FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 2-butyl-3-[p-(o-lH-tetrazol-5-ylphenyl)benzyl]-l,3-diazaspiro[4.4]non-l-en-4-one of Formula I

This relates to an invention disclosed and claimed in our co-pending application nos 745/CHE/2006 and 1540/CHE/2006 wherein, the present process is an improvement for the preparation of Irbesartan,
BACKGROUND OF THE INVENTION
2-Butyl-3-[p-(o-lH-tetrazol-5-ylphenyl)benzyl]-l,3-diazaspiro[4.4]non-l-en-4-one, is generically known as Irbesartan. Irbesartan is a non-peptide angiotensin II antagonist, which antagonizes the physiologic effects of angiotensin II by inhibiting the action of angiotensin II on its receptors, the compounds particularly prevent increase in blood pressure produced by the receptor interaction. Irbesartan is approved for the treatment of hypertension and is marketed in the US with the Brand Name, Avapro.
Elf Sanofi, first time disclosed Irbesartan and its pharmaceutical^ acceptable salts in US 5,270,317.
US 5,399,578 describes two different processes for the preparation of Irbesartan which are subsequently claimed in US 5,559,233. One of the processes involves the reaction of 2-n-butyl-4-spirocylopentane-2-imidazolin-5-one (II) with 4-bromomethyl-2-cyanobiphenyl (III) in the presence of NaH, followed by a column chromatography separation to yield l-[(2'-cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one (IV). This compound (IV) is further reacted with tributyltin azide and

the product treated with trityl chloride and separated by column chromatography. Finally, trityl protected irbesartan (V) is de-protected with hydrochloric acid and the final Irbesartan product is isolated.
The process is as shown in Scheme-I below:

The second process described in this patent for the preparation of Irbesartan, is as shown in Scheme-IP.


The major disadvantages with the above processes for the preparation of Irbesartan, involve a large number of steps such as protection and deprotection and tedious work¬up procedures to isolate the required product. This results in more production time,

which in turn renders the process more costly and less eco friendly. Further the above processes are low yielding and yield product of less purity.
WO 2005/113518 Al describes an alternative process for the preparation of Irbesartan which involves reacting N-pentanoylaminocyclopentanecarboxylic acid (XI) with 2-(4-aminomethylphenyl)benzonitrile (VII) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as a catalyst to produce the 4-[(a-N-pentanoylamino)cyclopentamidomethyl]-2-cyanobiphenyl (XII), and then cyclising using trifluoroacetic acid to result l-[(2'-cyanobiphenyl-4-yl)methyl]-2-n-butyl-4-spirocyclopentane-2-imidazolin-5-one (IV), which is finally converted to Irbesartan (I) by reaction with tributyl tin chloride and sodium azide.


We have now developed another process to prepare Irbesartan, which is novel and commercially viable process.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a simple, effective and industrially feasible process for the preparation of Irbesartan with high purity and good yields on a commercial scale.
SUMMARY OF THE INVENTION
Accordingly, the present invention relates to an improved process for the preparation of 2-butyl"3-[p-(o-lH-tetrazol-5-ylphenyl)benzyl]-l,3-diazaspiro[4.4]non-l-en-4-one (Irbesartan) of Formula (I),

wherein R represents -CN and -CONH2 groups with trialkyltin chloride and alkaline azide in an organic solvent to produce compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved process for the preparation of 2-butyl-3-[p-(o-lH-tetrazol-5-ylphenyl)benzyl]-l,3-diazaspiro[4.4]non-l-en-4-one (Irbesartan).
The compound of Formula (XVI) wherein R represents -CN and -CONH2 groups can be cyclized to form Irbesartan. The compound of Formula (XVI) is treated with trialkyltin chloride such as tributyltin chloride and alkaline azide selected from sodium azide, potassium azide in a solvent selected from aromatic hydrocarbons such as benzene, toluene, xylene, polar aprotic solvent such as dimethylformamide, N-methyl pyrrolidinone and mixtures there of, more preferably mixture of dimethylformamide and o-xylene. The reaction mixture is heated to 150-155°C and after completion of reaction, the reaction mass is cooled to about 20°C. o-Xylene and methylene chloride are added to the reaction mass followed by water. Subsequently hydrochloric acid is added at 20-25°C slowly over a period of 30 min and the slurry obtained was stirred for 60 min. The precipitated solid was filtered and washed with a mixture of o-xylene and methylene chloride and dried to give compound of Formula I.
The compound of Formula (XVII) i.e 4-aminomethyl-2'-cyanobiphenyl hydrochloride is converted to compound of Formula (XHIa) using a base selected from sodium hydroxide or potassium hydroxide in t-butanol as a solvent. In a preferred procedure, the compound of Formula (XVII) is suspended in a mixture of water and methylene chloride, and the pH of the suspension is adjusted to 9.0-9.5 with ammonium hydroxide

