Process for ^p urification of (S)-N-q-Carboxy-2-methvI-Drop-l-vI)-N-pentanoyl-N-r2'- (lH-tetrazol-5-yl)biphenyl-4-ylm ethvϊi -amine

Field of Invention:

The present invention relates to process for purification of (S)-N-(I -Carboxy-2-methyl- prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biplienyl-4-y lmethyl]-amine. Moreover it provides process for preparation of amorphous form of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4^ylmethy l]-amine. Present invention also provides process for preparation of various salts of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethy l]-amine. It also provides novel salts of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5- yl)biphenyl-4-ylmethyl]-amine.

Background of the invention and prior art:

(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5-yl)biphenyl-4- ylmethyl] -amine (Figure (I)) commonly referred as Valsartan, belongs to group of angiotensin II antagonists which are useful in the treatment of hypertension, anxiety, glaucoma and cardiac attacks. Valsartan is an orally active specific angiotensin II antagonist acting on the ATI receptor subtype. It is useful in regulating high blood pressure and cardiac insufficiency.

Valsartan is first disclosed in US Patent No. 5,399,578 which also discusses its process for preparation. The final product is recrystallized from ethyl acetate. Another example in same patent recites recrystallization from diisopropyl ether. However these processes for purification do not give Valsartan with high purity.

Journal of Labelled Compounds and Radiopharmaceuticals 2000, 43, 1245-1252 reports recrystallization of Valsartan a (1:1) mixture of ethyl acetate-hexane. However, it does not provide any enabling disclosure with respect to the crystallization i.e. crystallization by precipitation or slurrying or any the process. Moreover it also remains silent about the resultant form of Valsartan.

Various salts of Valsartan and their hydrates and polymorphs thereof are reported in US Patent No. 6,869,970 and US Patent Application Publication No. 2003/0207930.

It is therefore there is a need to develop a process for purification of Valsartan which is results in high purity of product as well as overall increase in the yield.

Object of the invention:

The primary object of the present invention is to provide an improved process for the purification of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5- yl)biphenyl-4-ylmethyl]-amine.

Another object of the present invention is to provide process for preparing amorphous (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5-yl)biphenyl-4- ylmethyl]-amine.

Also it is an object of the present invention to provide process for preparation of salts of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5-yl)biphenyl-4- ylmethyl] -amine.

Yet another object of the present invention is to provide novel salts of (S)-N-(l-Carboxy- 2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biph enyl-4-ylmethyl]-amine.

Summary of the invention: Accordingly present invention provides process for purification of (S)-N-(I -Carboxy-2- methyl-ρrop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphe nyl-4-ylmethyl]-amine which results in high purity of product as well as overall increase in the yield.

Another aspect of the present invention provides process for preparation of amorphous form of (S)-N-(I -Carboxy-2-methyl-proρ- 1 -yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5-yl) biphenyl-4-ylmethy 1] -amine .

Yet another aspect of the present invention provides process for preparing salts of (S)-N- ( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-( 1 H-tetrazol-5-yl)biphenyl-4- ylmethyl]-amine.

Further aspect of the present invention provides novel salts of (S)-N-(I -Carboxy-2- methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphen yl-4-ylmethyl]-amine.

Detailed description of the invention:

The term ^* '(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5- yl)biphenyl-4-ylmethyl] -amine" is interchangeable with "Valsartan" and is intended to include Valsartan and its pharmaceutically acceptable salts, and hydrates or solvates thereof in any state of purity unless specifically mentioned.

Surprisingly the inventors of present invention have found that it is possible to obtain (S)- N-(I -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N- [2'-(I H-tetrazol-5-yl)biphenyl-4- ylmethyl] -amine with high purity and yield by carrying out process of purification comprising steps of;

(a) mixing (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol- 5-yl)biphenyl-4-ylmethyl]-amine with alkali and alkaline earth metal carbonate, bicarbonate or hydroxide to form a reaction mass (b) treating the above reaction mass with suitable solvent to obtain desired salt of

(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine

(c) treating the salt obtained in step (b) with acid to obtain pure (S)-N-(l-Carboxy- 2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biph enyl-4-ylmethyl]- amine

