FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13]
1. Title of the invention: "An improved process for the preparation of Valsartan
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered
Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF VALSARTAN FIELD OF THE INVENTION
The present invention related to an improved process for the preparation of valsartan of structural formula I.
BACKGROUND OF THE INVENTION
Valsartan is chemically described as N-(l-oxopentyl)-N-[[2 '-(lH-tetrazol-5-yl) [1,1 '-biphenyI]-4-yI]methyl]-L-valine and is represented by structural formula I.

The Proprietary name of valsartan is diovan®. Diovan® is an angiotensis II receptor blocker (ARB) indicated for treatment of hypertension and heart failure.
Valsartan was first disclosed in U.S. Patent. No. 5,399,578. The patent describes two processes for the preparation of valsartan as depicted in Scheme I and Scheme II.


The process disclosed in the scheme I is not commercially viable due to the use of toxic tributyltin azide to build up the tetrazole ring and high demands on safety in order to prevent an explosion due to the formation of hydrogen azide during the reaction. Another disadvantage of the above method is the fact that all the intermediates are oily substances, which cannot be crystallized. The final product is therefore, strongly contaminated with undesired compounds and requires repeated crystallisation, resulting in a significant loss of yield.

Another process disclosed in US Patent No. 5,399,578 is depicted in Scheme II


The process depicted in Scheme II is also not commercially viable due to the use of expensive palladium catalyst in the deprotection of benzyl group from intermediate of structural formula VIII to get valsartan of structural formula I.
US Patent Publication No. 2009/0192318 describes a variation to the above process of preparing valsartan, which involves isolation of N-[[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine benzyl ester in the form of hydrochloride salt. This process also suffers with major disadvantage of low yield and low purity of N-[[2'-(l-triphenylmethyJtetrazol-5-yl) biphenyl-4-yl] methyl]-L-valinebenzylester, which is the key intermediate in the preparation of valsartan. The reason being that the triphenylmethyltetrazol group is highly unstable towards the strong acidic conditions (hydrochloric acid) and undergoes hydrolysis to generate undesired impurities, which get carried forward as impurities in valsartan. Removal of these impurities in the final stage is often proved to be difficult and requires repeated crystallisation, which finally results in the low yield of valsartan of structural formula I.
U.S. Patent. Nos. 7,199,144; 7,361,770 and 7,439,261 and US Publication Nos. 2006/0149079; 2006/0281801; 2006/0258878; 2006/0287537; 2006/0211866; 2006/0069268; 2007/0093540; 2007/0117987; 2007/0043098; 2008/0234490; 2009/0203921; 2009/0203920 and 2009/0124577 describes different processes for preparing valsartan and its intermediates.
Accordingly, there is a need in the art to develop an improved process for the preparation of valsartan, which obviates the above discussed disadvantages of prior-art processes of preparing valsartan of structural formula I.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide a commercial viable process for the preparation of valsartan of structural formula I,
A second aspect of the present invention is to provide an improved process for the preparation of valsartan of structural formula I. comprising the steps of:
a) reacting N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula IX with valeryl chloride to getN- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula X,

b) converting N- [[2'-(l -triphenylmethyl-tetrazol-5-yl) biphenyl-4-y]] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula X into N- (1-oxopentyl)-N-[[2'-(l#-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI and


c) hydrolyzing N- (1 -oxopentyl)-N-[[2 '-(1 H-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI into valsartan of structural formula I.

A third aspect of the present invention is to provide a process for the preparation of N-[[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula IX.


A fourth aspect of the present invention is to provide a process for the preparation of oxalate salt of N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XII comprising the steps of: a) reacting L-valine-2,2,2-trichloroethylester-4-methylbenzenesulphonate of structural formula XIII with 5-(4'-bromomethylbiphenyl-2-yl)-l-trityl-l// tetrazole of structural formula XIV to getN- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] meth3'l]-L-valine-2, 2, 2-trichloroethylester of structural formula IX and

b) converting N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula IX into oxalate salt of N-[[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XII

A seventh aspect of the present invention is to provide a novel intermediates of structural formula IX, X ,XI, XII and XIII used for the preparation of valsartan of structural formula I.
DETAILED DESCRIPTION OF THE INVENTION
N- [[2'-(l-triphenyIniethyl-tetrazoI-5-yl) biphenyI-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula IX may be prepared by reacting oxalate salt of N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2,2,2-trichloroethylester of structural formula XII with base in a mixture of organic solvent and water.

