PROCESS FOR PREPARING VALSARTAN
INTRODUCTION TO THE INVENTION
The present invention relates to a process for the preparation of valsartan and its intermediates. In particular, the present invention relates to (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine, an intermediate for the preparation of valsartan and a process for the preparation of valsartan starting from the intermediate.
Valsartan is described chemically as (S)-N- (1-carboxy-2-methyl prop-1-yl)-N-pentanoyl-N- [2'-1H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine, and is structurally represented by Formula I.
Formula I
Valsartan is a non-peptide, orally active, specific angiotensin II antagonist, acting on the AT1 receptor subtype. Valsartan is prescribed for the treatment of hypertension. It is commercially available in the market under the brand name DIOVAN™ as 40, 80, 160 and 320 mg tablets.
U.S. Patent No. 5,399,578 and its equivalent European Patent No. 0443983B1 disclose valsartan, its pharmaceutically acceptable salts, pharmaceutical compositions comprising valsartan and their use in treating high blood pressure and cardiac insufficiency. It also discloses a process for the preparation of valsartan.
Processes for the preparation of valsartan and its intermediates have also been described in US Patent Nos. 7,199,144, 5,965,592, 5,260,325, 6,271,375, PCT Application Publication No's WO 2002/006253, WO 2001/082858, WO 1999/67231, WO

1997/30036, Peter Buhlmayer, et al., Bioorganic and medicinal chemistry letters 4(1) 29-34 (1994), The moenius, et all, J. Labelled Cpd. Radiopharm., 43(13) 1245-1252 (2000), and many others.
There is a need in the art to provide a simple, ecofriendly, industrially feasible, cost effective, and robust process for the synthesis of valsartan and its intermediates in higher yield and purity.
The present invention provides processes for the preparation of valsartan, which involves a reduced number of stages, and can be practiced on an industrial scale. An advantage of the processes of the present invention is that all synthetic steps are performed under mild conditions providing a low content of by-products and thereby a high yield and high purity of the final product.
SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of valsartan. In particular, it relates to (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1 H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine, an intermediate for the preparation of valsartan, and a process for the preparation of valsartan starting from the intermediate.
One aspect of the present invention relates to (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1 H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine of Formula VII, an intermediate for the preparation of valsartan, and a process for its preparation.


In an embodiment, the process for the preparation of (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1 H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine of Formula VII comprises of reacting (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- [2'-(1H- tetrazole-5-yl)-biphenyl-4-yl methyl] amine of Formula V with 5-(phenylthio) valeryl halide of Formula VI.

Where X is CI, Br, or I
Another aspect of the present invention provides a process for the preparation of (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- [2'-(1H-tetrazole-5-yl)-biphenyl-4-yl methyl] amine of Formula V comprising:
a) reacting an acid addition salt of N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine
methyl ester of Formula II with a base to afford N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-
valine methyl ester of Formula III.

Where Y is an acid.
b) reacting N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester of Formula
III with tetrazole ring forming reagents to afford 3Methyl-2-{[2'-(1H-tetrazol-5-yl)-
biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula IV.


Formula IV
c) reacting 3-Methyl-2-{[2'-(1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula IV with a hydrolyzing agent to give the required compound of Formula V.
Yet another aspect of the present invention provides a process for the preparation of 5-(phenylthio) valeryl halide of Formula VI comprising:
a) reacting 5-halovaleric acid of Formula VIII with thiophenol in presence of a
base and a solvent to afford 5-(phenylthio) valeric acid of Formula IX.

Formula VIII Formula IX
Where X is CI, Br, or I.
b) reacting 5-(phenylthio) valeric acid of Formula IX with a halogenating agent to
give 5-(phenylthio) valeryl halide of Formula VI.

Still another aspect of the present invention provides a process for the conversion of (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1 H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine of Formula VII to valsartan comprising desulfurisation in the presence of a reducing agent.
A still further aspect of the present invention provides a pharmaceutical composition comprising valsartan or its pharmaceutically acceptable salts prepared

according to the process of the present invention along with one or more pharmaceutically acceptable carriers, excipients or diluents.
BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic representation of a process for the preparation of valsartan.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a process for the preparation of valsartan. In particular, it relates to (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine, an intermediate for the preparation of valsartan and a process for preparation of valsartan starting from the intermediate.
One aspect of the present invention relates to (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine of Formula VII, an intermediate for the preparation of valsartan, and a process for its preparation.
(S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine is structurally represented by Formula VII.

Formula VII
The structure of the molecule has been confirmed by H' NMR, Mass and IR spectrum.
In an embodiment, the process for the preparation of the compound of Formula VII comprises of reaction of (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- [2'-(1 H- tetrazole-5-yl)-biphenyl-4-yl methyl] amine of Formula V with 5-(phenylthio) valeryl halide of Formula VI.