The term "mixing" as used herein in specification and claims refers to create or form by combining ingredients or to combine or blend into one mass or mixture. The term "treating" as used herein in specification and claims refers to simple dictionary meaning: "To subject to a process, action, or change, especially to a chemical or physical process or application". The term high purity refers to Valsartan having D-isomer in an amount less than about 0.25%

The alkali and alkaline earth metal carbonate, bicarbonate or hydroxide is selected from group comprising of sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, barium carbonate, lithium carbonate, cesium carbonate, strontium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, barium bicarbonate, lithium bicarbonate, cesium bicarbonate, strontium bicarbonate, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, barium hydroxide, lithium hydroxide, cesium hydroxide, strontium hydroxide and like, preferably calcium hydroxide, cesium carbonate, lithium hydroxide and strontium hydroxide .

Suitable solvent can be selected from group comprising of water, C _3-6 ketone, C _1-6 alkanol, C _1-6 nitrile, C _1-6 esters or mixtures thereof, preferably water, acetone, ethanol, acetonitrile, ethyl acetate or mixtures thereof.

Acid can be mineral acid selected from group comprising of hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid and like.

Salts of (S)-N-(I -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5- yl)biphenyl-4-ylmethyl]-amine, can be prepared by mixing (S)-N-(I -Carboxy-2 -methyl - prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl methyl]-amine with suitable alkali and alkaline earth metal carbonate, bicarbonate or hydroxide to obtain solid mass.

This mixture is dissolved in suitable solvent at about ambient temperature to about reflux temperature of the solvent. After complete dissolution the reaction mixture is stirred for about 1 hour to about 10 hours. Further it is cooled to about 0°C to about 25°C to obtain

the desired salt. The desired salt can be isolated by conventional methods like filtration or centrifugation and dried.

The salt is further treated with acid in the presence of solvent preferably water, ethyl acetate, methylenedichloride or like and mixtures thereof. After regular work-up procedures, purified (S)-N-( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N- [2'-(I H- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is obtained.

Another aspect of the present invention is to provide a process for the preparation of amorphous form of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl] -amine comprising steps of;

(a) mixing (S)-N-(I -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N- [2'-( 1 H- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine with alkali and alkaline earth metal carbonate, bicarbonate or hydroxide to form a reaction mass (b) treating the above reaction mass with suitable solvent to obtain desired salt of

(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5- yl)biphenyl-4-ylmethyl]-amine (c) treating the salt obtained in step (b) with acid to obtain amorphous form of

(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine

Another aspect of the present invention is to provide a process for the preparation of amorphous form of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine comprising steps of; (a) preparing a slurry of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-N- [2'-

(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in ethyl acetate and a solvent selected from group comprising of alkanes or ether (b) stirring the slurry obtained in step (a) to obtain amorphous form of (S)-N-(I-

Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazo l-5-yl)biphenyl-4- ylmethyl] -amine

The slurry is prepared by stirring, suspending or contacting (S)-N-(I -Carboxy-2-methyl- prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl methyl]-amine in a suitable organic solvent, preferably ethyl acetate and a solvent selected from group comprising of alkanes or ether.

Examples of alkanes and ether solvents include but are not limited to n-pentane, n- heptane, hexane, diisopropyl ether and like. The stirring is preferably carried out at ambient temperature. The amorphous form thus obtained can be isolated by conventional methods such as centrifugation or filtration and dried.

The amorphous form of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-N- [2'-(I H- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is characterized by PXRD spectrum which is substantially the same as PXRD spectrum shown in Figure 1.

Another aspect of the present invention is to provide a process for the preparation of salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5-yl)biphenyl- 4-ylmethyl] -amine comprising steps of,

(a) mixing (S)-N-( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N- [2'-(I H-tetrazol-5- yl)biphenyl-4-ylmethyl]-amine with alkali and alkaline earth metal carbonate, . bicarbonate or hydroxide to form a reaction mass

(b) treating the above reaction mass with suitable solvent to obtain desired salt of (S)- N-( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N- [2'-(I H-tetrazol-5-yl)biphenyl- 4-ylmethyl] -amine

(c) isolating desired salt of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine

Another aspect of the present invention is to provide cesium salt of (S)-N-(I -Carboxy-2- methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphen yl-4-ylmethyl]-amine. The crystalline cesium salt of (S)-N-(l-Carboxy-2-methyl-prop~l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is characterized by PXRD peaks at 9.7, 21.6, 24.3, 27.9, 29.2 ± 0.2°-2θ. It can also be characterized by PXRD spectrum which is substantially the same as PXRD spectrum shown in Figure 2.

