FORM 2 THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)


Improved process for the preparation of (S)-N-(l-carboxy-2-methyI-prop-l-yl)-N-pentanoyl-N-(2'-(lH-tetrazole-5-yl)-biphenyl-4-ylmethyl]-
amine
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANY ACT,
1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400102, MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.


Improved process for the preparation of (S)-N-(l-carboxy-2-methyi-prop-l-yl)-N-pentanoyl-N-(2'-(lH-tetrazoIe-5-yl)-biphenyl-4-ylmethyl]-
amine
Field of the Invention
The present invention relates to an improved process for the preparation of (S)-N-(l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'(lH-tetrazole-5'yl)-biphenyl]-4-ylmethyl]-amine , i.e. Valsartan of Formula I, in substantially pure enantiomeric form

Background of the Invention
(S)-N- (l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetra2ole-5-yl)-biphenyl]-4-ylmethyl]-amine, which is commonly known as Valsartan, is a non-peptide, orally active and a very specific angiotensin II receptor blocker acting on the ATI receptor subtype. Valsartan, marketed as DIOVAN, is indicated for the treatment of hypertension. DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of Valsartan The combination of Valsartan with diuretics, such as hydrochlorothiazide, has specific advantage as antihypertensive agent.
Synthesis of Valsartan and its pharmaceutically acceptable salts has been disclosed by Ciba-Geigy in US Patent no. 5,399,578.
US 5,399,578 has disclosed two different processes for the preparation of Valsartan.

The first process involves the reaction of 4-bromomethyl-2'-cyanobiphenyl (II) with (L)-L-valine methyl ester followed by reaction with valeryl chloride to get 2-amino-N- [2'-cyanobiphenyl-4-yl) methyl]-2-methyl-N-valeryl propionate (IV). Compound (IV) upon treatment with tri-n-butyl tin azide gives N- (l-oxopentyl)-N- [[2'-(lH-tetrazol-5-yl)[l,l' biphenyl]-4-yl] methyl-L-valine methyl ester (V). This ester upon hydrolysis under basic condition yields Valsartan. The schematic representation of this process is as shown in SCHEME-I below:

This conventional route uses solvents like Dimethyl Formamide (DMF) during the preparation of compound of formula (III) & (IV), which needs to be avoided or to be minimized as this solvent is not environmentally friendly. Also, in this method tributyl tin azide is used for building tetrazole ring, which is highly toxic in nature and there is formation of hydrogen azide during this reaction, which is explosive in nature. Other disadvantages of this process are, it requires long reaction time, incomplete reactions, contamination of valsartan with a number of impurities of starting materials / intermediates and hence the resulting valsartan product is of lower chiral purity.
According to US Pat No.5,399,578, the second process for the preparation of Valsartan involves the reaction of 4-bromomethyl-2'-(l-triphenylmethyltetrazol-5-yl)biphenyl (VI) with L-valine benzyl ester to give N-[[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl]-methyl]-L-valine benzyl ester (VII), followed by reaction with valeroyl chloride to produce N-(l-oxopentyl)-N-[[2'-(l-triphenylmethyltetrazol-5-yl)[l,r-biphenyl]4-yl]methyl]-L-valine benzyl ester (VIII). Compound (VIII) is detritylated under acidic conditions to produce N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]-methyl]-L-valine benzyl ester (IX), which upon debenzylation using hydrogen in presence of Pd/C catalyst gives Valsartan. The process scheme is as shown in Scheme-II mentioned below:


A disadvantage of this process is the contamination with large amounts of various impurities especially organo tin impurities, in the penultimate intermediate stage of valsartan namely, (S)-N-[(2'-(lH-tetrazol-5-yl) biphenyl-4-yl-)methyl]-N-valeroyl-(L)-valine benzyl ester of the formula (IX) (benzyl valsartan ), during the tetrazole formation. The '578 patent does not disclose any purification method to remove the organo tin by products and other impurities obtained from benzyl valsartan. As a result of formation of

