FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
1. Improved process for the preparation of Irbesartan.
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD, 382210, GUJARAT, INDIA, AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

TITLE : Improved process for the preparation of Irbesartan
FIELD OF THE INVENTION
The present invention relates to a novel and improved process for the preparation Irbesartan an angiotensin-II receptor antagonist for the treatment of hypertension. Irbesartan is known by following chemical names:
(a) 2-Butyl-3-[[2'-(l//-tetrazol-5-yl)[l,l '-biphenyl]-4-yl]methyl]-l, 3-diaza-spiro[4, 4]non-l-en-4-one
(b) 2-Butyl-3-[p-(o-7//-tetrazol-5-ylphenyl)benzyl]-1,3-diazaspiro[4,4]non-1 -en-4-one
(c) 2-n-butyl-4-spirocyclopentane-l-[(2'-(tetrazol-5-yl) biphenyl-4-yl) methyl]-2-imidazolin-5-one.
Irbesartan has CAS No. [138402-11-6]. The structural formula of Irbesartan is represented below.


BACKGROUND OF THE INVENTION
The synthesis of irbesartan is first disclosed in US5270317 (EP equivalent EP0454511) and subsequently, several other patents disclose the synthesis of Irbesartan by different methods. Basically the synthesis of this molecule involves two common intermediates namely spiroimidazole and substituted 4'-bromomethylbiphenyl.
US 5270317 describes preparation of irbesartan wherein 2-n-Butyl-4-
spirocyclopentane-2-imidazolin-5-one is reacted with 4-bromomethyl-2'-
cyanobiphenyl using 80% sodium hydride as base in N,N-dimethylformamide at RT
to give l-[(2'-cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-
imidazolin-5-one which is reacted with tributyltin azide in xylene at reflux temperature for 66 hours to give a product which is isolated from the reaction mass as trityl irbesartan and then deprotected in methanol/THF mixture using 4N hydrochloric acid to get irbesartan.
The process involves column chromatographic purification of intermediates, multistep extractive workup, long reaction times of the order of 66 hours, additional step required to isolate irbesartan resulting in low yield (48 %) of irbesartan based on cyanobiphenyl methyl bromide intermediate.
US 5629331 describes a process for the preparation of Irbesartan from l-[(2'-cyanobiphenyl-4-yl) methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one using sodium azide, TEA.HCl in N-methylpyrrolidone. The product is isolated from the alkaline reaction mass after acidification to pH 4.7 to 5.8 and the crude product is recrystallised from IP A/water to get Form A and ethanol/water to get Form B.
WO 99/38847 ( equivalent to US 6162922) describes a process for the preparation or l-[(2'-cyanobiphenyl-4-yl) methyl]-2-n-butyl-4spirocyclopentane-2-imidazolin-5-one using a phase transfer catalyst which involves the reaction of 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one HCl with 4-bromomethyl-2'-cyanobiphenyl in

a water immiscible solvent such as MDC or toluene, in the presence of methyl-tributylammonium chloride and aqueous sodium hydroxide.
WO 2005/051943 Al describes a process for the preparing irbesartan wherein 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one is reacted with 4-bromomethyl-2'-cyanobiphenyl using potassium carbonate as base in acetonitrile at 80°C to give 1-[(2'-cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one. The resulting product is reacted with tributyltin chloride, sodium azide and TBAB in toluene at reflux temperature for 20 hours. Product is isolated from the reaction mass as trityl irbesartan and then deprotected in methanol and formic acid to get irbesartan.
In this process, irbesartan is isolated as trityl irbesartan which is again deprotected to give irbesartan thus makes the process lengthy, further formic acid is used for deprotection which is skin irritant and toxic.
WO 2006/023889 describes a method for preparing irbesartan , wherein 4-methyl-2'-cyanobiphenyl is brominated using sodium bromate to give 4-bromomethyl -2'-cyanobiphenyl and 4-dibromomethyl -2'-cyanobiphenyl which are reacted with 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one in the presence of reducing agent under phase transfer conditions to give l-(2'-cyanobiphenyl-4-yl) methyl)-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one which is reacted with sodium azide and triethylamine hydrochloride in N-methyl-2-pyrrolidone to give irbesartan.
WO 2004/007482 describes a process for the preparing irbesartan wherein 2-n-butyl-
4-spirocyclopentane-2-imidazolin-5-one is reacted with 5-(4'-
bromomethylbiphenyl-2-yl)-l -trityl- lH-tetrazole in presence of potassium hydroxide using a phase transfer catalyst- BU4NHSO4 in toluene and water as solvents. Trityl protected irbesartan is deprotected using acetone and sulfuric acid to give irbesartan.
This process uses trityl protected starting material which requires additional step of detritylation of trityl irbesartan to give irbesartan which makes the process lengthy and involves multistep extractive workup.

