent used ranges from 3 to 8 volumes based on the cyano-irbesartan of formula IV, preferably between 3 to 6 volumes, more preferably between 3 to 5 volumes.
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In another embodiment of the present invention, the reaction is carried out between 60 -130 °C, preferably between 70-120 °C, more preferably between 100 -110 °C.
In yet another embodiment of the present invention the reaction time ranges from 6-30 hrs, preferably from 8-24 hrs, more preferably from 12-18 hrs.
In.yet another embodiment of the present invention, sodium azide is employed in an amount ranging from 1 to 6 molar equivalents based on the cyano-irbesartan of formula IV, preferably between 2 to 4 molar equivalents , more preferably between 2.5 to 3.5 molar equivalents.
In yet another embodiment of the present invention, triethyl amine hydrochloride is used in an amount ranging from 1 to 6 equivalents based on cyano-irbesartan of formula IV preferably between 2 to 4 molar equivalents, more preferably between 2.5 to 3.5 equivalents.
In yet another embodiment of the present invention, triethylamine employed is in an amount ranging from 5 to 15% w/v based on cyano-irbesartan of formula IV, preferably between 8 to 10% w/v.
Thus, the process disclosed according to the present invention avoids the use of organotin reagent for the formation of tetrazole moiety from cyano-irbesartan of formula IV, as disclosed in the prior art. Further, the process is carried out in the presence of organic solvent such as halobenzenes, which can be easily recovered and recycled, thereby providing Irbesartan of formula-I with high quality without using multiple purification steps in a very short time period. The process disclosed according to the present invention does not involve any chromatographic purification method for intermediates or final product.
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The experimental details for the preparation of tetrazole moiety of Irbesartan of formula I by reacting cyano-irbesartan of formula IV with sodium azide, triethylamine and triethylamine hydrochloride in various organic solvents are as given below in Table I.
Table I

Batch No. NaN3 (Mol. equiv.) Solvent Time
(hrs) %
conversion to Irbesartan
2008/027/BZAR/37 2.5 Chlorobenzene 12 88.26
2008/027/BZAR/37 2.5 Chlorobenzene 18 92.58
2008/027/BZAR/19 3.0 Chlorobenzene 12 92.82
2008/027/BZAR/19 3.0 Chlorobenzene 18 96.16
2008/027/BZAR/48 3.5 Chlorobenzene 6 93.34
2008/027/BZAR/48 3.5 Chlorobenzene 12 97.45
2008/027/BZAR/39 2.5 1,2-Dichlorobenzene 12 77.72
2008/027/BZAR/39 2.5 1,2-Dichlorobenzene 18 85.91
2007/173/BZAR/05 3.0 1,2-Dichlorobenzene 12 95.0
2007/173/BZAR/05 3.0 1,2-Dichlorobenzene 18 91.83
2008/027/BZAR/40 3.5 1,2-Dichlorobenzene 12 90.28
2008/027/BZAR/40 3.5 1,2-Dichlorobenzene 18 93.51
2007/173/BZAR/02 3.0 1,3-Dichlorobenzene 12 88.8
2007/173/BZAR/02 3.0 1,3-Dichlorobenzene 18 89.47
2007/173/BZAR/01 3.0 Toluene 12 84.90
2007/173/BZAR/01 3.0 Toluene 18 84.06
2008/027/BZAR/21 3.0 Methyl isobutyl ketone 12 72.7
2008/027/BZAR/21 3.0. Methyl isobutyl ketone 18 82.12
2008/027/BZAR/44 3.5 Methyl isobutyl ketone 12 88.98
2008/027/BZAR/44 3.5 Methyl isobutyl ketone 18 93.03
2008/027/BZAR/28 3.0 Anisole 12 87.1
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2008/027/BZAR/28 3.0 Anisole 18 92.38
2007/173/BZAR/03 3.0 Diphenyl ether 12 91.83
2007/173/BZAR/03 3.0 Diphenyl ether 18 93.99
Note: Molar equivalents of triethyl amine hydrochloride used are the same as of sodium azide, as shown in table. Triethyl amine used is 10% w/v and solvent is 3-6 volumes based on cyano-irbesartan of formula IV. % conversion to Irbesartan is reported by HPLC method. Reaction is carried out at a temperature of 100-106 °C.