tin impurities, the catalyst (palladium on charcoal) gets poisoned during debenzylation
and hence require in large quantity for the reaction to reach completion.
Another disadvantage of the synthesis of valsartan disclosed in '578 patent is that the
valsartan and its various intermediates are highly susceptible to partial recemisation
during the reaction conditions or purification processes.
This route also has its disadvantages, such as, all the intermediates except the compound
(IX), are oily mass in nature, as a result of it requires multiple crystallizations to get the
pure product which overall affect on the yield of the product. Furthermore, the use of
very expensive hydrogenating catalysts like palladium on charcoal for debenzylation
makes the process economically unviable.
WO 2004101534 (RADL, S. et al, 2004) involves isolation of N-[[2'-(l-
triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-(L)-valine benzyl ester
(VII), in the form of hydrochloride salt which is then converted into Valsartan. This
particular process suffers disadvantages like low yield and low HPLC purity of
Valsartan. In addition to this, it also doesnot mentions anything about the chiral purity of
the Valsartan.
In US20060281801 (Ashok Kumar et al, 2006), 4-bromomethyl-2'-cyanobiphenyl (II),
& L-valine benzyl ester tosylate salt (X), are reacted in presence of potassium carbonate
and potassium iodide, in toluene and water at 50 to 55 °C for about 25 hours, to give (S)-
N- [(2'-cyanobiphenyl-4-yl) methyl]-(L)-valine benzyl ester hydrochloride (XI).
Tetrabutyl ammonium bromide was used as PTC for this reaction. Compound (XI), upon
reaction with valeroyl chloride, in presence of N, N-diisopropylethyl amine as a base,
with toluene as a solvent, gives (S)-N-[(2'-cyanobiphenyl-4-yl)methyl]-N-valeroyl-(L)-
valine benzyl ester(XII). Compound (XII) was reacted with sodium azide and tributyl tin
chloride, at reflux temperature for 45 hours to yield (S)-N- (l-benzyloxycarbonyl-2-
methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)-biphenyl-4-ylmethyl]-amine
[also called as benzyl valsartan] (XIII). This product is purified from ethyl acetate- n-
Hexane mixture. Product (XIII), upon debenzylation uses palladium charcoal and
hydrogen, yields Valsartan (I).
The schematic representation of this process is depicted in SCHEME-III given below: -


N,N Diisopropyl ethyl amine

VALSARTAN
As already mentioned above, this '801 also involves the problem of handling of sodium azide. At the higher temperature like 112 to 115 ° C , which is reflux temperature of toluene , and this high temperature range may be is hazardous can cause explosion. This scheme also involves additional stage of purification of benzyl Valsartan and debenzylation using palladium on charcoal & hydrogen gas which requires a special autoclave for the reaction.

As this reaction process uses very costly palladium on charcoal for debenzylation stage, which is not commercially viable at large scale reactions.
WO 2008/004110 (Budidet, S R et al, 2008) involves reaction of l-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (VI), (also called as TTBB), with L-valine methyl ester hydrochloride, in N,N-dimethyl formamide as a solvent, and Diisopropyl ethylamine as a base , at 45 to 50 ° C for about 16 hours. Upon work up, it is followed by treatment of ethyl acetate layer with oxalic acid dihydrate to give N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester oxalate salt ( Xa). The base is generated from compound (Xa), and it is reacted with valeroyl chloride in presence of N, N-Diisopropylethylamine as a base, in toluene as a solvent to get N-[ [2' -(1 -triphenylmethyltetrazole-5-yl] biphenyl-4-yl]methyl] -N-valery 1-L-val ine methyl ester (XI), as an oily mass. It was detritylated using anhydrous IPA.HC1 in methanol, used as a solvent, at 0 -5° C, to give N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)(l,l'-biphenyl]-4-yl]methyl-L-valine methyl ester (V). This methyl ester, upon hydrolysis with dilute sodium hydroxide solution, yields Valsartan (I). The schematic representation of this process is depicted in SCHEME-IV given below.: -
SCHEME-IV:-


This patent is silent about the HPLC purity of the crude condensation product between TTBB and L-valine methyl ester hydrochloride, and also about the purity of oxalate salt (Xa). In addition to this, the '110 is not describing any chiral purity of Valsartan and also not disclosing the impurities and its percentage in the final Valsartan. It does not disclose the polymorphic form obtained after following this process.