Cesium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5- yl)biphenyl-4-ylmethyl] -amine can be prepared by process comprising steps of;

(a) mixing (S)-N-( 1 -Carboxy-2-methyl-proρ- 1 -yl)-N-ρentanoyl-N- [2'-(I H- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine with carbonate, bicarbonate or hydroxide salt of cesium to form a reaction mass

(b) treating the above reaction mass with suitable solvent to obtain cesium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5- yl)biphenyl-4-ylmethyl]-amine (c) isolating cesium salt of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-

N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine

According to preferred embodiment cesium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl] -amine can be prepared by mixing (S)-N-( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine with cesium carbonate and dissolving this solid mass in acetone. Further the reaction mixture is stirred at about ambient temperature for about 1 to 10 hours and then cooled to obtain cesium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl] -amine.

Another aspect of the present invention is to provide lithium salt of (S)-N-(I -Carboxy-2- methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphen yl-4-ylmethyl]-amine. Lithium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine is substantially amorphous. It can also be characterized by PXRD spectrum which is substantially the same as PXRD spectrum shown in Figure 3.

Lithium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-ρentanoyl-N-[2'-(lH- tetrazol-5- yl)biphenyl-4-ylmethyl] -amine can be prepared by process comprising steps of;

(a) mixing (S)-N-( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N- [2'-( 1 H- ^• tetrazol-5-yl)biphenyl-4-ylmethyl]-amine with carbonate, bicarbonate or hydroxide salt of lithium to form a reaction mass

(b) treating the above reaction mass with suitable solvent to obtain lithium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5- yl)biphenyl-4-ylmethyl] -amine

(c) isolating lithium salt of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl- N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine

According to preferred embodiment lithium salt of (S)-N-(I -Carboxy-2 -methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl] -amine can be prepared by mixing (S)-N-( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-( 1 H-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine with lithium hydroxide and dissolving this solid mass in mixture of ethanol-water. Further the reaction mixture is stirred at about ambient temperature for about 1 to 10 hours and then cooled to obtain lithium salt of (S)-N-(I- Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5 -yl)biphenyl-4-ylmethyl]- amine.

Another aspect of the present invention is to provide strontium salt of (S)-N-(I -Carboxy- 2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biph enyl-4-ylmethyl]-amine. The crystalline strontium salt of (S)-N-(I -Carboxy-2 -methyl-prop- 1 -yl)-N-pentanoyl-N- [2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is characterized by PXRD peaks at 6.2, 8.4, 9.2, 9.8, 19.6, 20.5 ± 0.2°-2θ. It can also be characterized by PXRD spectrum which is substantially the same as PXRD spectrum shown in Figure 4.

Strontium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol- 5-yl)biphenyl-4-ylmethyl]-amine can be prepared by process comprising steps of; (a) mixing (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine with carbonate, bicarbonate or hydroxide salt of strontium to form a reaction mass

(b) treating the above reaction mass with suitable solvent to obtain strontium salt of (S)-N-(I -Carboxy-2-methyl-ρrop- 1 -yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5- yl)biphenyl-4-ylmethyl] -amine

(c) isolating strontium salt of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N- pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine

According to preferred embodiment strontium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl] -amine can be prepared by mixing (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5- yl)biphenyl-4-ylmethyl] -amine with strontium hydroxide and dissolving this solid mass in mixture of water-acetonitrile. Further the reaction mixture is stirred at about 50-55°C for about 1 to 10 hours and then cooled to obtain strontium salt of (S)-N-(I -Carboxy-2- methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphen yl-4-ylmethyl]-amine.

Another aspect of the present invention is to provide calcium salt of (S)-N-(I -Carboxy-2- methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphen yl-4-ylmethyl]-amine. The crystalline calcium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is characterized by PXRD peaks at 5.6, 11.1, 12.7, 15.2, 19.6, 20.6 ± 0.2°-2θ. It can also be characterized by PXRD spectrum which is substantially the same as PXRD spectrum shown in Figure 5.