The following non-limiting examples illustrate specific embodiments of the present invention. They are however not-intended to be limiting the scope of the present invention in any way.
Example I:
2-n-Butyl-3- [[2'-cyanobiphenvl-4-yl] methyl]-l, 3-diazaspiro[4. 4]non-l- en-4-one
(Cyano-irbesartan):
To the stirred solution of 2-n-butyl-l,3-diazaspiro[4.4]non-l-ene-4-one hydrochloride (250g, 1.083 moles), tetrabutylammonium bromide (12.5g, 5 wt%) in dichloromethane (1000ml) was slowly added aqueous sodium hydroxide solution (242g of'NaOH, 6.05 moles + 375ml of water) at 0-5 °C. Solution of 4'-bromomethyl[l,l'-biphenyl]-2-carbonitrile (295g, 1.083 moles) in dichloromethane (1200 ml) was added at 0-5 °C and the reaction mixture was allowed to warm to room temperature and stirred until the completion of reaction and the organic layer was concentrated under reduced pressure to give a thick oily residue (400g (95.76%), HPLC purity = 96%). The crude product was crystallized using isopropyl alcohol-water to obtain highly pure cyano-irbesartan. Yield: 355g (84.99%), HPLC purity = 99.7%.
1H NMR in CDC13: 5 7.91-7.94 (dd, 1H, ArH), 7.73-7.79 (dd, 1H, ArH), 7.53-7.60 (m, 4H, -ArH), 7.29-7.3l(d, 2H, CH2), 2.32-2.37 (t, 2H, -CH2), 2.78-2.82 (t, 2H, J- 12Hz, -CH2).
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13C NMR in CDC13: 5 185.87,161.16, 144.18, 137.92, 137.09, 133.99, 133.64, 130.19, 129.31, 128.37, 126.87, 118.60, 110.33, 76.02, 42.46, 36.97, 27.67, 26.81, 25.60, 21.68, 13.72.
IR (KBr): 3053.32, 3028.24, 2974.22, 2951.09, 2906.73, 2870.08, 2220.07, 1720.50, 1627.92, 1481.33, 1446.61, 1402.25, 1330.88, 1311.59,1205.51,1170.79,1107.14, 1006.84,941.26, 812.03, 775.38, 759.95, 630.72,426.27 cm-1.
Example II:
2-n-ButyI-3-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,3-diazaspiro[4.4] no'n-l-en-4-one (Irbesartan):
In a round bottom flask was taken 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]-l,3-diazaspiro-[4.4]non-l-en-4-one (lOOg, 0.2594 moles), sodium azide (54.2g, 0.834 moles), triethylamine hydrochloride (120g, 0.872 moles) and triethylamine (10ml) in chlorobenzene (400 ml) and the mixture was gradually heated to 105-106 °C. Reaction mixture was continued heating at 105-106 °C for 15-18 hrs. After completion of the reaction, it was cooled to room temperature. Sodium nitrite solution (65g NaN02 + 300ml water) was then added slowly over a period of 1.0 hr and stirred further for 15 minutes. The pH of reaction mixture was then adjusted to 3.6 to 3.9 by using aq. HC1. The reaction mixture was stirred for 1 hrs. Solid product precipitated in the solution was filtered out and washed with water and dried under vacuum to obtain crude Irbesartan (HOg, HPLC purity = >95%). Crude product was crystallized using aqueous ethanol. Finally pure Irbesartan was dried under vacuum at 60-70 °C to yield white material. Yield = 89g (80.0%), HPLC purity = 99.87%.
1H NMR in DMSO-d6: 57.69-7.64 (dd, 1H, ArH), 7.51-7.59 (dd, 1H, ArH), 7.08 (s,
4H, ArH), 4.67 (s, 2H,-CH2), 2.25-2.30 (t, 2H, -CH2), 1.81-1.83 (t, 6H, J= 12Hz, -
CH2), 1.65 (m, 2H, -CH2), 1.45 (m, 2H, -CH2), 1.25 (m, 2H, -CH2), 0.79 (t, 3H, -
CH3).