From the afore mentioned approaches, it thus appears that, in the current state of the art there is a need for an improved and commercially viable process for the synthesis of Valsartan and which is free from the afore mentioned disadvantages i.e. a process which can be undertaken on an industrial scale under milder/simpler conditions and environment friendly with good yield and chiral purity. Thus, there exists a need for an improved process for the preparation of valsartan, which is safe, cost effective and industrially advantageous and eliminates the disadvantages of the prior art, reported processes.
Object of the Invention
The object of the present invention is to provide a simpler, cost effective and safe process for the synthesis of Valsartan.
Another object of the present invention is to provide a Valsaratn with a good yield and enantiomeric purity.
Another object of the present invention is to provide an Efficient Ecofriendly, and Industrially scalable process for the synthesis of Valsartan.
Summary of the Invention:
The present invention relates to an improved process for preparing (S)-N- (l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine, (Valsartan, of Formula-I),


comprising the steps of:
a) Coupling of l-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of
Formula (VI), with L- valine methyl ester hydrochloride in dipolar aprotic
organic solvent, in presence of an inorganic base and copper halide as a catalyst to
get crude product, at 25° C to 45 ° C , preferably at 30 to 35 ° C
b) Reacting the crude product of step a. with malonic acid gives N-[[2'-(l-
triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester malonate
salt, of Formula (XVIII).

c) Treating N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine
methyl ester malonate salt, of Formula (XVIII), with a base in a solvent, to yield
pure N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine
methyl ester, of Formula (XIV).

XIV
d) Reacting N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester, of Formula (XIV), with valeryl chloride in presence of an inorganic base, and copper halide catalyst, in a solvent to produce N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester, Formula (XVI), at 0 to -10 ° C, preferably at -5 ° C.

XVI
e) Deprotecting N-[[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester, Formula (XVI) is done by using catalytic quantity of organic acid to produce N- (l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)(l,l'-biphenyl]-4-yl]methyl-L-valine methyl ester of Formula (XVII), at 10 to 20 ° C , preferably at 15 °C.


XVII
f) Treating the compound of Formula (XVII), with a base in a solvent to produce (S)-N- (1 -carboxy-2-methyl-prop-1 -yl)-N-pentanoyl-N- [2' -(1 H-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine, (Valsartan of Formula-I ) at 25 ° C to 35 ° C , preferably at 30 ° C

In another aspect of the present invention that it provides the malonate salt of N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester (XVIII) obtained by reacting the crude product of step a. involved in valsartan preparation as mentioned above with malonic acid. MeOv^O
COOH
COOH
XVIII Another aspect of the present invention is that it provides the process of preparing N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester malonate salt (XVIII), comprises, reacting crude N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester with an equimolar quantity of malonic acid


Further, the present invention also involves the use of copper halide catalyst for coupling TTBB with L-valine methyl ester hydrochloride and for acylation with valeroyl chloride.
Detailed description of the Invention
The present invention (Scheme V) relates to an improved process for preparation of an antihypertensive agent, (S)-N-( 1 -carboxy-2-methyl-prop-1 -yl)-N-pentanoyl-N-[2'(1H-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine, (valsartan), which comprises, selective reaction of 4-bromomethyl-2'-(l-triphenylmethyltetrazol-5-yl)biphenyl with L-valine methyl ester hydrochloride, in dipolar aprotic organic solvent, in presence of a base and catalyst to produce corresponding ester compound. It is subsequently reacted with malonic acid in a solvent to produce the corresponding malonate salt with high purity. The malonate salt is reacted with a base in a solvent, followed by reaction with valeroyl chloride in presence of an inorganic base, catalyst and solvent to obtain methyl ester, (XVI), which is de-protected using organic acid to produce (XVII), which is then hydrolyzed with an aqueous alkali solution to produce amorphous Valsartan, having chiral purity is 99.8%.
In the process of present invention, it is found that coupling of the TTBB with L-valine methyl ester hydrochloride is carried out in a solvent like dimethyl acetamide which is more economical in use.
Similarly the costly base N, N-di isopropyl ethylamine is substituted by a commonly available, less costlier inorganic base such as anhydrous potassium carbonate. The reaction time required to get this product is generally 16 to 20 hours period at about 50 ° C, which can be enhanced by using copper halide like cuprous iodide as a catalyst. The