Examples of base may include inorganic base such as alkali metal carbonate such as sodium carbonate or potassium carbonate.
Examples of base may include inorganic base such as alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.

Examples of organic solvent may include methylene chloride, ethylene dichloride, chloroform, toluene, xylene, acetonitrile, ethyl acetate, propyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
Oxalate salt of N- [[2'-(l-triphenylmethyl-tetrazol-5~yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XII may be prepared by reacting N- [[2'-(l-triphenylmethyI-tetrazoI-5-yI) biphenyI-4-yI] methyI]-L-valine-2, 2, 2-trichloroethylester of structural formula IX with oxalic acid dihydrate in an organic solvent.
Examples of organic solvent may include ester solvents such as ethyl acetate, propyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.
N- [[2J-(I-triphenylmethy]-tetrazol-5-yl) biphenyI-4-yl] methyI]-L-valine-2, 2, 2-trichloroethylester of structural formula IX may be prepared by reacting L-valine-2,2}2-trichloroethylester-4-methylbenzenesulphonate of structural formula XIII with 5-(4'-bromomethylbiphenyl^-yiyi-trityl-lHtetrazole of structural formula XIV in acetonitrile solvent in the presence of inorganic base.
Examples of inorganic base may include sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or mixture(s) thereof.
The reaction of L-valine-2, 2, 2-trichloroethylester-4-methylbenzenesulphonate of structural formula XIII with 5-(4'-bromomethylbiphenyl-2-yl)-l-trityl-l// tetrazole of structural formula XIV may be carried out at a temperature in the range of 45°C to 80°C for 2 hours to 8 hours.
5-(4'-bromomethylbiphenyl-2-yl)-l-trityl-l//tetrazole of structural formula XIV may be prepared by methods known in the art.

L-valine-2, 2, 2-trichloroethylester-4-methylbenzenesulphonate of structural formula XIII may be prepared by reacting L-valine of structural formula XV with trichloroethanol in the presence of /?-toluenesulfonic acid monohydrate in hydrocarbon solvents.
Examples of hydrocarbon solvents may include toluene, xylene or mixture(s) thereof.
The reaction of L-valine of structural formula XV with trichloroethanol in the presence of/7-toluenesulfonic acid monohydrate may be carried out at a temperature in the range of 90°C to 110°C for 20 hours to 30 hours.
L-valine-2, 2, 2-trichloroethylester-4-methylbenzenesulphonate of structural formula XIII may be isolated by crystallization in ether or alcoholic solvents.
Examples of ether solvents may include diethyl ether, diisopropyl ether, methyl tert-butyl ether or mixture(s) thereof.
Examples of alcoholic solvents may include methanol, ethanol, n-propanol, isopropanol, rc-butanol, isobutanol or mixture(s) thereof.
The reaction of N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula IX with valeryl chloride may be carried out in a mixture of water and aromatic hydrocarbon solvents at a temperature in the range of-5°C to 10°C for 6 hours to 14 hours.
Examples of aromatic hydrocarbon solvents may include toluene, xylene, benzene or mixture(s) thereof.

N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula X may be converted into N- (l-oxopentyl)-N-l[2'-(]H-tetrazo\-5-yl) bipheny]-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI by refluxing N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula X in alcoholic solvents for 8 hours to 20 hours.
Examples of alcoholic solvents may include methanol, ethanol, n-propanol, isopropanol, «-butanol, isobutanol or mixture(s) thereof.
N- (l-oxopentyl)-N-[[2'-(l//-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI may be hydrolyzed into valsartan of structural formula I by reacting N- (l-oxopentyl)-N-[[2'-(l//-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI with acid in the presence of zinc at a temperature in the range of 110°C to 120°C for 5 hours to 12 hours.
Examples of acid may include sulfuric acid, hydrochloric acid, acetic acid, methane sulfonic acid or ethane sulfonic acid.
The acid used for the hydrolysis of N- (l-oxopentyl)-N-[[2'-(l//-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI may be used as such or may be diluted with water.
The valsartan of structural formula I may be isolated by crystallization from ester solvents.
Examples of ester solvents may include ethyl acetate, propyl acetate, n-butyl acetate, isobutyl acetate or mixture(s) thereof.