Formula V Formula VI
Suitable solvents which can be used for the reaction include, but are not limited to halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like; ethers such as diethyl ether, tetrahydrofuran and the like.
Suitably, the reaction is carried out in the presence of a base. Suitable bases which can be used for the reaction include, but are not limited to inorganic bases like hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; azides such as sodium azide, tributyl tin azide, organo boron, organo aluminum azide and the like, organic bases such as pyridine, N,N-dimethyl formamide (DMF), trimethyl amine, triethyl amine, N-methylpyrolidine and the like.
(S)-N- (1-carboxy-2-methyl prop-1-yl)-N- [2'-(1H- tetrazole-5-yl)-biphenyl-4-yl methyl] amine of Formula V and the base, can be added to a solution of 5-(phenylthio) valeryl halide of Formula VI in any sequence, or they may be added alternatively in small lots.
Suitable temperatures for conducting the reaction range from about -20 °C to about 100 °C, or from about 0 °C to about 50 °C.
pH of the reaction mass is maintained below about 7.0 to below about 3.0 throughout the reaction.
After completion of the reaction, the product can be isolated by crystallization from the solvent into which the product is extracted after the reaction. Optionally crystallization may be initiated by methods such as cooling, seeding, partial removal of

the solvent from the solution, by adding an anti-solvent to the solution or a combination thereof.
Suitable solvents which can be used for extracting the product from the reaction mass include, but are not limited to chlorinated solvents, such as C1-C6 straight chain or branched chlorohydrocarbons such as dichloromethane, ethylene dichloride, chloroform, carbon tetrachloride, chloro benzene, dichlorobenzene and the like; hydrocarbon solvents such as toluene, xylene and the like, or mixtures thereof.
Suitable solvents which can be used as antisolvents for crystallization include, but are not limited to hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, and the like; or mixtures thereof or their combinations with water in various proportions.
Another aspect of the present invention provides a process for the preparation of (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- [2'-(1H- tetrazole-5-yl)-biphenyl-4-yl methyl] amine of Formula V comprising:
a) reaction of N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester
hydrochloric acid of Formula II with a base to give N- [(2'-cyanobiphenyl-4-yl) methyl]-
(L)-valine methyl ester of Formula III.

Formula II Formula III
b) reacting N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester of Formula
III with a tetrazole ring forming reagent to get 3-Methyl-2-{[2'-(1H-tetrazol-5-yl)-biphenyl-
4-ylmethyl]-amino}-butyric acid methyl ester of Formula IV.


Formula IV
c) reacting 3-Methyl-2-{[2'-(1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula IV with a hydrolyzing agent to give the compound of Formula V.
Step a) involves reaction of an acid addition salt of N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester acid of Formula II with a base to give N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester of Formula III.
Suitable acid addition salts of N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester acid which can be used for the reaction include, but are not limited to the salts formed from any of the inorganic acids like hydrochloric acid, hydrobromic acid, phosphoric acid; or organic acids such as acetic acid, formic acid, tartaric acid and the like.
Suitably, breaking of the acid addition salt is carried out by treating with a base.
Suitable bases which can be used include, but are not limited to: alkali metal hydrides such as lithium hydride, sodium hydride and the like; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; ammonia; and mixtures thereof. These bases can be used in the form of solids or in the form of aqueous solutions.
Suitably, aqueous solutions containing about 5% to 50%, or about 10% to 20%, (w/v) of the corresponding base can be used. Any concentration is useful, which will convert the acid addition salt to a free base.
When the reaction is carried out in an aqueous phase, the product may be extracted into an organic solvent from the aqueous solution.

Suitable organic solvents which can be used to extract the ester include, but are not limited to hydrocarbon solvents such as toluene, xylene, ortho-xylene, n-heptane, n-hexane, cyclohexane, methylcyclohexane and the like; ethers such as tetrahydrofuran, 1,4-dioxane and the like; aprotic polar solvents such as DMF, DMSO, DMA and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like and mixtures thereof.
Suitable temperatures for conducting the reaction range from about -20 °C to about 50 °C, or form 10 °C to 30 °C.
In an embodiment, the product N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester of Formula III formed in the reaction medium is progressed to step b) without isolating the compound, thus giving rise to an in-situ process.
Step b) involves the reaction of N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester of Formula III with a tetrazole ring forming reagent to get 3-Methyl-2-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula IV.
The reagent that is used for the formation of tetrazole ring can be selected from sodium azide or with an organo tin azide such tributyl tin azide or with a silyl azide, or by cycloaddition of trialkyl tin or triaryl tin azides.
Suitably, the reaction is carried out in two stages, first the tetrazole ring is formed in-situ and then it is condensed with N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester of Formula III to give the required product of Formula IV.
Suitably, the reaction is carried out in the presence of a base. Suitable bases which can be used for the reaction include, but are not limited to inorganic bases like hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; azides such as sodium azide, tributyl tin azide, organo boron, organo aluminum azide and the like.
Suitable solvents for conducting the reaction include, but are not limited to C1-C5 ketones such as acetone, ethyl methyl ketone, butanone and the like; alcohols such as ethanol, methanol, and isopropanol; ethers such as tetrahydrofuran, 1,4-dioxane, ethyl