WO 2005/122699 describes a process of preparing l-[(2'-cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one by reacting 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one HC1 with 4-bromomethyl-2'-cyanobiphenyl in a water-miscible solvent such as acetone and aqueous sodium hydroxide at 45-
55°C.
This process .uses aqueous sodium hydroxide and acetone during condensation and uses ethyl acetate for extraction which is being washed with aqueous sodium hydroxide during workup. Acetone and ethyl acetate both are reactive towards aqueous sodium hydroxide and creates workup problems during isolation of the product, which minimizes the yield.
WO 2005/ 122699 describes a method for preparing trityl irbesartan by reacting 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one with 5-(4'-bromomethylbiphenyl-2-yl)-l -trityl- lH-tetrazole in presence of a 10% sodium hydroxide in acetone at 45 C for 6 hours. The trityl irbesartan is isolated in 47% yield with HPLC purity of 98.5%.
WO 2006/046043 describes a method for preparing irbesartan hydrochloride in one pot by reacting 2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one hydrochloride with 5-(4'-bromomethylbiphenyl-2-yl)-l-trityl-lH-tetrazole in presence of a base with a phase transfer catalyst in toluene and water as solvents. After completion of the reaction, layers are separated and the organic layer is treated with 4N hydrochloric acid to give Irbesartan hydrochloride in hydrated form.
WO 2004/072064 describes process for preparing trityl irbesartan comprising steps of
a) reacting l(N'-pentanoylamino)cyclopentanecarboxylic acid amide with 5-(4'-bromomethylbiphenyl-2yl)-l-trityl-lH-tetrazole in the presence of an inorganic base, a solvent and a phase transfer catalyst;
b) cooling the mixture;
c) adding water to the mixture whereby two phases are obtained;
d) separating the two phases obtained; and
e) recovering trityl irbesartan.

This is a lengthy process requiring many steps with multistep extractive workup resulting in low yields of intermediates.
WO 2005/113518 describes a process for preparing irbesartan involving pentanoylation of cycloleucine in the presence of sodium hydroxide to form n-pentanoylcycloleucine, condensing this product with 2-(4-aminomethyl phenyl)' benzonitrile using DCC and HOBt as a catalyst to form the intermediate, which by cyclization in the presence of trifluoroacetic acid gives cyano irbesartan which is. reacted with tributyltin chloride and sodium azide to form irbesartan.
WO 2006/089927 describes a method of preparing for preparing irbesartan by reacting 2-(lH-tetrazol-5-yl)phenylboronic acid with 2-butyl-3-(4'-iodobenzyl)-l,3-diazaspiro[4,4]non-l-en-4-one using sodium hydroxide, triphenyl phosphine and palladium chloride in methanol.
A comprehensive review of the prior art reveals use of column chromatographic purification of intermediates, long reaction times, additional steps of protection and deprotection, processes resulting in low yields, multistep extractive workup procedures; use of palladium based reagents during coupling reaction and use of raw materials that are possible skin irritant.
There is a long felt need of the industry to provide a commercially scalable process of preparing irbesartan which is high yielding and devoid of disadvantages described in the prior art.

SUMMARY OF THE INVENTION
The main object of the present invention is to provide a process for the commercially
scalable preparation of irbesartan in high yield.
Another object of the present invention is to provide a process for preparing irbesartan
with shorter reaction times.
Another object of the present invention is to provide a process for preparing irbesartan
which does not involve column chromatographic isolation of any intermediate.
Yet another object of the present invention is to provide a process for preparing
irbesartan, with less number of steps, without the use of skin irritant reagents.
Yet another object of the present invention is to provide a process for preparing
irbesartan without the use of multistep extractive workup.