resulting product N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] valine methyl ester is purified by making its malonic acid addition salt (XVIII) and which subsequently produces Valsartan with chiral purity of above 99.8%
Acylation of the free base, obtained from above malonic acid addition salt (XVIII), with valeroyl chloride is carried out using acetonitrile as a solvent, instead of toluene in the presence of commonly available, less costlier inorganic base like anhydrous potassium carbonate instead of N,N-di isopropyl ethyl amine .
According to the literature reported earlier, the recommended procedure for detritylation involves anhydrous isopropanolic HC1. In the present invention, the detritylation stage is carried out with methanol as a solvent and by using catalytic quantity of chlorosulphonic acid. The reaction is completed in about two hours at room temperature (28 to 35 ° C).
The methyl ester formed is hydrolyzed using aqueous sodium hydroxide to get crude valsartan. It is crystallized from ethyl acetate to give pure valsartan; having chiral purity more than 99.8%.
The product contains unwanted (R) enantiomer less than 0.2%. Valsartan is an amorphous form, and has OVI content well within the limits specified by the ICH guidelines.
The inventors have observed that coupling of l-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole (VI), (also called as TTBB), with L- valine methyl ester hydrochloride gets enhanced / catalysed upon using copper halides like copper chloride , copper bromide or Cuprous iodide , preferably cuprous iodide as a catalyst, The reaction is carried out under nitrogen atmosphere at room temperature and is completed in about 24 hours. The reaction can be carried out in solvents like N, N Dimethyl formamide, acetonitrile, N-methyl pyrrolidone, Hexamethyl phosphorous triamide, N,N Dimethyl acetamide, preferably N,N dimethyl acetamide as a reaction medium in presence of base like sodium carbonate, anhydrous potassium carbonate, preferably anhydrous potassium carbonate.

Since the crude product is impure, it is reacted with molar equivalent of malonic acid in an organic solvent selected from the alcohols such as ethanol, n-propanol, isopropanol , n-butanol, isobutanol , methylene chloride, ethyl acetate, or mixtures thereof, at a temperature of about -10 ° C to about 88° C and the product obtained is isolated by filtration and dried to get crystalline malonate salt. Malonate salt (XVIII) has HPLC purity above 99%.

The malonate salt (XVIII) is dissolved in a solvent like methylene chloride, ethyl acetate, chloroform, ethylene dichloride, carbon tetra chloride, toluene, preferably methylene chloride etc. and is treated with inorganic base such as aqueous solution of alkali metal carbonate like sodium carbonate, sodium bi carbonate, potassium carbonate, potassium bi carbonate, most preferably aqueous sodium bicarbonate in a solvent selected from methylene chloride, ethyl acetate, chloroform, ethylene dichloride, carbon tetra chloride, toluene, etc., separating the organic layer and concentrating to get pure N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester (XIV). The isolated product has HPLC purity of about 99%


N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester (XIV) is dissolved in acetonitrile and is reacted with valeroyl chloride in presence of an inorganic base like potassium carbonate and cuprous iodide as a catalyst at 0° C to -10 ° C, preferably at -5° C, in about one and a half hour period, and after reaction work up, to give N-[[2'-(l-triphenylmethyltetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-N-valeryl-L-valine methyl ester (XVI).

The other solvents can be used for acylation with valeryl chloride is selected from toluene, methylene chloride, chloroform, carbon tetra chloride, ethylene dichloride, ethyl acetate, acetonitrile, preferably acetonitrile in presence of inorganic base selected from the lithium carbonate, sodium carbonate, potassium carbonate, preferably anhydrous
potassium carbonate.
The trityl-protecting group of N- [[2'-(l-triphenylmethyltetrazol-5-yl)[l,l'-biphenyl]-4-yl] methyl]-N-valeryl-L-valine methyl ester (XVI) is deprotected by using catalytic amount of catalyst like chloro sulphonic acid, benzene sulphonic acid, methane sulphonic acid, glacial acetic acid, preferably chloro sulphonic acid to produce N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-L-valine methyl ester (XVII), which upon hydrolysis with a base selected from aqueous alkali and alkaline earth metal hydroxides, such as sodium, potassium, or barium hydroxide, preferably sodium hydroxide is converted to crude Valsartan. The crude product upon crystallization from ethyl acetate gives pure Valsartan. The solvents used for crystallization so of malonate

salt is selected from alcohols such as ethanol, n-propanol, isopropanol, isobutanol, methylene chloride, ethyl acetate or mixtures thereof, preferably ethyl acetate

Isolated valsartan is dried, at a temperature below 60 ° C, by air drying, vacuum drying, fluidized bed drying or by other similar drying methods of solids known to those skilled in the art or any combination of such drying techniques. Valsartan is having chiral purity above 99.8%.

