FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
AN IMPROVED PROCESS FOR PREPARATION OF
IRBESARTAN
PIRAMAL HEALTHCARE LIMITED, a company incorporated under the Companies Act, 1956, of Piramal Tower, Ganpatrao Kadam Marg, Lower Parel, Mumbai - 400 013, State of Maharashtra, India
The following specification particularly describes the invention and the manner in which it is to be performed

FIELD OF THE INVENTION
The present invention relates to a process for preparing 2-butyl-3-[[2'-(2H-tetrazol5yl[l, 1 '-biphenyl] -4-yl]methyl]-l ,3-diazaspiro[4.4]non- 1 -en-4-one (Irbesartan or the compound of formula I). In particular, the present invention provides an improved process for the conversion of 4'-[(2-butyl-4-oxo-l,3-diazaspiro[4.4]non-1 -en-3-yl)methyl]-[ 1,1 '-Biphenyl]-2-carbonitrile ("referred to herein as "cyano Irbesartan" or the compound of formula II) to the compound of formula I (Irbesartan).
BACKGROUND OF THE INVENTION
Irbesartan, 2-butyl-3-[[2'-(2H-tetrazol5yl[ 1,1 '-biphenyl]-4-yl]methyl]-1,3-
diazaspiro[4.4]non-l-en-4-one, represented by the following formula I (hereinafter referred to as "the compound of formula I").

Irbesartan 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 complications of heart failure.

There are several methods known in the art for the preparation of tetrazole compounds. Irbesartan is also a tetrazole compound. Generally, preparation of terazole moiety involves the reaction of cyanide with trialkyltin azide (US7652147).
The compound of formula I (Irbesartan) is disclosed in US Patent No. 5,270,317. This patent also discloses a process for the preparation of tetrazole moiety of the compound of formula I (Irbesartan) comprising cyclization of cyano group using trialkyltin azide in the presence substituted benzenes, such as xylene as a solvent to obtain the reaction mixture. The resulting reaction mixture is then refluxed for 110 hours and then cooled to room temperature. The reaction mixture is then diluted with toluene and extracted with sodium hydroxide solution; the separated aqueous layer is then washed with xylene. Further, the aqueous layer is acidified with concentrated hydrochloric acid to precipitate the product. The process disclosed in said patent necessitates use of trialkyltin azide as a reagent for cyclization of cynide compound, handling of such hazardous reagent is difficult on commercial scale. Also, trialkyltin azide is an expensive reagent and therefore, use of the same in manufacturing renders the whole process costly. Moreover, the process requires long reaction time of 36 hours to 110 hours, which renders the process industrially nonviable.
The Indian patent application no. 1426/MUM/2008 discloses a process for the preparation of saltans involving reaction of cyano group with sodium azide in the presence of triethylamine as a catalyst and triethylamine hydrochloride in an organic solvent such as chlorobenzene at a temperature of 60-130°C for 15-18 hours. After completion of the reaction, the reaction mass is cooled to room temperature and quenched with sodium nitrite solution. The pH of the reaction mixture is then adjusted to 3.6 to 3.9 by using aqueous hydrochloric acid to

precipitate the solid product. The use of sodium nitrite during workup renders the whole process less safe and less eco friendly
The Indian patent application no. 1615/MUM/2008 discloses a process for the preparation of the compound of formula I (Irbesartan) by reacting the compound of formula II (cyano Irbesartan) with sodium azide in the presence of an organic base and sulphuric acid in n-butanol as a solvent, and the resulting reaction mixture is heated at reflux temperature till the reaction completes. After completion of the reaction, the reaction mass is cooled to room temperature and washed with water. The organic layer is then concentrated under reduced pressure to obtain an oily residue. The traces of the solvent are removed by azeotropic distillation to obtain a solid, which is dissolved in water and the product, the compound of formula I (Irbesartan) is isolated at pH of 4.2 to 7.5.
The process for the preparation of Irbesartan, the compound of formula I disclosed in the prior art generally involves cyclization of the compound of formula II (cyano Irbesartan) using trialkyltin azide or sodium azide in the presence of a base such as triethylamine, triethylamine hydrochloride to yield the compound of formula I (Irbesartan). The processes hitherto reported in the prior art involve carrying out the reaction at a high temperature and also require long duration of time. Also these processes involve tedious workup procedures as well as separations by column chromatography results in excessive production time, which in turn render the process more costly and less eco-friendly and therefore, such processes are not viable for industrial manufacturing.
Hence, there is a continuous need to develop simple, commercially advantageous and industrially viable process for the preparation of the compound of formula I (Irbesartan) in good yield and purity and reduces overall reaction time.