acetate and the like; hydrocarbon solvents such as toluene, xylene and the like; and mixtures thereof.
Suitable temperatures for tetrazole ring formation range from about -20 °C to about 50 °C, and for condensation of the tetrazole ring with N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester of Formula III temperatures of the range of about 50 °C to about 200 °C are used.
In an embodiment, the product 3-Methyl-2-{[2'-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula IV formed in the reaction medium is progressed to step c) without isolating the compound, thus giving rise to an in-situ process.
Step c) involves reaction of 3-Methyl-2-{[2'-(1 H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amino}-butyric acid methyl ester of Formula IV with a hydrolyzing agent to give the compound of Formula V.
Suitably, hydrolysis is carried out in alkaline medium. Suitable bases which can be used for providing the alkaline environment include, but are not limited to inorganic bases like hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; azides such as sodium azide, tributyl tin azide, organo boron, organo aluminum azide and the like, organic bases such as pyridine, N,N-dimethyl formamide (DMF), trimethyl amine, triethyl amine, N-methylpyrolidine and the like.
These bases can be used as solids or as their solutions in suitable solvents and the quantity of base that can be used in the reaction can vary depending upon the base used. Suitably, solutions of the base in water or an organic solvent containing about 5% to 50%, or about 10% to 20%, (w/v) of the corresponding base can be used. Any concentration is useful, which will convert the acid addition salt to a free base.
Suitable temperatures for conducting the reaction range from about -20 °C to about 50 °C, or form about 20 °C to about 30 °C.
The product obtained may be optionally purified by recrystallization or slurry in suitable solvents.

Recrystallization involves providing a solution of crude compound of Formula V in a suitable solvent and then crystallizing the solid from the solution.
Suitable solvents which can be used for purification include but are not limited to: C1-C5 ketones such as acetone, ethyl methyl ketone, butanone and the like; alcohols such as ethanol, methanol, and isopropanol; ethers such as ethers such as tetrahydrofuran, 1,4-dioxane, ethyl acetate and the like; water; and mixtures thereof.
Yet another aspect of the present invention provides a process for the preparation of 5-(phenylthio) valeryl halide of Formula VI comprising:
a) reaction of 5-halovaleric acid of Formula VIII with thiophenol in presence of a
base and a solvent to afford 5-(phenylthio) valeric acid of Formula IX.

Formula VIII Formula IX
b) reacting 5-(phenylthio) valeric acid of Formula IX with a halogenating agent to
give 5-(phenylthio) valeryl chloride of Formula VI.
Step a) involves reaction 5-halovaleric acid of Formula VIII with thiophenol in presence of a base and a solvent to afford 5-(phenylthio) valeric acid of Formula IX.
Suitably, the reaction is conducted in the presence of a base. Suitable bases which can be used for the reaction include, but are not limited to inorganic bases like hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; alkali metal hydrides such as sodium hydride, lithium aluminium hydride and the like.
Suitable solvents which can be used for the reaction include, but are not limited to ketones like acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ester solvents such as ethyl acetate, propyl acetate and the like; dimethylformamide, dimethylsulphoxide, dioxane, tetrahydrofuran, water and the like; or mixtures thereof.
The product obtained may be optionally purified by recrystallization or slurry in suitable solvents.

Suitable solvents which can be used for purification include but are not limited to: C1-C5 ketones such as acetone, ethyl methyl ketone, butanone and the like; alcohols such as ethanol, methanol, and isopropanol; ethers such as ethers such as tetrahydrofuran, 1,4-dioxane, ethyl acetate; hydrocarbons such as toluene, xylene, n-heptane, cyclohexane, and the like, or mixtures thereof.
Step b) involves reaction of 5-(phenylthio) valeric acid of Formula IX with a halogenating agent to give 5-(phenylthio) valeryl chloride of Formula VI.
Suitable halogenating agents which can be used include, but are not limited to, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, bromine, hydrogen iodide, and the like, or mixtures thereof.
Suitable solvents which can be used for the reaction include, but are not limited to; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like, esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, t-butyl acetate and the like or mixtures thereof.
Suitable temperatures for conducting the reaction range from about -20 °C to 100 °C, or from about 0 °C to 50 °C.
Suitably, the product 5-(phenylthio) valeryl chloride of Formula VI formed in the reaction medium is prepared just before the condensation reaction with the compound of Formula V to avoid decomposition of the product during storage.
Still another aspect of the present invention provides a process for the conversion of (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1 H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine of Formula II in presence of a reducing agent.
Suitable reducing agents which can be used include, but are not limited to metal hydrides such as sodium hydride, potassium hydride and the like; silanes, boranes, metal hydrides like sodium borohydride, lithium aluminium hydride, formates, hypophosphorous acid salts and the like; potassium borohydride, lithium borohydride and the like; combination of hydrogen and a metal catalyst. The metal catalysts can be selected from a group consisting of palladium absorbed on carbon, platinum, Raney nickel, platinum dioxide, and the like.