The temperature at which reactions are carried out, reaction conditions, product isolation, and drying are very critical for obtaining highly enantiomeric excess, as at higher temperature, valsartan has tendency to racemize.
Valsartan obtained by following the process of the present invention has a chiral purity of at least 99.8% for the S-isomer, and less than about 0.2% for the R-isomer. This substantial yield and purity improvement caused by the present invention thus leads to an efficient, safe, and commercially viable synthetic process for the preparation of valsartan.

According to another aspect of the present invention, wherein valsartan produced, has less than 0.2% ((R) -N- Valeryl-N-( [2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]-methyl)-valine
Yet, according to another aspect of the present invention, wherein valsartan produced, has less than 0.2% of ((S)-N-butyryl-N-{[2'-(l-H-tetrazol-5-yl)-biphenyl-4-yl]-methyl}-valine).
This higher enantiomeric purity and yield starting from TTBB, constitutes a considerable technical advance with respect to the prior art processes.
All the likely residual solvents like ethyl acetate, methylene chloride, isopropanol, acetonitrile, n-Hexane, methanol, N,N-dimethyl acetamide are well below the limits as specified by ICH guidelines in Valsartan, obtained by the present invention.
SCHEME-V:

Although the invention has been described with reference to specific embodiments, this description is not meant to be construed in a limiting sense. Various modifications of the disclosed embodiments, as well as alternate embodiments of the said invention, will become apparent to persons skilled in the art upon reference to the description of the invention. It is therefore contemplated that such modifications can be made without departing from the true spirit or scope of the present invention as defined herein above and as exemplified and claimed herein below.
Examples
The following examples are presented for illustration only, and are not intended to limit the scope of the invention or appended claims.
Example
Step A
N- f[2)-(l-triphenvlmethvltetrazol-5-vn biphenvl-4-vll methvll-L-valine methyl ester (XIV): -
To a solution of N-triphenylmethyl-5-[4'-(bromomethyl) (l,l'-biphenyl) -2-yl]tetrazole ,
(also called as TTBB),(Formula-VI), (200g, 0.358 mol), in Dimethyl acetamide (1200 ml), freshly powdered anhydrous potassium carbonate (126.6 g, 0.315 mol) was charged under nitrogen atmosphere, at room temperature (28 ° C to 35 ° C). To it, cuprous iodide (10 g, 0.059 mol) was charged with stirring and at RT, charged L-valine methyl ester hydrochloride (68 g, 0.408 mol). The reaction mass was stirred at 28 ° C to 35 ° C for the next eight hours. The progress of the reaction was monitored by TLC. (Mobile phase for TLC, Ethyl acetate: n-Hexane, 20:80). As the reaction had not gone to completion, freshly powdered anhydrous potassium carbonate (20 g, 0.144 mol) was added to the reaction mass and stirred for the next 16 hours. (Total reaction time was 24 hours). The reaction mass was quenched in 6600 ml of cold water at 7 °C for about half an hour period and stirred for the next thirty minutes. Methylene chloride (600 ml) was charged and stirred at RT for the next fifteen minutes. The separation of layers was carried out.

The aqueous layer was back extracted with 2 x 400 ml of methylene chloride under stirring. The layers were separated. Methylene chloride layer was washed with 2 x 800 ml of water, followed by washing with 800 ml of saturated brine solution. The organic layer was dried over anhydrous sodium sulphate (10 g) and filtered off on a cotton plug. It was washed with MDC (50 ml). The filtrate was stirred with activated carbon (10 g ) for half an hour at RT, filtered off on a celite bed and concentrated under vacuum at 40- 45 ° C to give pale lemon yellow oil (217 g), having HPLC purity 90.06% as measured by HPLC area percentage.
The pale lemon yellow oily mass (215 g, 0.353 mol) was dissolved in ethyl acetate (1075 ml). To the clear lemon yellow solution at RT under stirring, malonic acid (38.5 g, 0.356 mol) was charged and stirred at RT for six hours. The reaction mass was cooled to 20 ° C and stirred for the next one hour. White solid was filtered off on buchner funnel, washed with 2 x 50 ml of cold ethyl acetate and dried in air oven at 50 ° C for eight hours to give N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester malonate salt, (XVIII)(173 g), having purity 98.25% as measured by HPLC area percentage.
To 10% sodium bicarbonate solution (550 ml), at RT, N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester malonate salt, (170 g) was charged in a lot wise manner, slowly for 15 minutes. Then methylene chloride (500 ml) was charged at RT and stirred for 15 minutes. The layers were separated. The aqueous layer was back extracted with 150 ml of methylene chloride. The combined MDC layer was washed with 2 x 500 ml of water, followed by washing with 300 ml of saturated brine solution. The organic layer was concentrated under vacuum to yield 152 g of N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester, (Formula-XIV), as a colorless oily mass, having purity 98.10% as measured by HPLC area percentage and 72% yield.

