PROCESS FOR PREPARING VALSARTAN
CROSS-REFERENCE TO RELATED APPLICATION
This application is a nonprovisional filing of copending Provisional Application No. 1269/CHE/2005 filed on September 12, 2005, the entire content of which is hereby incorporated by reference.
INTRODUCTION TO THE INVENTION
The present invention relates to an improved process for the preparation of valsartan and its pharmaceutically acceptable salts.
Valsartan is chemically known as N-(1-oxopentyl)-N-[[2'-(1H-tetrazol-5-yl) [1,1'-biphenyl]-4-yl] methyl]-L-valine and can be represented structurally by Formula I.

Valsartan is a non-peptide, orally active, specific angiotensin II antagonist, useful in the treatment of hypertension and 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 discloses 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, which can be depicted by Scheme 1.

Formula IV to valsartan also involves flash chromatography, which makes the process difficult to operate on an industrial scale.
Consequently, there is a long-felt need for a process for the preparation of valsartan which not only overcomes the problems in the art processes as mentioned above, but is also safe, cost effective, and industrially feasible.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of valsartan of Formula I, and pharmaceutically acceptable salts thereof, comprising the steps of:
a) condensation of N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester compound of Formula II or its hydrochloride salt with the valeryl chloride compound of Formula III in the presence of an inorganic base and a suitable solvent to give the (N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester compound of Formula IV;
b) tetrazole formation of (N«[(2'«cyanobiphenyl-4-yl)methyl]-N«valeryl-(L)-valine methyl ester compound of Formula IV in the presence of suitable reagents and suitable solvents to provide an intermediate compound of Formula V;
c) hydrolysis of the compound of Formula V using a suitable base in the presence of a suitable solvent to yield valsartan; and
d) optionally, recrystallisation of the valsartan of step (c) in a suitable solvent(s) to provide the purified valsartan of Formula I.
DETAILED DESCRIPTION
The present invention relates to an improved process for the preparation of valsartan of Formula I, and pharmaceutically acceptable salts thereof, comprising the steps of:
a) condensation of N- [(2'-cyanobiphenyl-4-yI) methyl]-(L)-valine methyl ester compound of Formula II or a salt thereof

x
Formula II
with the valeryl chloride compound of Formula III
o
>s,//Nv/^ci
Formula III
in the presence of an inorganic base and a suitable solvent to provide (N-[(2'-cyanobiphenyl-4-yl)-methyl]-N-valeryl-(L)-valine methyl ester of Formula IV;
%^^-^N^COOCH3
l^^ll CN
Formula IV
b) tetrazole formation of the N-[(2'-cyanobiphenyl-4-yl)methyl]"N-valeryl-(L)-valine methyl ester compound of Formula IV in the presence of suitable reagents and suitable solvents, to give an intermediate compound of Formula V;


c) hydrolysis of the intermediate compound of Formula V using a suitable base in
the presence of a suitable solvent to provide valsartan of Formula I; and
d) optionally, recrystallization of crude valsartan in a suitable solvent(s) to give
purified valsartan of Formula I.
Step a) involves condensation of N- [(2'-cyanobiphenyl-4-yl)-methyl]-(L)-valine methyl ester or a salt, such as its hydrochloride salt, with valeryl chloride in the presence of an inorganic base and a suitable solvent to give (N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester.
Suitable inorganic bases that can be used in step a) include but are not limited to: 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; or mixtures thereof.
The amount of base that can be used in the reaction can vary depending upon the base used. Suitably, the molar ratio of base to the starting material compound of Formula II can range from about 3 to 6, or about 4 to 5, or about 4.5.
Suitable solvents that can be used include but are not limited to: ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and the like; nitriles such as acetonitrile, propionitrile and the like; hydrocarbons such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane, chloroform and the like;

aprotic polar solvents such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N.N-dimethylacetamide (DMA) and the like; and water; or mixtures thereof in
various proportions.
Suitable temperatures for conducting the reaction can range from about -15° C to
50° C, or about 25° C to 35° C, or about 0° C to 5° C.
Step b) involves tetrazole formation of the compound of Formula IV in the presence of a suitable tetrazole forming reagents and suitable solvent to give an intermediate compound of Formula V.
Suitable tetrazole formation reagents include but are not limited to tributyltin azide and the like, which may be prepared insitu by the reaction of tributyltin chloride and sodium azide.
Suitable solvents that can be used in the tetrazole formation reaction include any solvent or mixture of solvents. Examples include, without limitation thereto ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and the like; halogenated hydrocarbons such as, dichloromethane, chloroform and the like; and aromatic hydrocarbons such as benzene, toluene, xylene and the like.
Suitable temperatures for the tetrazole formation reaction can range from about 0°Cto 120° C, or about 50° C to 100° C, or at the reflux temperature of the solvent used.
The intermediate tetrazole compound of Formula V thus formed may or may not be isolated and can be converted into corresponding acid in step c).
Step c) involves hydrolyzing the intermediate compound of Formula V using a suitable base in presence of a suitable solvent to provide crude valsartan of Formula I
Suitable inorganic bases that can be used in step c) include but are not limited to: 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; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate, and the like; or mixtures thereof.
In one embodiment these bases can be used as their solutions in suitable solvents.