The inventors of the present invention have now found that the compound of formula I (Irbesartan) can be obtained in good yield and purity from the compound of formula II (cyano Irbesartan) through an improved process involving use of 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst.
OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan) from the compound of formula II (cyano Irbesartan), using l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst.
Another object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan) with 98% conversion of the compound of formula II (cyano Irbesartan) to the compound of formula I (Irbesartan).
Another object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan) by avoiding the use of toxic reagents such as trialkyltin azide and sodium nitrite thereby rendering the process environment friendly.
Yet another object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan) involving carrying out the reaction at a shorter duration of time.
Further object of the present invention is to provide an improved process for the preparation of the compound of formula I (Irbesartan), by avoiding any

chromatographic purification method for intermediates or final product and providing the compound of formula I (Irbesartan) with good yield and purity > 99.0%.
SUMMARY OF THE INVENTION
In accordance with an aspect of the present invention, there is provided an improved process for the preparation of the compound of formula I (Irbesartan) comprising the steps of,
a. reacting the compound of formula II (cyano Irbesartan) with sodium azide
in the presence of l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and
triethylamine hydrochloride in an organic solvent at a temperature of 120-
140°C for 15-40 hours and isolating the compound of formula I (Irbesartan)
from the resulting reaction mixture;
b. optionally, purifying the compound of formula I (Irbesartan) obtained in
step (a) using a polar solvent to yield the pure compound of formula I
(Irbesartan).
The process for the preparation of the compound of formula I (Irbesartan) is
depicted in scheme-I herein
below


In accordance with another aspect of the present invention, the process for the preparation of the compound of formula I (Irbesartan) from the compound of formula II (cyano Irbesartan) results with 98% conversion with good yield and purity > 99.0%.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of the compound of formula I (Irbesartan).
According to the present invention, the improved process for the preparation of the compound of formula I (Irbesartan) involves use of readily available raw materials and reagents.
The improved process for the preparation of the compound of formula I (Irbesartan);

comprises the steps of, a. reacting the compound of formula II (cyano Irbesartan),


Formula II
with sodium azide in the presence of l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst and triethylamine hydrochloride as a base in an organic solvent at 120-140°C for 15-40 hours and isolating the compound of formula I (Irbesartan) from the resulting reaction mixture; b. optionally, purifying the compound of formula I (Irbesartan) obtained in step (a) using a polar solvent to yield the pure compound of formula I (Irbesartan).
In an embodiment of the present invention, the organic solvent used in step (a) of the process is substituted benzene, selected from toluene, xylenes (o-, m- or p-xylene) or chlorobenzene.
In a specific embodiment, o-xylene may be used as the organic solvent in step (a) of the process.
In accordance with an embodiment of the present invention, the organic solvent used in step (a) ranges from 4 to 6 volumes based on the compound of formula II (cyano Irbesartan).
In accordance with an embodiment of the present invention, the step (a) of the process is carried out at a temperature of 120 -140°C.

In a specific embodiment, the step (a) of the process may be carried out at a temperature of 125-130°C.
In accordance with an embodiment of the present invention, the step (a) of the process is carried out over a time period of 15-40 hours.
In a specific embodiment, the step (a) of the process may be carried out over a time period of 20-30 hours.
In accordance with an embodiment of the present invention, the sodium azide used in the step (a) ranges from 2.5 to 4 molar equivalents based on the compound of formula II (cyano Irbesartan).
In a specific embodiment, the sodium azide may be used in an amount ranging from 3 to 3.5 molar equivalent based on the compound of formula II (cyano Irbesartan).
In accordance with an embodiment of the present invention, the triethyl amine hydrochloride used in the step (a) ranges from 2.5 to 4 molar equivalents based on the compound of formula II (cyano Irbesartan).
In a specific embodiment, the triethyl amine hydrochloride may be used in an amount ranging from 3 to 3.5 molar equivalents based on the compound of formula II (cyano Irbesartan).
In accordance with an embodiment of the present invention, 1,8-Diazabicyclo [5.4.0]undec-7-ene (DBU) used in the step (a) ranges from 0.15-0.5 molar equivalents based on the compound of formula II (cyano Irbesartan).