DETAILED DESCRIPTION
The present invention uses a Lewis acid such as magnesium halide like magnesium chloride, magnesium bromide, zinc halides such as zinc chloride, zinc bromide; preferably zinc chloride along with sodium azide for the conversion of nitrile to tetrazole in the preparation of irbesartan.
The process involving use of zinc salt for the transformation of nitrile to tetrazole is a safe and efficient process as reported in JOC (2001) 66 , 7945-50.The use of zinc salt for transforming nitrile to tetrazole has also been published in W09637481 and US5502191.
In accordance with the present invention, synthesis of irbesartan comprises: [1] Reacting 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one with 4-bromomethyl-2'-cyanobiphenyl, using a base such as sodium or potassium alcoholate such as sodium methoxide, potassium tert.butoxide sodium tert.butoxide, sodium isopropoxide, alkali metal hydroxides, alkali metal hydride such as sodium hydride, potassium hydride ; preferably sodium hydride,
in solvents such as THF,N,N-Dimethyl acetamide, DMF DMSO,N-methyl 2-pyrrolidone, tetramethyl urea, preferably in DMF and isolating l-(2'-cyanobipehnyl-4-yl) methyl)-2-n-butyl-4-spirocyclopentane - 2-imidazolin-5-one after extractive workup,
[2] Reacting the product of step [1], with sodium azide in conjunction with lewis acid such as magnesium halide like magnesium chloride, magnesium bromide, zinc halide: such as zinc chloride, zinc bromide; preferably zinc chloride, in polar solvent such as DMF, NMP, preferably DMF, followed by extractive workup to give irbesartan.
In step [1]
Solvent used for the reaction is selected from THF, DMA, DMF DMSO, N-methyl 2-
pyrrolidone, tetramethyl urea, preferably in DMF. Base used, for example, Sodium
hydride (60 % wt/ wt) is about 1.24 M eq. with respect to 2-n-butyl-4-
spirocyclopentane-2-imidazolin-5-one.
The temperature of the reaction is maintained at about -5°C, during sodium salt
formation and after addition of bromo compound, the temperature of the reaction is
maintained at 5-15°C. The progress of the reaction is monitored on TLC.
The product is isolated by extractive workup in about 80 % yield.

In step [2],
The solvent used for the reaction is polar solvent such as DMF, NMP, preferably DMF. Lewis acid used along with sodium azide is selected form salts such as magnesium halide like magnesium chloride, magnesium bromide, zinc halide such as zinc chloride, zinc bromide, preferably zinc chloride. For tetrazole formation, sodium azide is used. The reaction mass is refluxed for about 15 hours. The progress of the reaction is monitored on TLC. The product is isolated by aqueous extractive workup. Irbesartan is isolated in 80 % yield.
The present invention is illustrated with following examples which do not limit the scope of invention in any way.
Preparation of 2-n-butyl-3-[((2(tetrazol-5-yl)-biphenyl-4-yl) methyl]-l, 3-diazaspiro-[4, 4] - non-1-ene-4-one (Irbesartan)
Step-[1]:
Preparation of l-(2'-cyanobiphenyl-4-yl) methyl)-2-n-butyl-4-spirocyclopentane - 2-
imidazolin-5-one (Cyano Irbesartan)
A suspension of 60% sodium hydride (26.4g, 0.66 mol) in DMF (150ml) is cooled to -5°C and a solution of 2-n-Butyl-4-spirocyclopentane-2-imidazolin-5-one (l00g, 0.514 mol) in 250ml DMF is added. After stirring the reaction mass for 15 minutes, a solution of 4-bromomethyl-2'-cyanobiphenyl (134g, 0.492 mol) in 600ml DMF over 30minutes at -5°C is added. The reaction mass is stirred at 5-15°C for l hour and the progress of the reaction is monitored by TLC. After the completion of reaction, 50ml IPA is added to quench the excess sodium hydride and then it is concentrated to get a residue. The residue is dissolved toluene (500ml) and water (500ml) mixture, stirred for 15minutes and separated the layers. The aqueous layer was extracted with toluene (100ml). The combined organic layer is acidified with dilute hydrochloric acid to adjust the pH to 3-4. Reaction mass is stirred for 3 hours at room temperature, filtered and washed with 100ml toluene. The resulting cyano irbesartan hydrochloride was basified by 5% sodium bicarbonate solution to give 160g of cyano irbesartan free base (84.4 %).

Step-[2]
Preparation of 2-n-butyl-3-[(2'-(tetrazol-5-yl) biphenyl-4-yl) methyl)-l, 3-
diazospiro-(4, 4) - non-l-ene-4-one [Irbesartan]
To a solution of l-(2'-cyanobiphenyl-4-yl) methyl)-2-n-butyl-4-spirocyclopentane -2-imidazolin-5-one (Cyano irbesartan) (50g, 0.129mol) in DMF is added zinc chloride (22.12 g, 0.162mol) and sodium azide (21.10g, 0.324mol). The reaction mass is refluxed for 15hrs and the progress of the reaction is monitored by TLC. After the reaction is over, it is cooled to room temperature and basified using 10% sodium hydroxide solution to pH 11-12. The reaction mass is stirred for l hr and filtered. The filtrate is washed with toluene (250ml). 75 ml of IPA is added to the aqueous layer and adjusted the pH to 4-5 with con. HC1. Reaction mass is stirred for 3 hours, filtered and washed with water. The product is dried at 60°C to give 45g (81%) of irbesartan.