to get a clear solution. The organic layer is separated, concentrated and to the resulting mass tert. butanol is added, followed by addition of powdered potassium hydroxide at 70-75°C, the reaction mixture is heated to reflux for completion. After completion of the reaction, water is added and the product extracted with methylene chloride and thereafter the pH of the methylene chloride layer is adjusted to 1.2-1.4 with hydrochloric acid wherein the compound of Formula (XHIa) precipitates out as a hydrochloride salt.
The compound of formula (XVI) wherein R represents -CN and -CONH2 groups can be prepared N-Pentanoylaminocyclopentanecarboxylic acid (XI) is condensed with 4-aminomethyl-l,r-biphenyl-2'-carboxamide hydrochloride (XHIa) in presence of base selected from, triethylamine, diethylamine, N,N-diisopropylethylamine, preferably diisopropyethylamine in a solvent selected from dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetone and chlorinated hydrocarbon such as methylene chloride, chloroform, 1,2-dichloroethane, preferably methylene chloride. Condensation is carried out in presence of condensing agent such as N,N'-dicyclohexylcarbodiimide, N-hydroxysuccinimide and a catalyst selected from 1-hydroxybenzotriazole at a temperature of about 20°C to about 40°C. Condensation can also be carried out without using base. After completion of reaction, as ascertained by the known detection methods such as HPLC/TLC, the reaction mass is cooled to room temperature and filtered. The filtrate is washed with saturated sodium bicarbonate solution and the solvent evaporated to l/4th volume. The obtained solid is cooled to 0-5°C and filtered to give compound of Formula (XVI).
Similarly, the compound of Formula (XVII) is condensed with N-pentanoylaminocyclopentanecarboxylic acid (XI) employing the same reaction conditions described as above to result in compound of Formula (XVI). This condensation of compound of Formula (XVII) with compound of Formula (XI) to give compound of Formula (XVI) is a significant improvement over the prior-art methods which has hitherto not been reported. By using compound of Formula (XVII), irbesartan can thus be produced in two steps only which consist of condensing with

compound of Formula (XI) and subsequent cyclization of the resulting compound of Formula (XVI) to yield compound of Formula I.
Crude Irbesartan I is purified by suspending in a solvent selected from alcohols such as methanol, ethanol, isopropanol, butanol at reflux temperature to get a clear solution and cooling the resulting solution to 10°C - 15°C, filtering the solid obtained, followed by drying to produce pure Irbesartan
The compound of Formula (XVII) is prepared by known methods in literature.
The following examples to prepare Irbesartan illustrate the nature of the invention and are provided for illustrative purpose only and should not be construed to limit the scope of the invention
Example 1
Preparation of 4-AminomethyH,l,-biphenyI-2'-carboxamide hydrochloride
4-Aminomethyl-2'-cyanobiphenyl hydrochloride (100 g, 0.408 mole) was suspended in a mixture of water (500 ml) and methylene chloride (200 ml) at 25-30°C and adjusted the pH to 9.0-9.5 with ammonium hydroxide (65 ml, 20 %w/w) at 25-30°C to get a clear solution. Organic layer was separated, washed with water (100 ml) and dried over sodium sulfate. Thereafter, organic layer was concentrated at below 60°C and tert.butanol (300 ml) was added to the residue. The reaction mass was heated to 70-75°C. Thereafter, powdered potassium hydroxide (32.35 g, 0.491 mole) was added and heated to reflux for completion of the reaction. Water (400 ml) was added and aqueous layer was separated and extracted with methylene chloride (500 ml). The combined organic layer was washed with water (200 ml) and dried over sodium sulfate. Methylene chloride solution was cooled to 2-5°C and the pH adjusted to 1.2-1.4 with hydrochloric acid. The precipitated product was stirred for one hour and filtered, washed with methylene chloride to afford the title compound as white powder (90g, 84.1% yield).
lH NMR in DMSO-d6 (5 in ppm): 4.03-4.05 (d, 2H), 7.31-7.74 (m, 10H), 8.53 (bs, 3H).