Suitable solvents which can be used for the reaction include, but are not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; nitriles such as acetonitrile, propionitrile and the like; water and mixtures thereof.
Suitable temperatures for conducting the reaction range from about 20 °C to 200 °C, or from about 25 °C to 100 °C.
Suitably, the reaction is carried out in the presence of a base. Suitable bases which can be used for the reaction include, but are not limited to inorganic bases like hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate, and the like; and bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like.
Valsartan obtained above can be purified by recrystallization or slurrying in a suitable solvent.
Suitable organic solvents which can be used for recrystallization or slurry formation include but are not limited to: esters such as ethyl acetate, n-butyl acetate, tertiary-butyl acetate, and isopropyl acetate and the like; ketonic solvents such as acetone, ethyl methyl ketone, and the like; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, cyclohexane and the like; nitrile solvents such as acetonitrile, propionitrile and the like; and mixtures thereof in various proportions.
For recrystallization, a solution can be prepared at an elevated temperature if desired to achieve a desired concentration. Any temperature is acceptable for the dissolution as long as a clear solution of the rimonabant is obtained and is not detrimental to the drug substance chemically or physically. The solution may be brought down to room temperature for further processing if required or an elevated temperature may be used.
Valsartan obtained using the process of the present invention has a purity of more than about 99.5% or more than about 99.9 % by HPLC.
Valsartan of Formula I obtained by the process of the present invention contains less than about 5000 ppm, or less than about 3000 ppm, or less than about 1000 ppm of methanol, and less than about 200 ppm, or less than about 100 ppm of individual residual organic solvents.

A still further aspect of the present invention provides a pharmaceutical composition comprising valsartan or its pharmaceutically acceptable salts prepared according to the process of the present invention along with one or more pharmaceutically acceptable carriers, excipients or diluents.
The pharmaceutical composition comprising valsartan or its pharmaceutically acceptable salts along with one or more pharmaceutically acceptable carriers of this invention may further formulated as: solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as but not limited to syrups, suspensions, dispersions, and emulsions; and injectable preparations such as but not limited to solutions, dispersions, and freeze dried compositions. Formulations may be in the form of immediate release, delayed release or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared by direct blending, dry granulation or wet granulation or by extrusion and spheronization. Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated or modified release coated. Compositions of the present invention may further comprise one or more pharmaceutically acceptable excipients.
Pharmaceutically acceptable excipients that find use in the present invention include, but are not limited to: diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methylcellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants; complex forming

agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methylcellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but are not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
In the compositions of present invention valsartan or its pharmaceutically acceptable salts is a useful active ingredient in the range of 20 mg to 350 mg, or 40 mg to 320 mg.
Certain specific aspects and embodiments of this invention are described in further detail by the examples below, which examples are provided only for the purpose of illustration and are not intended to limit the scope of the appended claims in any manner.
EXAMPLE 1 PREPARATION OF (S)-N- (1-CARBOXY-2-METHYL PROP-1-YU-N- r2'-(1H-TETRAZOLE-5-YD-BIPHENYL-4-YL METHYL! AMINE (FORMULA V)
Step 1:1000 ml of water was taken into a round bottom flask and 211g of sodium bicarbonate was added to it and subjected to stirring for a period of 25 minutes. The reaction mass was filtered. 200 g of N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester hydrochloric acid of Formula II was added to the filtrate with stirring followed by addition of 1000 ml of ortho xylene. The reaction mass was subjected to stirring for 3 hours. The organic layer was separated and dried over sodium sulphate to afford the compound of Formula III, which was present in the organic layer.
Step II: 400 ml of water was taken into a round bottom flask and cooled to a temperature of 15 °C. 125.6 g of sodium azide was added to it and the mixture was further cooled to 5 °C. 630.8 g of tributyl tin chloride was slowly added to the above reaction mixture at the same temperature followed by the addition of 400 ml of ortho xylene. The reaction mass was stirred at 5 °C for 15 minutes. The organic layer was separated and the aqueous layer was extracted into 400 ml of ortho xylene.