Calcium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5- yl)biphenyl-4-ylmethyl]-amine can be prepared by process comprising steps of;

(a) mixing (S)-N-( 1 -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N-[2'-( 1 H- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine with carbonate, bicarbonate or hydroxide salt of calcium to form a reaction mass

(b) treating the above reaction mass with suitable solvent to obtain calcium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol-5- yl)biphenyl-4-ylmethyl] -amine (c) isolating cesium salt of (S)-N-(I -Carboxy-2-methyl-prop- l-yl)-N-pentanoyl-

N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine

According to preferred embodiment calcium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1- yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl] -amine can be prepared by mixing (S)-N-(I -Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol- 5- yl)biphenyl-4-ylmethyl]-amine with calcium hydroxide and dissolving this solid mass in mixture of acetone-water. Further the reaction mixture is stirred at about reflux

temperature for about 1 to 10 hours and then cooled to obtain calcium salt of (S)-N-(I- Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5 -yl)biphenyl-4-ylmethyl]- amine.

It was found that crude Valsartan prepared in accordance with processes know in prior art contained D-isomer as impurity in amount greater than about 1.5% by HPLC method. The inventors of the present invention have accidentally found that it is possible to obtain Valsartan substantially free from D-isomer by carrying out process of purification comprising steps of; (a) preparing a slurry of (S)-N-(I -Carboxy-2 -methyl-prop- 1 -yl)-N-pentanoyl -N-

[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in ethyl acetate and diisopropyl ether

(b) stirring the slurry obtained in step (a) to obtain (S)-N-(I -Carboxy-2 -methyl- prop- 1 -yl)-N-pentanoyl-N-[2'-( 1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine substantially free from D-isomer

The slurry is prepared by stirring, suspending or contacting (S)-N-(I -Carboxy-2-methyl- prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl methyl]-amine in ethyl acetate and diisopropyl ether.

The term "substantially free" as referred herein in specification and claims refers to (S)- N-(l-Carboxy-2-methyl-prop-l-yl)-N-ρentanoyl-N-[2'-(lH-tetr azol-5-yl)biphenyl-4- ylmethyl] -amine containing impurity of D-isomer in amount less than about 0.25% preferably by HPLC method.

Another aspect of the present invention is to provide a process for the preparation of amorphous form of (S)-N-(I -Carboxy-2 -methyl-prop- l-yl)-N-pentanoyl-N- [2'-(I H- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine substantially free from D-isomer comprising steps of; (a) preparing a slurry of (S)-N-(I -Carboxy-2 -methyl-prop- l-yl)-N~pentanoyl-N-

[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in ethyl acetate and diisopropyl ether

(b) stirring the slurry obtained in step (a) to obtain amorphous form of (S)-N-(I - Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5 -yl)biphenyl- 4-ylmethyl] -amine substantially free from D-isomer

The slurry is prepared by stirring, suspending or contacting (S)-N-(I -Carboxy-2 -methyl - prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-yl methyl]-amine in ethyl acetate and diisopropyl ether.

(S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(l H-tetrazol-5-yl)biρhenyl-4- ylmethyl] -amine or its amoiphous form obtained by any of the processes of the present invention can be isolated by conventional methods such as filtration or centrifugation and dried.

The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.

Example 1

Preparation of Calcium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl- N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine

The solid mixture of (S)-N-(I -Carboxy-2-methyl-prop~l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine (80 gm) and calcium hydroxide (15.1 gm ) was stirred for 15 min. and a mixture of water and acetone (160+400 ml respectively) was added. The reaction mixture was refiuxed for 1 hour and cooled to 20-25°C. The solid material was filtered and washed with acetone and dried under reduced pressure at 40- 45 ⁰ C to obtain the 60 gm of title compound. HPLC Purity: 99.75%

Example 2

Preparation of Cesium salt of (S)-N-(l-Carboxy-2-methyI-prop-l-yl)-N-pentanoyl-N-

[2 ' -(I H-tetrazol-5-yI)bipheny 1-4-y lmethy 1] -amine

The solid mixture of crude (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'- (lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine (20 gm) containing D-valsartan(3.05%) and Cesium carbonate (15 gm) was stirred for 15 min. and acetone (120 ml) was added. The reaction mixture was stirred for 4 hour at 20-25°C and cooled to 10-15°C. The solid material was filtered and washed with acetone and dried under reduced pressure at 40- 45 ⁰ C to obtain the 23 gm of title compound. D-Valsartan content 0.05% HPLC Purity: 99.92%