Example 2
Preparation of 4-[(a-N-pentanoylamino)cycIopentamidomethyl]-2'-
carboxamidobiphenyl
4-Aminomethyl-l,r-biphenyl-2'-carboxamide hydrochloride (XHIa) (200 g, 0.762 mole), N-pentanoylaminocyclopentanecarboxylic acid (XI) (162.4 g, 0.762 mole), 1-hydroxybenzotriazole (20.60 g, 0.152 mole) and dicyclohexylcarbodiimide (172.8 g, 0.8388 mole) were added to methylene chloride (5000 ml) at 25-30°C. Thereafter, diisopropylethylamine (109 g, 0.838 mole) was added and the reaction mixture was heated to 30-32°C and maintained at this temperature for completion of the reaction. Thereafter, the contents were cooled to 20-30°C and filtered the salts. The filtrate obtained was washed with water (2 X 400 ml) and concentrated to collect the methylene chloride (2000 ml). The slurry obtained was cooled to 2-5°C and stirred for one hour. The solid was filtered, washed with precooled methylene chloride (400 ml), (0-5°C) and dried to obtain the title compound as a white (272 g, 84.5 % yield).
lH NMR in DMSO-de (5 in ppm), 0.83-0.88 (t, 3H), 1.22-1.29 (m, 2H), 1.45-1.50 (m, 2H), 1.62 (m, 4H), 1.87-2.11 (m, 4H), 2.13-2.16 (t, 2H), 4.28-4.30 (d, 2H), 7.22-7.48 (m, 10H), 7.89 (bs, 1H), 8.02-8.06 (t, 1H). Mass (+ve ion mode): 422.
Example 3
Preparation of 4-[(a-N-pentanoylamino)cycIopentamidomethyl]-2,-cyanobiphenyl
4-Aminomethyl-l,r-biphenyl-2'-carbonitrile (10 g, 0.0408 mole), N-pentanoylaminocyclopentanecarboxylic acid (98.71 g, 0.0408 mole), 1-hydroxybenzotriazole (1.10 g, 0.0081 mole) and dicyclohexylcarbodiimide (9.27 g, 0.045 mole) were added to methylene chloride (200 ml) at 25-30°C and thereafter, diisopropylethylamine (5.85, 0.045 mole) was added to the reaction mixture. The reaction mixture was heated to 30-32°C and maintained at this temperature for completion of the reaction. Thereafter, the reaction mixture was cooled to 25-30°C and filtered. The filtrate obtained was washed with water (2 X 20 ml) and concentrated to

collect the methylene chloride (100 ml). The slurry obtained was cooled to 2-5°C and stirred for one hour. The solid obtained was filtered, washed with precooled methylene chloride (20 ml, 0-5°C) and dried to obtain the title compound as a white amorphous powder. (14 g, 84.9 % yied).
!H NMR in DMSO-d6 ( 5 in ppm) ; 0.82-0.87 (t, 3H), 1.24-1.127 (q, 2H), 1.45-1.50 (sextet, 2H), 1.63 (m, 4H), 2.11-2.16 (t, 2H), 4.34-4.35 (d, 2H), 7.32-7.95 (m, 9H), 8.07-8.10 (t, 1H).
Example 4
Preparation of 2-butyI-3-[p-(o-lH-tetrazol-5-ylphenyl)benzyl]-l,3-
diazaspiro[4.4]non-l-en-4-one (Irbesartan)
Tributyltin chloride (47.80 g, 0.147 mole) and sodium azide (9.57 g, 0.147 mole) were stirred for 30 min at 15-30°C. N,N-Dimethylformamide (6.90 g, 0.095 mole) was added and stirred for 30 min. Thereafter, 4-[(a-N-pentanoylaminocyclopentamidomethyl]-2'-carboxamidobiphenyl (20 g, 0.0475 mole) was added followed by o-xylene (20 ml). The reaction mass was heated to 150-155°C and stirred for completion of the reaction. The reaction mixture was cooled to 20°C, o-xylene (40 ml), methylene chloride (40 ml) were added followed by water (40 ml). Hydrochloric acid (4.95 g, 35 % w/w) was added at 20-25°C slowly in 30 min and the slurry obtained was stirred for 60 min. The solid was filtered, washed with 1: 1 v/v mixture of o-xylene and methylene chloride (40 ml) and dried to get the crude Irbesartan as a pale yellow powder (18 g, 88.5 % yield).
Example 5
Preparation of 2-butyl-3-[p-(o-lH-tetrazoI-5-ylphenyl)benzyl]-l,3-
diazaspiro[4.4]non-l-en-4-one (Irbesartan)
Tributyltin chloride (12.11 g, 0.037 mole) and sodium azide (2.42 g, 0.037 mole) were stirred for 30 min at 15-30°C. N N-Dimethylformamide (2.00 g, 0.027 mole) was added and stirred for 30 min. Thereafter, 4-[a-N-pentanoylamino)cyclopentamidomethyl]-2'-