Step III: The organic layer that was obtained in step II and the free base of compound of Formula III that was present in the organic layer obtained from step I were taken into a round bottom flask and subjected to stirring followed by heating to 143 °C. The reaction mass was maintained at 143 °C for 12 hours. Then the reaction mass was gradually cooled to 27 °C to afford the tetrazole compound of Formula IV.
Step IV: A solution of 110g of sodium hydroxide and 110 ml of water was added to compound of Formula IV obtained in step III and maintained at 27 °C for 9 hours. The aqueous layer was separated washed with 400 ml of toluene. The aqueous layer was the taken into a separate round bottom flask and 200 ml of dichloromethane was added to it and the pH of the aqueous layer was adjusted to 6.87 using 20% aqueous acetic acid solution. The aqueous layer was separated and extracted into 200 ml of dichloromethane. Then 800 ml of dichloromethane was added to the aqueous layer and the pH of the reaction mass was adjusted to 5.29 with 20% aqueous acetic acid solution. The reaction mass was subjected to stirring for 2 hours followed by filtering the reaction mass. The filtered solid was washed with 120 ml of dichloromethane. The wet solid was dried under suction followed by drying in oven at 100 °C under a vacuum of 650 mm/Hg to afford 135.2 g of the title compound.
Chiral purity by HPLC: 99.9%.
EXAMPLE 2 PREPARATION OF 5-(PHENYLTHIO) VALERIC ACID (FORMULA IX)
120 g of 60% sodium hydride was taken into a round bottom flask and 700 ml of N,N-dimethyl formamide was added to it, and stirring given. A mixture of 100g of 5-chlorovaleric acid of Formula IV, 88.6 g of thiophenol, and 2000 ml NaN-dimethyl formamide were added slowly to the above reaction solution over a period of 2 and a half hours with simultaneous cooling. Reaction completion was checked using thin layer chromatography. After the reaction was completed, 3000 ml of water was slowly added to the reaction mass with simultaneous cooling to maintain the temperature at 25 °C followed by the addition of 2400 ml of 20% sodium hydroxide solution. 2300 ml of hydrochloric acid was added to the above reaction mass with simultaneous cooling followed by the filtering the solid. The solid was dried at a temperature of 37 ° C for 9

hours. The obtained dry compound was taken into a round bottom flask and 1500 ml of cyclohexane was added to it. The reaction mass was heated to a temperature of 65 °C and stirred for 15 hours. The reaction mass was then filtered and the filtrate was transferred into another round bottom flask and cooled to a temperature of 10 °C. The separated solid was filtered and the wet solid was dried at 40 °C for 14 hours to afford 110.1 g (71.5%) of the title compound. Purity by HPLC: 99.131%.
EXAMPLE 3 PREPARATION OF (S)-N- (1-CARBOXY-2-METHYL PROP-1-YU-N- (5-PHENYLTHIO) PENTANOYL-N- T2'-1 H-TETRAZOL-5-YL) BIPHENYL-4-YL METHYL1-AMINE (FORMULA VII)
Step I: 10 g of 5-(phenylthio) valeric acid of Formula V obtained according to a process described in Example 2 was taken into a round bottom flask equipped with a magnetic stirrer and kept under nitrogen atmosphere. 150 ml of dichloromethane was added to the above reaction mass and subjected to stirring. Then 3.7 ml of N,N-dimethyl formamide was added to it. The reaction mass was then cooled to a temperature of 2 °C and 4.5 ml of oxalyl chloride was added to it. The reaction mass was maintained at 2 °C for 2 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the reaction mass was distilledoff at 45 °C, and then co-distilled with 75 ml of dichloromethane. The obtained residue was further distilled to remove traces of oxalyl chloride. 42.4 ml of tetrahydrofuran was added to the obtained residue at 27 °C followed by decanting the organic layer containing the acid chloride compound of Formula VI.
Step II: (S)-N-(1-carboxy-2-methyl prop-1-yl)-N- [2'-(1H-tetrazole-5-yl)-biphenyl-4-yl methyl] amine of Formula V obtained according to a process described in Example 1 and 42.4 ml of tetrahydrofuran were taken into a round bottom flask and cooled to a temperature of -3 °C. The acid chloride compound of Formula VI obtained from step I was slowly added to the above reaction mass. pH of the reaction mass was ensured to be below 0.15 and then a solution of 3.8 ml of pyridine in 38 ml of tetrahydrofuran was added to it. The reaction mass was maintained at -3 °C for 2 hours. 10.4 ml of methanol