Example 3

Preparation of Lithium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl- N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine

The solid mixture of (S)-N-(l-Carboxy-2-methyl-pr,op-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yl)biphenyl-4-ylmethyl]-amine ( 20 gm) and lithium hydroxide (3.85 gm) was stirred for 15 min. and mixture of denatured alcohol and water was added. The reaction mixture was stirred for 3 hours and solvent was recovered completely under reduced pressure. Acetone (320 ml) was added and reaction mixture was stirred for 30 min. and further ethyl acetate (200 ml) was added. It was stirred for 30 min. at room temperature and cooled to 10-15 ⁰ C. The solid material was filtered and dried under reduced pressure at 40-45 ⁰ C to obtain the 20 gm of title compound. HPLC Purity: 99.92%

Example 4

Preparation of Strontium salt of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N- pentanoyl-N- [2' -(lH-tetrazol-5-yl)biphenyl-4-ylmethyl] -amine

The solid mixture of crude (S)-N-(I -Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'- (lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine (5 gm) and strontium hydroxide (1.39 gm) wash stirred for 15 min. and a mixture of water and acetonitrile (5+25 ml respectively) was added. The reaction mixture was stirred at 50-55 ⁰ C for 1 hour and

cooled to 20-25°C. The solid material was filtered and washed with acetonitrile and dried under reduced pressure at 40-45°C to obtain the 1.63 gm of title compound.

Example 5 Preparation of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N~[2'-(lH- tetrazoI-5-yl)biphenyl-4-ylmethyl]-amine

Calcium salt of (S)-N-(I -Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol- 5- yl)biphenyl-4-ylmethyl] -amine (50 gm) was suspended in a mixture of water ( 200 ml) and ethyl acetate (500 ml) and treated with hydrochloric acid to adjust pH 2.0-3.0. The organic layer was separated and washed with water and concentrated to a solid residue. Ethyl acetate (100 ml) added to it to get thick slurry. Further diisopropyl ether (500 ml) was added under stirring. The material was filtered and washed with diisopropyl ether and dried to get the 35gm (83%) of title product. D-isomer: 0.16% (HPLC method)

Example 6 ^x

Preparation of (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH- tetrazol-5-yI)biphenyI-4-ylmethyI]-amine

Cesium salt of (S)-N-(I -Carboxy-2-methyl-prop- 1 -yl)-N-pentanoyl-N- [2'-(I H-tetrazol-5- yl)biphenyl-4-ylmethyl]-amine (15 gm) was suspended in a mixture of water ( 60 ml) and ethyl acetate (150 ml) and treated with hydrochloric acid to adjust pH 2.0-3.0 . The organic layer was separated and washed with water and concentrated to a solid residue Ethyl acetate (30 ml) added to it to get thick slurry. Further diisopropyl ether (150 ml) was added under stirring. The material is filtered and washed with diisopropyl ether and dried to get the 6.8 gm (70%) of title product.

Example 7

Preparation of amorphous form of (S)-N~(l-Carboxy-2-methyI-prop-l-yl)-N- pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyI-4-ylmethyl]-amine To 15 g of solid (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-t etrazol- 5-yl)biphenyl-4-ylmethyl]-amine was added ethyl acetate (30 ml) to get thick slurry.

Further hexaiie (225 ml) was added under stirring. The material is filtered and washed with hexane and dried to get title compound.

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.

Brief description of the drawings:

FIGURE-I represents PXRD of amorphous form of (S)-N-(I -Carboxy-2-methyl-prop-l- yl)-N-pentanoyl-N-[2'-( 1 H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine.

FIGURE-2 represents PXRD of Cesium salt of (S)-N-(I -Carboxy-2-methyl-prop-l-yl)-N- pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine .

FIGURE-3 represents PXRD of lithium salt of (S)-N-(I -Carboxy-2-methyl-prop-l-yl)-N- pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine .

FIGURE-4 represents PXRD of strontium salt of (S)-N-(I -Carboxy-2-methyl-prop-l-yl)- N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-ami ne.

FIGURE-5 represents PXRD of calcium salt of (S)-N-(I -Carboxy-2-methyl-ρrop-l-yl)- N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)biphenyl-4-ylmethyl]-ami ne.