cyanobiphenyl (10 g, 0.0248 mole) was added followed by o-xylene (10 ml). The reaction mass was heated to 150-155°C and stirred for completion of the reaction. The reaction mixture was cooled to 20°C, and a mixture of o-xylene (20 ml), methylene chloride (60 ml) and water (40 ml) were added. Thereafter hydrochloric acid was added to precipitate the solid and stirred for 1 hr. The solid obtained was filtered, washed with 1:1 v/v mixture of o-xylene and methylene chloride (20 ml) and dried to get the crude Irbesartan as pale yellow powder (9.55 g, 90 % yield).
Example 6
Purification of Irbesartan
Irbesartan-crude, obtained as above was suspended in methanol (270 ml) and heated to reflux temperature (60-65°C) to get a clear solution. Carbon (1.5 g) was added followed by hyflo (5 g) and the reflux continued for 30 min. Carbon was filtered and washed with hot methanol (30 ml, 50-55°C). The filtrate was concentrated to a volume of 150 ml and cooled to 25-30°C. Stirred the reaction mixture at the same temperature for 2 h, cooled to 10-12°C and further stirred for 2 h. The resulting solid was filtered, washed with precooled methanol (15 ml, 5°C) and dried to obtain irbesartan as a white crystalline powder (7.5 g).

WE CLAIM:
1. An Improved process for the preparation of 2-butyl-3-[p-(o-lH-tetrazol-5-
ylphenyl)benzyl]-l,3-diazaspiro[4.4]non-l-en-4-one (Irbesartan) of Formula I,

wherein R represents -CN and -CONH2 groups with trialkyltin chloride and alkaline azide in an organic solvent to produce compound of Formula I.
2. The process according to claim 1, wherein the trialkyltin chloride is tributyltin
chloride.
3. The process according to claim 1, wherein the alkaline azide is selected from
sodium azide, potassium azide, more preferably sodium azide.
4. The process according to claim 1, wherein solvent is selected from aromatic
hydrocarbons, polar aprotic organic solvents or mixtures there of.

5. The process according to claim 4, wherein aromatic hydrocarbons selected from benzene, toluene, xylenes more preferably o-xylene.
6. The process according to claim 4, wherein the polar aprotic organic solvent employed is selected from dimethylformamide, N-methyl pyrrolidinone, more preferably dimethylformamide.
7. The process according to claim 1, wherein the compound of Formula (XVI) is prepared by condensing the compound of Formula (XVII) or (XHIa) with N-pentanoylaminocyclopentanecarboxylic acid of Formula (XI) in presence of condensing agent and optionally in presence of base in a solvent.
8. The process according to claim 7, wherein the condensing agent employed is selected from N,N'-dicyclohexylcarbodiimide, N-hydroxysuccinimide.
9. The process according to claim 6, wherein the condensation is carried out in presence of catalyst selected from 1-hydroxybenzotriazole.
10. The process according to claim 6, wherein base used is selected from organic bases such as triethylamine, diethylamine, diisopropylethylamine, butylamine, more preferably diisopropylethylamine.
11. The process according to claim 6, wherein solvent used in condensation step is selected from methylene chloride, chloroform, 1,2-dichloroethane, acetone, N,N-dimethyl formamide, more preferably methylene chloride.
12. A process for the preparation of compound of Formula (XHIa) by converting the compound of Formula (XVII) using a base in tert. butanol.
13. The process according to claim 11, wherein the base employed is selected from potassium hydroxide, sodium hydroxide, and potassium ter-butoxide, more preferably potassium hydroxide.

14. A process for the preparation of compound of Formula (XIIIa) and its further conversion to Irbesartan of Formula I.