Suitable solvents that can be used in the hydrolysis of the tetrazole intermediate compound include any solvent or mixture of solvents in which the required components are soluble. Examples include alcohols such as methanol, ethanol, propanol and the like; ketonic solvents such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and the like; halogenated solvents such as, dichloromethane, chloroform and the like; aromatic hydrocarbons such as benzene, toluene, xylene and water.
Step d) involves crystallization by dissolving crude valsartan in a suitable solvent to form a clear solution and then cooling to give a pure valsartan compound of Formula I. For obtaining high product yield, the solute concentration should be high, and frequently elevated temperatures will be required to dissolve sufficient solute.
Suitable solvents that can be used in step d) include any solvent or mixture of solvents in which the required components are soluble. Examples include without limitation: ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and the like; halogenated solvents such as, dichloromethane, chloroform and the like; nitriles such as acetonitrile, propionitrile and the like;
Suitable temperatures for dissolving crude valsartan in solvent to form clear solution can range from about 0-120° C, or about 50-100° C, or at the reflux temperature of the solvent used.
In one embodiment, clear solution thus obtained during the process can optionally be treated with activated charcoal or any other adsorbent material to improve the color of the compound.
Suitable temperatures for solid separation can range from about -20 to 50° C, about -10 to 10° C, about 0 to 5° C, or any other temperature below the solute dissolution temperature.
Isolation of the solid can be carried out by using conventional techniques such as centrifugation, decantation, gravity filtration, vacuum filtration, or other techniques known in the art for the separation of solids.
A solid product can be dired using any technique, such as for example fluidized bed drying, aerial drying, oven drying, or other techniques known in the art. Drying can

30° C; 113.2 ml of cyclohexane was added to the residue and stirred for about 55 minutes at 28-30° C. The resultant solid was filtered and washed with cyclohexane (28.3 ml). The obtained solid was dried at about 50° C for about 6 hours to give 22.3 g of the crude valsartan. (Purity by HPLC 98.75 area-%)
EXAMPLE 4
PURIFICATION OF VALSARTAN
55 g of crude valsartan prepared according to Example 2 was charged into a round bottomed flask containing ethyl acetate (330 ml) and the contents were heated to reflux under stirring to form a clear solution. To the clear solution, 5.5 g of activated charcoal was added and stirred at reflux for about 35 minutes. The reaction mass was filtered hot through a flux calcined diatomaceous earth (Hyflow) bed and the bed was washed with ethyl acetate (27.5 ml). The resultant filtrate was cooled to about 35° C and seeded with 2.75 g of pure valsartan. The seeded solution was stirred for 1 hour, 15 minutes at 35° C and subsequently cooled stepwise: to 30° C for 1 hour, 15 minutes; further to 15° C for about 40 minutes; and further to about 5° C for about 2 hours, 20 minutes; all accompanied by stirring. The separated solid was filtered and washed with ethyl acetate (27.5 ml) to get the wet solid compound.
The wet solid was dried under a reduced pressure of about 700 mm Hg using a cone vacuum drier at 30° C for about 3 hours. It was then further dried at 50-52° C for about 4 hours in the cone drier followed by sieving through a 40-mesh sieve. The resultant partially dried material was kept in a vacuum oven and dried at about 70° C for about 24 hours to afford 39.3 g of the title compound. (Purity by HPLC: 99.86 area-%)
EXAMPLE 5
COMMERCIAL SCALE DRYING OF VALSARTAN
9.5 kg of wet valsartan solid prepared similarly to Example 4 was charged into a cone vacuum drier and dried under reduced pressure of about 650-670 mm Hg at about 30° C for about 4 hours and subjected to multi milling using a 40 mesh screen at

WE CLAIM:
1. A process for preparing valsartan, comprising condensing N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester, or a salt thereof, with valeryl chloride in the presence of an inorganic base to form N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeryU(L)-valine methyl ester.
2. The process of claim 1, wherein an inorganic base comprises at least one alkali metal hydroxide, carbonate, or bicarbonate.
3. The process of claim 1, wherein a molar ratio of inorganic base to N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester is between about 3 and about 6.
4. The process of claim 1, wherein a molar ratio of inorganic base to N-[(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester is between about 4 and about 5.
5. The process of claim 1, further comprising reacting N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeryl-(L)-valine methyl ester with a tetrazole forming reagent, to form a compound having the formula

6. The process of claim 5, wherein a tetrazole forming reagent comprises tributyltin
azide.