StepB N-f[2)-a-triphenvlmethvltctrazol-5-vnbiphenyl-4-vllmethvll-N-valervl-L-valine
methyl ester (XVI):-
To acetonitrile (1200 ml), N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-L-valine methyl ester (150 g, 0.246 mol) was charged and heated to 40 to 45 ° C to get a clear solution. It was cooled to RT. Freshly powdered anhydrous potassium carbonate (78 g 0.5643 mol) was charged to it and stirred at RT for ten minutes. Cuprous iodide (7.5 g) was added to it and cooled to 0° C to -5 ° C. To it, a solution of valeroyl chloride (48 g, 0.31 mol) in acetonitrile (50 ml) was charged for forty five minutes. The reaction mass was stirred at 0 to -5 ° C for the next two hours. The progress of the reaction was monitored by TLC. (Mobile phase for TLC, Ethyl acetate: n-Hexane, 20:80). As the starting material was completely converted in the next stage, the reaction mass was carefully quenched in ice cold water (3750 ml) and stirred for ten minutes. Methylene chloride (780 ml) was charged and the reaction mass was stirred at RT for thirty minutes. The layers were separated. The aqueous layer was back extracted with 2 x 250 ml of methylene chloride. The combined organic layer was washed with 2 xlOOO ml of water, washed with 10% sodium bicarbonate solution (440 ml) and with 5% oxalic acid solution (210 ml). The organic layer was dried over 50 g of anhydrous sodium sulphate. It was filtered and the filtrate was concentrated under vacuum at about 40 to 45 °C to obtain N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester (171 g), as colorless oil, having purity 97.56 % as measured by HPLC area percentage with quantitative yield. Step C: -
N-fl-oxopenrvn-N-frZ'-aH-tetrazol-S-vnri.r-biphenvll^-vllmethvI-L-vaHne methyl ester (XVID
In a two liter clean five necked RB flask, methanol (460 ml) was charged. To it, under stirring, charged N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester (170 g, 0.2454 mol) at RT. A solution of chlorosulphonic acid (1 ml ) in methanol (30 ml), was separately prepared, which was added to the flask in a drop wise manner, keeping temperature at 20 ° C to 25 ° C for about 15 minutes and stirred at RT for the next 90 minutes. The progress of the reaction was monitored by