In a specific embodiment, l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) may be used in an amount ranging from 0.2 to 0.3 molar equivalents based on the compound of formula II (cyano Irbesartan).
In another embodiment of the present invention, the crude compound of formula I (Irbesartan), obtained in the step (a) is isolated from the reaction mixture using sodium hydroxide (NaOH) at a temperature of 25-30°C.
In accordance with another embodiment of the present invention, isolation of the compound of formula I (Irbesartan) from the reaction mixture of the step (a) described above comprises the steps of:
(i) charging sodium hydroxide solution to the reaction mixture obtained in step
(a) at a temperature of 25-30°C, (ii) extracting the compound of formula I (Irbesartan) from the resulting
reaction mixture of the above step (i) in water, (iii) precipitating the compound of formula I (Irbesartan) by adding ethyl acetate to the reaction mixture and adjusting the pH of the reaction mixture using 50% hydrochloric acid.
In accordance with another embodiment of the present invention, in the process for the isolation of the compound of formula I (Irbesartan), the pH of the reaction mixture adjusted in the step (iii) is to 2.0 to 4.5.
The compound of formula I (Irbesartan) obtained in the step (a) of the present invention is of pharmaceutically acceptable purity; however, optionally the compound of formula I (Irbesartan) may be further purified to yield the pure compound of formula I (Irbesartan). The purification of the compound of formula I (Irbesartan) carried out using a polar solvent selected from methanol, ethanol, n-

propyl alcohol or isopropyl alcohol. The purification of the compound of formula I (Irbesartan) is preferably carried out using isopropyl alcohol.
The starting material of the process, i.e. the compound of formula II (cyano Irbesartan) is a known compound and can be prepared by a person skilled in the art by following methods described in the literature. For example, process described in US 5270317 can be used for the preparation of the compound of formula II. The said compound of formula II (cyano Irbesartan) can be prepared by the condensation of a 2-n-butyl-l,3-diazaspiro-[4,4]non-en-4-one hydrochloride with a halomethyl-cyanobiphenyl using a phase transfer catalyst such as tetrabutyl ammonium bromide and a base in an organic solvent such as dichromethane. The reaction mixture was stirred for 1-2 hours at a room temperature followed by addition of water; separated organic layer was distilled completely to obtain the crude compound of formula II (cyano Irbesartan). The crude compound of formula II (cyano Irbesartan) was optionally crystallized to obtain the pure compound of formula II (cyano Irbesartan).
According to the present invention, the process for the preparation of the compound
of formula I (Irbesartan) involves charging of the compound of formula II (cyano
Irbesartan), sodium azide, triethylamine hydrochloride, 1,8-
Diazabicyclo[5.4.0]undec-7-ene (DBU) and substituted benzene such as o-xylene as a solvent to the reaction flask and the reaction mixture heated to a temperature of 120-140°C for 15 to 40 hours. To the reaction mixture then water and 30% sodium hydroxide solution were charged at a room temperature. The two layers formed were separated and ethyl acetate was added to the aqueous layer. The pH of the reaction mixture was then adjusted to 2.0-4.5 with aqueous hydrochloric acid to precipitate the solid. The resulting solid was filtered, and washed with water and then with ethyl acetate. The solid was dried under vacuum at 60-65°C to produce