was added to the above reaction at a temperature of -3 °C and the reaction mass was allowed to raise to a temperature of 21 °C. Then 30 ml of water was added to the above reaction mass and maintained at 27 °C for 1 hour. Then the reaction mass was cooled to 4 °C. pH of the reaction mass was adjusted to 1.7 with 50 ml of 10% sodium carbonate solution, and the obtained reaction mass was subjected distillation at a temperature of 45 °C. The obtained residue was then cooled to a temperature of 30 °C. The aqueous layer was transferred into another round bottom flask and 74 ml of ethyl acetate was added to it. The reaction mass was then cooled to 5 °C and 30 ml of 2N hydrochloric acid was added to it to adjust the pH to 1.1. The reaction mass was then subjected to stirring at a temperature of 2 °C. The reaction mass was then filtered and the organic layer was separated and distilled a temperature of 48 °C. The residue obtained was dissolved in a mixture of 20 ml of dichloromethane and 60 ml of petroleum ether and stirred at 28 °C for 5 minutes followed by decanting the solvent. The residue was again dissolved in 20 ml of dichloromethane to which was slowly added 60 ml of petroleum ether and the same process was repeated one more time. The obtained solid was filtered, washed with a mixture of 4ml of dichloromethane and 16 ml of petroleum ether followed by suction drying. The wet solid was dried aerially for 8 hours to afford 8.1 g (50.3%) of title compound.
IR : 3444 (O-H), 2965 (Ali-C-H), 2931 (AN C-H), 1731(-C=0)(acid), 1603 (-C=0) amide, 824 p-substituted, 740 (ortho-substituted) and 777 (mono substituted).
1H NMR: (DMSO-d6, 400 MHz): 8 7.0-7.6 (m, 13H), 5 3.0 (t, 2H), 51.9 (m, 2H), 51.9 (m, 2H), 52.6 (t, 2H), 63.6 (d, 1H), 5 2.6-2.7 (m, 1H), 5 0.9 (d, 3H), 6 1.0 (d, 3H), 5 4.2&4.9(dd, 2H), 5 8.0(d, 1H).
MS: m/z 564.
EXAMPLE 4 PREPARATION OF (S)-N- (1-CARBOXY-2-METHYL PROP-1-YU-N-PENTANOYL-N-f2'-1H-TETRAZOL-5-YL) BIPHENYL-4-YL METHYL1-AMINE (VALSARTAN FORMULA
1)

10 g of (S)-N- (1-carboxy-2-methyl prop-1-yl)-N- (5-phenylthio) pentanoyl-N- [2'-1 H-tetrazol-5-yl) biphenyl-4-yl methyl]-amine of Formula VII obtained in Example 3 and 600 ml of methanol were taken into a round bottom flask and subjected to stirring. 43.8 g of nickel chloride hexahydrate was added with stirring and cooling to a temperature of 10 °C. A solution of 50 g of sodium hydroxide and 20.8 g of sodium borohydride in 125 ml of water was slowly added to the above reaction mass at temperature of 3 °C. The reaction mass was then filtered through a celite_bed and the celite bed was washed with 100 ml of methanol. The filtrate was distilled at a temperature of about 55 °C followed by cooling to 28 °C and the obtained reaction mass was transferred into another round bottom flask followed by the addition of 100 ml of water. The above reaction mass was subjected to stirring and 50 ml of dichloromethane was added to it followed by the adjusting thepH of the reaction mass to 5.19 using 20% aqueous acetic acid. The organic layer was separated and the aqueous layer was extracted into 100 ml of dichloromethane. The combined organic layer was dried over sodium sulfate and distilledat a temperature of 42 °C. 50 ml of cyclohexane was added to the above residue and distilled at a temperature of 55 °C. 75 ml of cyclohexane was added to the reaction mass under stirring followed by filtering the reaction mass and finally subjected to drying at temperature of about 50 °C for 4 hours to afford 3.7 g (46.2%) of the title compound.
EXAMPLE 5 PREPARATION OF (S)-N- (1-CARBOXY-2-METHYL PROP-1-YU-N- T2'-(1H-TETRAZOLE-5-YU-BIPHENYL-4-YL METHYL] AMINE (FORMULA V)
10 liters of water was taken into a reactor and cooled to 10 °C. 0.5435 kg of sodium azide was added to it at 10 to 11 °C and maintained for 15 minutes. The reaction mass was further cooled to 2 °C and 1.3565 kg of tributyl tin chloride was added to it. The reaction mass was maintained at 1 to 2 °C for 1.5 hours, and then heated to 28 °C. 10 liters of ortho xylene was then added to it and maintained at the same temperature for 20 minutes. The aqueous layer was separated and extracted into 10 liters of ortho xylene. The combined organic layer was taken into another reactor and 25 liters of ortho xylene was added to it. 5 kg of cyanobiphenyl was added to the above