13C NMR in DMSO-d6: 5185.81, 161.31, 155.19, 141.19, 138.54, 136.47, 131.23,
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130.76, 130.73, 129.43, 127.99, 126.43, 123.66, 75.97, 42.39, 38.87, 27.64, 26.74, 25.61, 21.67, 13.78.
IR (KBr): 2958.80, 2873.94, 1732.08, 1614.42, 1556.55, 1435.04, 1408.04, 1336.67, 1238.30,1178.51, 939.33, 758.02, 665.44, 522.71 cm-1.
Example III:
2-n-Butyl-3-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-l,3-diazaspiro[4.4] non-l-en-4-one (Irbesartan):
In a round bottom flask was taken 2-n-butyl-3-[[2'-cyanobiphenyl-4-yl]methyl]-l,3-diazaspiro-[4.4]non-l-en-4-one (lOg, 0.0259 moles), sodium azide (5.89g, 0.0906 moles), triethylamine hydrochloride (12.48g, 0.0906 moles) and triethylamine (1.0 ml) in methyl isobutyl ketone (50 ml) and the mixture was gradually heated to 105 °C. Reaction mixture was continued heating at 100-105 °C for 20-24 hrs. After completion of the reaction, it was cooled to room temperature. Sodium nitrite solution (6.5g NaN02 + 30.0ml water) was then added slowly over a period of 1.0 hr and stirred further for 15 minutes. The pH of reaction mixture was then adjusted to 3.6 to 3.9 by using aq. HC1. The reaction mixture was stirred for 1 hrs. Solid product precipitated in the solution was filtered out and washed with water and dried under vacuum to obtain :rude Irbesartan (9.7g, HPLC purity = 96.21%). Crude product was crystallized using method described in example II and obtained pure Irbesartan (HPLC purity = 99.7%).
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W,e claim:
1. An improved process for the preparation of tetrazole moiety of Irbesartan of formula I comprising:

Formula I
reacting 2-n-butyl-3- [[2'-cyanobiphenvl-4-yl] methyl]-1, 3-diazaspiro[4. 4]non-l-en-4-one of formula IV

Formula IV
with sodium azide, triethylamine and triethylamine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 60-130 °C.
2. An improved process for the preparation of Irbesartan of formula I, comprising:
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a) reacting 2-n-butyl-3- [[2'-cyanobiphenvl-4-yl] methyl]-l, 3-diazaspiro[4. 4]non-
1- en-4-one of formula IV
with sodium azide, triethylamine and triethylamine hydrochloride in an organic solvent such as substituted benzenes, ethers or ketones at 60-130 °C
b) continue heating the reaction mixture at 100-110 °C for 12-18 hrs.
c) isolating the product Irbesartan by usual work-up procedure
3. The process as claimed in claim 1 or 2, wherein the organic solvent such as substituted benzenes, ethers or ketones is selected from toluene, mono, di or tri-substituted benzenes, xylenes, ethers or ketones, preferably halobenzenes such as chlorobenzene, 1,2-dichlorobenzene, 1,3-dichlorobenzene, anisole, diphenyl ether or methyl isobutyl ketone, and more preferably halobenzenes such as chlorobenzene or 1,2-dichlorobenzene.
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4. The process as claimed in claim 3, wherein the amount of organic solvent used ranges from 3 to 8 volumes based on cyano-irbesartan of formula IV, preferably between 3 to 6 volumes, more preferably between 3 to 5 volumes.
5. The process as claimed in claim 1 or 2, wherein the reaction is carried out at temperature ranging from 60-130 °C, preferably from 70-120 °C, more preferably from 100-110 °C
6. The process as claimed in claim 1 or 2, wherein the reaction is carried out for 6-30 hrs, preferably for 8-24 hrs., more preferably for 12-18 hrs.
7. The process as claimed in claim 1 or 2, wherein amount of sodium azide used in the reaction varies from 1 to 6 molar equivalents based on cyano-irbesartan of formula IV, preferably from 2 to 4 molar equivalents, more preferably from 2.5 to 3.5 molar equivalents
8. The process as claimed in claim 1 or 2, wherein triethyl amine hydrochloride is used in an amount ranging from 1 to 6 equivalents based on cyano-irbesartan of formula IV, preferably between 2 to 4 molar equivalents, more preferably between 2.5 to 3.5 molar equivalents.