the compound of formula I (Irbesartan). The product, the compound of formula I (Irbesartan) optionally crystallized using aqueous isopropyl alcohol (IP A) to yield the pure compound of formula I (Irbesartan).
The inventors of the present invention have observed that the process for the preparation of the compound of formula I (Irbesartan) when carried out in the presence of l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst, it promotes the reaction in which more basic, bulkier base catalyst such as triethylamine (TEA) and N,N-Diisopropylethylamine (DIPEA) have not been found to be effective. It has been observed that when DBU is used as a catalyst in the process for the preparation of the compound of formula I (Irbesartan), complete conversion of the reaction takes place without any major impurity formation thereby providing the compound of formula I (Irbesartan) with good yield and 99% purity, even without requirement of any additional step of purification.
The process for the preparation of the compound of formula I (Irbesartan) involving use of l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) as a catalyst results in a product which is off white to white in color and thus, avoids the further charcolisation and subsequent yield loss. The process according to the present invention does not involve any chromatographic purification for final product i.e. the compound of formula I (Irbesartan) thereby avoiding any loss resulting in the final product in higher yield.
The following examples which fully illustrate the practice of the preferred embodiments of the present invention are intended to be for illustrative purpose only and should not be construed in any way to limit the scope of the present invention.

Example-1
a) Preparation of 2-buryl-3-[[2'-(2H-tetrazol5yl[l,r-biphenyl]-4-y]]methyl]-l,3-diazaspiro[4.4] non-l-en-4-one (Irbesartan)
In a round bottom flask, 4'-[(2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl]-[l,r-Biphenyl]-2-carbonitrile (lOg; 0.0259 moles), sodium azide (5.9g; 0.0907 moles), triethylamine hydrochloride (12.5g; 0.0908 moles) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (lgm; 0.0065 moles) in o-xylene (40 ml) was charged and the reaction mixture was gradually heated to 125-130°C for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and water (30ml) and 30% sodium hydroxide solution (10ml) were added to the reaction mixture. The two layers formed were separated. To the aqueous layer was then added ethyl acetate (70 ml) and the pH of the reaction mixture was adjusted to 2.0-4.5 using aqueous hydrochloric acid to precipitate a solid. The precipitated solid was filtered and washed with water (40ml) and then with ethyl acetate (40 ml). The solid was dried under vacuum at a temperature of 60-65°C to yield the compound of formula I (Irbesartan). Yield 95%, HPLC purity 99%. The compound of formula I (Irbesartan) obtained was crystallized using aqueous isopropyl alcohol and dried under vacuum at 60-65°C to yield pure white the compound of formula I (Irbesartan). Yield 85%, Purity 99.95%.
1H NMR in DMSO-D6: 7.68 (d. 2H, Ar-H), 7.52 (d, 2 H, Ar-H), 7.08 (s, 4 H, Aril), 4.68(s, 2H, -CH2), 2.69(t,2H,-CH2),2.18(m,2H,-CH2),1.83(m.2H,-CH2),1.81 (t, 2H, -CH2), 1.65 (t, 2H, -CH2), 1.45 (m, 2 H, -CH2), 1.24(m , 2H, -CH2), 0.77 (t, 3H, -CH3),
IR (KBR): 3061 (Aromatic C-H stretching), 2960 (Aliphatic C-H stretching), 3443 (N-H stretching), 1733 (C=0 stretching), 1617(CN stretching), 1337.99(CN