organic layer at 28 °C followed by addition of a solution of 2.34 kg of sodium bicarbonate in 23.4 liters of water at 28 °C. The reaction mass was maintained at the same temperature for 30 minutes and then the aqueous layer was separated. The organic layer was heated to 145 °C and maintained for 14 hours. Reaction completion was checked using thin layer chromatography. After the reaction was completed, the reaction mass was cooled to 30 °C and a solution of 2.75 kg of sodium hydroxide in 27.5 liters of water was added to it at the same temperature. The reaction mass was maintained at 30 °C for 8 hours and 40 minutes. The aqueous layer was separated and washed with 10 liters of ortho xylene in two equal lots. The aqueous layer was then taken into another reactor and pH was adjusted to 2.26 with a solution of 6 liters of hydrochloric acid in 54 liters of water. The reaction mass was maintained at 30 °C for 2 hours and then filtered. The filtered cake was washed with 15 liters of water. The wet material and 20 liters of methanol were taken into another reactor and stirred for 15 minutes at 30 °C. The reaction mass was then heated to 53 °C and maintained for 45 minutes. Then the solution was cooled to 26 °C and maintained for 1 hour. The separated solid was filtered and washed with 5 liters of methanol. The wet material was dried at a temperature of 26 °C and a vacuum of 650 mm/Hg for hour followed by drying at 73 °C and a vacuum of 650 mm/Hg for 5 hours to yield 3.7 kg of the title compound.
EXAMPLE 6 PREPARATION OF 5-(PHENYLTHIO) VALERIC ACID (FORMULA IX):
15 liters of water was taken into a reactor and 9.15 kg of 40 % aqueous sodium hydroxide solution was added to it. The mixture was stirred for 10 minutes and then cooled to 25 °C. 3.75 kg of thiophenol was added to the mixture slowly at 26 °C and stirred at the same temperature for 45 minutes. Then 5.0 kg of 5-chloro valeric acid was added at 31 °C and stirred for 6 hours at the same temperature. Reaction completion was checked using thin layer chromatography. After the reaction was completed, pH of the reaction mass was adjusted to 2.18 using 25 % aqueous hydrochloric acid. The reaction mass was maintained at 31 °C for 4 hours, and then filtered. The filtered solid was washed with 5 liters of water. The wet material was taken into another reactor and

25 liters of cyclohexane was added to it and heated to 51 °C. The reaction mass was maintained at 51 °C for 10 minutes and then cooled to 25 °C and maintained for another 1 hour 30 minutes. The solid was filtered and washed with 5 liters of cyclohexane. The wet material was dried at 38 °C under a vacuum of 650 mm/Hg for 10 hours to yield 5.8 kg of the title compound. Purity By GC: 99.5%
EXAMPLE 7 PREPARATION OF (SVN- (1-CARBOXY-2-METHYL PROP-1-YU-N- (5-PHENYLTHIO) PENTANOYL-N- f2'-1 H-TETRAZOL-5-YL) BIPHENYL-4-YL METHYL1-AMINE (FORMULA VII)
5.25 kg of 5-(phenylthio) valeric acid was taken into a reactor and 3.57 kg of thionyl chloride was added to it and stirred at 21 °C for 2 hours and 45 minutes. Reaction completion was checked using thin layer chromatography. After the reaction was completed, 21 liters of tetrahydrofuran was added to it and the reaction mass was cooled to -3 °C. A solution of 7.8 kg of (S)-N- (1-carboxy-2-methyl prop-1-yl)-n- [2'-(1h-tetrazole-5-yl)-biphenyl-4-yl methyl] amine in 45 liters of tetrahydrofuran was added to the cooled reaction mass at -3 °C. A solution of 1.13 kg of pyridine in 12 liters of tetrahydrofuran was then added to the reaction mixture such that pH of the reaction mixture was constantly maintained below 2.5. The reaction mass was stirred at -3 °C for 1 hour and 30 minutes. Reaction completion was checked using thin layer chromatography. After completion of the reaction, 112.5 liters of water was added to it and stirred for 35 minutes at 20 °C. the aqueous layer was separated and 30 liters of water was added to the reactor followed by addition of 22.5 liters of dichloromethane. The reaction mass was stirred for 30 minutes and the organic layer was separated. The aqueous layer was extracted into 30 liters of dichloromethane in two equal lots. The combined organic layer was washed with water 45 liters of water in three equal lots. The total organic layer was then distilled off at 45 °C under a vacuum of 650 mm/Hg. The residue was cooled to 30 °C and again co-distilled with 7.5 liters of dichloromethane at 45 °C under a vacuum of 650 mm/Hg. The residue obtained was again cooled to 30 °C