The valsartan of structural formula I may be isolated by filtration, washing, centrifugation, drying and combination thereof.
The valsartan of structural formula I may be dried at a temperature in the range of 50°C to 60°C under reduced pressure.
While the present invention has been described in terms of its specific embodiments, 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
EXAMPLE 1: PREPARATION OF VALSARTAN OF STRUCTURAL FORMULA I
STEP 1: PREPARATION OF L-VALINE -2, 2, 2-TRICHLOROETHYLESTER -4-METHYLBENZENESULPHONATE OF STRUCTURAL FORMULA XIII
A solution of L-valine (10 gm, 0.085 mole), trichloroethanol (65.6 ml, 0.68 mole), p-tohienesulfonic acid monohydrate (29.3 gm, 0.17 mole), and toluene (70 ml) was refluxed at 100-110°C in a device with a Dean-Stark trap for 30 hours. The resulting reaction mass was concentrated under reduced pressure and precipitated by diisopropylether (200 ml) to get crude compound, which was recrystallized from isopropanol (200 ml; at 25 °C) to get pure L-valine-2, 2, 2-trichIoroethyIester-4-methylbenzenesulphonate of structural formula XIII. Yield: 29.5 gm

STEP 2: PREPARATION OF N-[[2'-(l-TRIPHENYLMETHYL-TETRAZOL-5-YL) BIPHENYL-4-YL] METHYL]-L-VALINE-2,2, 2-TRICHLOROETHYLESTER OXALATE OF STRUCTURAL FORMULA XII
A solution of L-valine-2, 2, 2-trichloroethylester-4-methylbenzenesulphonate (10 gm3 0.023 mole) in DM water (70 ml) and methylene chloride (115 ml) was treated with 20% K2CO3 solution (25 ml) for 30 minutes at 25 - 30° C and the organic layer was separated, washed with water (2*50 ml) and concentrated under reduced pressure to get residue. The residue was added 5-(4'-(Bromomethyl) biphenyl-2-yl)-1 -trity 1-1 //-tetrazole (20.18 gm, 0.036 mole), milled K2CO3 (16.65 gm, 0.12 mole) and acetonitrile (70 ml) and resulting solution was stirred for 7 hours at 75-80° C and then it was concentrated under reduced pressure to get residue (44 gm). The residue was dissolved in ethyl acetate (130 ml) and oxalic acid dihydrate (8.7 gm, 0.097 mole) was added at 25-30°C and resulting reaction mixture was stirred for 1 hour at 0-5° C and filtered to getN-[[2'-(l-triphenylmethyl-tetrazol-5-y]) biphenyl-4-yl] methyl]-l-valine-2, 2, 2-trichloroethylester oxalate of structural formula XII. Yield: 13 gm (85.19%)
STEP 3: PREPARATION OF N-[[2'-(l-TRIPHENYLMETHYL-TETRAZOL-S-YL) BIPHENYL-4-YL] METHYL]-L-VALINE-2, 2, 2-TRICHLOROETHYLESTER OF STRUCTURAL FORMULA X
The solution of N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2,2-trichloroethylester oxalate (10 gm, 0.012 mole) in toluene (50 ml) and DM water (50 ml) was treated with aqueous K2CO3 solution (11.87 gm, 0.085 mole) at 25-30°C for 15 minutes. Valeryl chloride (11.57 ml, 0.096 moles) was added at 0-10°C and resulting reaction mixture was stirred for 12 hours at 0-10°C. Organic layer was separated, washed with 5 % NaHCOs (50 ml) solution and DM water (50 ml) and then it was concentrated under reduced pressure at 50-55°C to get N-[[2'-(l-triphenylmethyl-

tetrazol-5-yl) biphenyl-4-yl] methyl]-l-valine-2, 2, 2-trichloroethylester of structural
formula X
Yield: 9.03 g (80.91 %)
STEP 4: PREPARATION OF VALSARTAN OF STRUCTURAL FORMULA I
A solution of N-[[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester (10 gm) in methanol (200 ml) was refluxed for 16 hours and resulting solids were filtered at 25°C and discarded. The filtrate was concentrated under reduce pressure to get residue of N- (l-oxopentyl)-N-[[2'-(l//-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI. The residue was treated with aqueous acetic acid (90%, 50 ml) and Zn (1.1 gm) at 116-18°C for 10 hrs and then methylene dichloride (100 ml) and DM water (100 ml) was added at 25-30°C. Organic layer was separated, concentrated under reduced pressure to get residue, which was crystallized from ethyl acetate to get valsartan of structural formula I. Yield: 4.39 gm (81.76%). Purity: 99.87 %( By HPLC)