stretching), 1407(N=N stretching) cm"1. Example-2
b) Preparation of 2-butyl-3-[[2'-(2H-tetrazol5yl[l,l'-biphenyl]-4-yl]methyl]-1,3-diazaspiro [4.4] non-l-en-4-one (Irbesartan)
In a round bottom flask, 4'-[(2-butyl-4-oxo-l,3-diazaspiro[4.4]non-l-en-3-yl)methyl]-[l,r-Biphenyl]-2-carbonitrile (lOg; 0.0259 moles), sodium azide (5.9g; 0.0907 moles), triethylamine hydrochloride (12.5g; 0.0908 moles) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (lgm; 0.0065 moles) in chlorobenzene (40 ml) was charged and the reaction mixture was gradually heated to 125-130°C for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and water (30ml) and 30% sodium hydroxide solution (10ml) was added to the reaction mixture. The two layers formed were separated. To the aqueous layer was then added ethyl acetate (70 ml) and the pH of the reaction mixture was adjusted to 2.0-4.5 using aqueous hydrochloric acid. The precipitated solid was filtered and washed with water (40ml) and then with ethyl acetate (40 ml). The solid was dried under vacuum at a temperature of 60-65°C to yield the compound of formula I (Irbesartan). Yield 95%, HPLC purity 99%. The crude compound of formula I (Irbesartan) obtained was crystallized using aqueous isopropyl alcohol and dried under vacuum at 60-65°C to yield pure white the compound of formula I (Irbesartan) Yield 85%, Purity 99.95%.
]H NMR in DMSO-D6: 7.68 (d. 2H, Ar-H), 7.52 (d, 2 H, Ar-H), 7.08 (s, 4 H, Aril), 4.68(s, 2H, -CH2), 2.69(t,2H,-CH2),2.18(m,2H,-CH2),1.83(m,2H,-CH2),1.81 (t, 2H, -CH2), 1.65 (t, 2H, -CH2), 1.45 (m, 2 H, -CH2), 1.24(m , 2H, -CH2), 0.77 (t, 3H, -CH3),

IR (KBR): 3061 (Aromatic C-H stretching), 2960 (Aliphatic C-H stretching), 3443 (N-H stretching) Cm"1, 1733 (C=0 stretching), 1617 (ON stretching), 1337 (C-N stretching), 1407 (N=N stretching) cm"1

WE CLAIM,
1. A process for the preparation of compound of formula I (Irbesartan),

Formula I
comprising,
a. reacting the compound of formula II (cyano Irbesartan),

Formula II
with sodium azide using l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) and triethylamine hydrochloride in an organic solvent at a temperature of 120-140°C for 15-40 hrs and isolating the compound of formula I (Irbesartan) from the resulting reaction mixture ; b. optionally purifying the compound of formula I (Irbesartan) obtained in step (a) in a polar solvent to yield the pure compound of formula I (Irbesartan).

2. The process as claimed in claim h wherein said organic solvent is selected from substituted benzenes.
3. The process as claimed in claim ?-, wherein said organic solvent is selected from toluene, chlorobenzene or xylene (o-, m- or p-xylene).
4. The process as claimed in claim 3, wherein said organic solvent is o-xylene.
5. The process as claimed in claim l, wherein said organic solvent is used in a range of 4 to 6 volumes based on the compound of formula II (cyano Irbesartan).
6. The process as claimed in claim 1, wherein the step (a) is carried out at temperature ranging from 125-130°C.
7. The process as claimed in claim 1, wherein the step (a) is carried out for 20-30 hours.
8. The process as claimed in claim 1, wherein said sodium azide is used in a range from 2.5 to 4 molar equivalents based on the compound of formula II (cyano Irbesartan).
9. The process as claimed in claim 1, wherein said triethylamine hydrochloride is used in a range from 2.5 to 4 equivalents based on the compound formula II (cyano Irbesartan).
10. The process as claimed in claim 1, wherein said 1,8-
Diazabicyclo[5.4.0]undec-7-ene (PBU) is used in a range from 0.15 to 0.5

equivalent based on the compound formula II (cyano Irbesartan).
11. The process as claimed in claim 1, wherein isolation of the compound of
formula I (Irbesartan) from the reaction mixture of step (a) comprises the
steps of:
(i) charging sodium hydroxide solution to the reaction mixture obtained in
step (a) recited in claim 1 at a temperature of 25-30°C, (ii) extracting the compound of formula I (Irbesartan) from the resulting
reaction mixture of above step (i) in water, (iii) precipitating the compound of formula I (Irbesartan) by adding ethyl
acetate to the reaction mixture and adjusting the pH of the reaction
mixture using 50% hydrochloric acid.
12. The process as claimed in claim 11, wherein the pH of the reaction mixture is adjusted to 2.0 to 4.5.
13. The process as claimed in claim 1, wherein the polar solvent used in step (b) is selected from methanol, ethanol, n-propyl alcohol or isopropyl alcohol.
14. The process as claimed in claim 13, wherein the polar solvent is isopropyl alcohol.