and 17.5 liters of dichloromethane was added to it. the reaction mass was stirred at 22 °C for 25 minutes and then 70 liters of cyclohexane was added to it. The reaction mass was stirred for 2 hours at the same temperature and filtered. The wet solid was dried at 30 °C under a vacuum of 600 mm/Hg for 11 hours to yield 4.6 kg of the title compound. Purity by HPLC; 95.8%
EXAMPLE 8 PREPARATION OF (S)-N- (1-CARBOXY-2-METHYL PROP-1-YU-N-PENTANOYL-N-r2'-1H-TETRAZOL-5-YU BIPHENYL-4-YL METHYL1-AMINE (FORMULA I)
28 liters of water was taken into a reactor and 2.85 kg of sodium hydroxide flakes were added to it. The mixture was stirred for 10 minutes and then cooled to 30 °C. 2.8 kg of (S)-N- (1-carboxy-2-methyl prop-1-yl)-n- (5-phenylthio) pentanoyl-n- [2'-1h-tetrazol-5-yl) biphenyl-4-yl methyl]-amine was added to the above mixture and stirred for 10 minutes for clear dissolution. A slurry of 20 kg of Raney nickel and 28 liters of water was added to the above reaction mass and heated to 66 °C. The reaction mass was maintained at 66 °C for 10 hours and 30 minutes. Reaction completion was checked using HPLC. After the reaction was completed, the reaction mass was cooled to 30 °C and filtered. The filtered bed was washed with 14 liters of water in 2 equal lots. The filtrate was taken into another reactor and pH was adjusted to 1.51 with aqueous hydrochloric acid solution. The reaction mass was then stirred for 1 hour at 30 °C and then filtered. The filtered solid was washed with 5.6 liters of water. The wet material was dried at 30 °C under a vacuum of 600 mm/Hg for 1 hour followed by drying at 45 °C and a vacuum of 600 mm/Hg for 4 hours to yield 1.78 kg of the title compound.
Purity By HPLC: 99.2%
EXAMPLE 9 PURIFICATION OF (S)-N- (1-CARBOXY-2-METHYL PROP-1-YLVN-PENTANOYL-N-r2'-1H-TETRAZOL-5-YL) BIPHENYL-4-YL METHYL1-AMINE (FORMULA I)
3 kg of crude valsartan obtained according to a process described in Example 8 and 18 liters of ethyl acetate were taken into a reactor and heated to 56 °C. The reaction mass was maintained at 56 °C for 10 minutes and checked for clear

dissolution. 0.183 kg of carbon was added to the solution at 56 °C and maintained at the same temperature for 15 minutes. The reaction mass was then filtered and the filtered bed was washed with 3.5 liters of hot ethyl acetate. The combined filtrate was taken into another reactor and allowed to cool to 37 °C. Seeding 0.025 kg of the title compound was added as seed, and the reaction mass was maintained at 37 °C for 2 hours. The reaction mass was then further cooled to 32 °C and maintained for 1 hour and 30 minutes. The reaction mass was further cooled to 11 °C and maintained for 1 hour. The reaction mass was further cooled to 8 °C and maintained for 2 hours. The separated solid was filtered and washed with 2.5 liters of chilled ethyl acetate. The wet material was dried at 35 °C for 1 hour and then sieved through a 10 No. mesh. The sifted material was again dried at 45 °C for 1 hour and 30 minutes, followed by drying in an FBD at 52 °C for 2 hours and 30 minutes, and at 70 °C for 1 hour and 45 minutes. The dry material was again sifted through a 20 No. mesh to yield 1.2 kg of the title compound.
Purity by HPLC: 99.97.
% by HPLC of other individual impurities: Less than 0.05% Residual organic solvent content: Ethyl acetate: 1038 ppm, cyclohexane: 33 ppm, dichloromethane: 29 ppm. All other solvents: Less than 200 ppm.

We Claim:
1. A process for preparing valsartan, comprising reacting a compound having a
Formula VII,
with a reducing agent.
2. The process of claim 1, wherein the reducing agent is selected from a group
consisting of palladium absorbed on carbon, platinum, Raney nickel, platinum dioxide,
and the like in combination with hydrogen.
3. The process according to claim 1, wherein the reaction is conducted in an
alkaline medium provided by an alkali metal hydroxide in a solid or a solution form.
4. A process for preparing the compound of Formula VII, comprising reacting a
compound having a Formula V

with a compound having a Formula VI.

5. The process of claim 4, wherein the reaction is conducted in the presence of
a solvent selected from diethyl ether, diisopropyl ether, ortetrahydrofuran, and a base
selected from pyridine, or triethylamine.

6. The process of claim 5, wherein the reaction is conducted at a pH of less
than about 7.0.
7. The process of claim 2, wherein a compound having a Formula V is prepared
by a process comprising:
a) reacting a compound of Formula II,

with a base to give a compound of Formula III.

b) Reacting the compound of Formula III with a tetrazole ring forming reagent to
give the compound of Formula IV,

c) followed by hydrolysis of the compound of Formula IV.
8. The process of claim 6, wherein a compound having a formula IV is not
isolated, prior to hydrolysis.

9. The process of claim 3, wherein, a compound having a Formula VI is
prepared by a process comprising:
a) reacting a compound of Formula VIII
with thiophenol to give a compound of Formula IX,

b) halogenating the acid compound of Formula IX.
10. A compound having a Formula VII.