WE CLAIM,
1. A process for the preparation of valsartan of structural formula I. comprising the
steps of:
a) reacting N- [[2'-(l-triphenyimethyl-tetrazoI-5-yl) biphenyl-4-yI] methyl]-L-
valine-2, 2, 2-trichloroethylester of structural formula IX with valeryl chloride to
getN- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2,
2-trichloroethylester of structural formula X,

b) converting N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula X into N- (l-oxopentyl)-N-[[2'-(l//-tetrazol-5-yl) biphenyl-4-yl] methyi]-L-valine-2, 2, 2-trichloroethylester of structural formula XI and


c) hydrolyzing N- (l-oxopentyl)-N-[[2'-(l#-tetrazol-5-yI) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI into valsartan of structural formula I.

2. The process according to claim 1, wherein reaction of N- [[2'-(l-triphenylrnethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2V 2-trichloroethylester of structural formula IX with valeryl chloride is carried out in a mixture of water and aromatic hydrocarbon solvents such as toluene, xylene, benzene or mixture(s) thereof at a temperature in the range of-5°C to 10°C for 6 hours to 14 hours.
3. The process according to claim 1, wherein N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula X is converted into N- (l-oxopentyl)-N-[[2'-(l//-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI by refluxing N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula X in alcoholic solvents such as methanol, ethanol, n-propanol, isopropanol, «-butanol, isobutanol or mixture(s) thereof for 8 hours to 20 hours.
4. The process according to claim 1, wherein N- (l-oxopentyl)-N-[[2'-(l//-tetrazoI-5-yl) biphenyl-4-yI] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI is hydrolyzed into valsartan of structural formula I by reacting N- (1-oxopentyl)-

N-[[2'-(l//-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XI with acid such as sulfuric acid, hydrochloric acid, acetic acid, methane sulfonic acid or ethane sulfonic acid in the presence of zinc at a temperature in the range of 110°C to 120°C for 5 hours to 12 hours.
5. A process for the preparation of oxalate salt of N- [[2'-(l-triphenylmethyl-tetrazol-
5-y]) biphenyI-4-yl] methylj-L-valine-2, 2, 2-trichloroethylester of structural
formula XII comprising the steps of:
a) reacting L-valine-2,2,2-trichloroethylester-4-methylbenzenesulphonate of
structural formula XIII with 5-(4'-bromomethylbiphenyl-2-yl)-l-trityl-l//
tetrazole of structural formula XIV to getN- [[2'-(l-triphenylmethy]-tetrazol-5-yl)
biphenyI-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula
IX and

b) converting N- [[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula IX into oxalate salt of N-[[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine-2, 2, 2-trichloroethylester of structural formula XII


6. The process according to claim 5, wherein L-valine-2, 2, 2-trichloroethylester-4-methylbenzenesulphonate of structural formula XIII is reacted with 5-(4'-bromomethylbiphenyl-2-yl)-l-trityl-l# tetrazole of structural formula XIV in acetonitrile solvent in the presence of inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide or mixture(s) thereof.
7. A process for the preparation of L-valine-2, 2, 2-trichloroefhylester-4-methylbenzenesulphonate of structural formula XIII comprising the steps of:
a) reacting L-valine of structural formula XV with trichloroethanol in the presence of />~toluenesulfonic acid monohydrate and

b) isolating L-valine-2, 2, 2-trichloroethylester-4-methylbenzenesulphonate of structural formula XIII.
8. The process according to claim 7, wherein reaction of L-valine of structural formula XV with trichloroethanol is carried out in hydrocarbon solvents such toluene, xylene or mixture(s) thereof at a temperature in the range of 90°C to 110°C for 20 hours to 30 hours.
9. A novel intermediates of structural formula IX, X, XI, XII and XIII used for the preparation of valsartan of structural formula I.
10. A process for the preparation of valsartan of structural formula I as herein described in specification, example and scheme III.