TLC. [Mobile phase was Ethyl acetate: n-Hexane, 20:80]. As the starting material was completely reacted, the reaction mass was cooled to 0 to -5 ° C. The solid product was filtered off on buchner, washed with methanol (50 ml) and the filtrate was concentrated at 40 to 45° C on a rotary flash evaporator to obtain an oily residue. To it, charged 10% sodium carbonate solution (1230 ml) and stirred at RT for fifteen minutes. Charged n-hexane (468 ml) and stirred at RT for fifteen minutes. The layers were separated. The aqueous layer was washed with additional n-hexane (375 ml). The pH of the aqueous layer was adjusted to 8.1 to 8.3 using 15% aqueous acetic acid. Now the aqueous layer was washed with 2 x 375 ml of n-hexane. The layers were separated. To the aqueous layer, was added ethyl acetate (480 ml) and its pH was adjusted to 4.5 to 5.0 using 25% aqueous acetic acid and stirred at RT for ten minutes. The layers were separated. The aqueous layer was re-extracted with 480 ml of ethyl acetate. Both the ethyl acetate layers were combined and washed with 350 ml of water. Distilled off the solvent under vacuum at 50 ° C, to yield N- (l-oxopentyl)-N- [[2'-(lH-tetrazol-5-yl)(l,l'.biphenyl]-4-yl] methyl-L-valine methyl ester (111 g), as an oily mass, purity 96.21%, as measured by HPLC area percentage quantitative yield.
Step D: -
(S)-N-(l-carboxv-2-methvl-prop-l-vl)-N-pentanovI-N-[2,-(lH-tetrazole-5-vl)-biphenvll-4-vlmethvll-amine. (Valsartan , Formula-I)
In water (440 ml), N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester (110 g) was charged at RT. To it, 22% sodium hydroxide solution (250 ml) was charged and the reaction mass was stirred at RT (27 ° C to 32 ° C), for four hours. The progress of the reaction was monitored by TLC (mobile phase for TLC methanol: methylene chloride, 10:90). TLC showed that the reaction had gone to completion. To the reaction mass, methylene chloride (480 ml) was charged and stirred at RT for fifteen minutes. The layers were separated. The aqueous layer was extracted with 400 ml of n-Hexane. The pH of the aqueous layer was adjusted to 7.00 with 20% hydrochloric acid solution (380 ml). The aqueous layer was washed with methylene chloride (480 ml), followed by ethyl acetate (480 ml). To the aqueous layer, activated charcoal (5 g) was added and it was charcoalised at RT for 30 minutes. The solution was

filtered off on a celite bed and the pH of the aqueous layer was carefully adjusted to 2.00 to 2.20, using 20% dilute hydrochloric acid (340 ml of 20% dilute HC1 is required). A white solid valsartan separated out. The reaction mass was extracted with 2 x 480 ml of ethyl acetate. The ethyl acetate layer was washed with 2 x 1000 ml of water, followed by washing with 20% brine solution (1000 ml). The ethyl acetate layer was dried over anhydrous sodium sulphate (25 g) for half an hour and the filtrate was concentrated under vacuum on a rotary flash evaporator to obtain crude valsartan (100 g) as a white solid. It was dissolved in ethyl acetate (1000 ml) at about 50 °C. The clear solution was filtered off on celite bed, the filtrate was slowly cooled to 0 ° C and stirred at 0 ° C to -5 ° C for two hours. The product was filtered off on buchner, washed with ethyl acetate (2 x 25 ml) at -5 ° C and dried at 50 to 55 ° C under vacuum for 30 hours (till constant wt) to get 61 g of pure valsartan, having assay by HPLC 100.4%. Chiral purity was above 99.8% with 57.16% yield
XRPD of the product showed that it was in amorphous form. All the likely residual solvents, (determined by GC method), like ethyl acetate, methylene chloride, isopropanol, acetonitrile, n-Hexane, methanol, N,N-dimethyl acetamide were well below the limits specified by ICH guidelines.

Claims We Claim:
1. An improved process for preparing (S)-N- (l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine, (Valsartan, of

comprising the steps of:
b) Coupling of l-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazole of
Formula (VI), with L- valine methyl ester hydrochloride in dipolar aprotic
organic solvent, in presence of an inorganic base and copper halide as a catalyst to
get crude product, at 25° C to 45 ° C , preferably at 30 to 35 ° C
b) Reacting the crude product of step a. with malonic acid gives N-[[2'-(l-
triphenyImethyltetrazo 1-5 -yl)biphenyl-4-yl]methyl]-L-valine methyl ester malonate

XVIII
c) Treating N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester malonate salt, of Formula (XVIII), with a base in a solvent, to yield

pure N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine
methyl ester, of Formula (XIV).

d) Reacting N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester, of Formula (XIV), with valeryl chloride in presence of an inorganic base, and copper halide catalyst, in a solvent to produce N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester, Formula (XVI), at 0 to -10 ° C, preferably at -5 ° C.

e) Deprotecting N-[[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester, Formula (XVI) is done by using catalytic quantity of organic acid to produce N- (l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)(l,l'-biphenyl]-4-yl]methyl-L-valine methyl ester of Formula (XVII), at 10 to 20 ° C , preferably at 15 °C.


f) Treating the compound of Formula (XVII), with a base in a solvent to produce (S)-N- (l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine, (Valsartan of Formula-I ) at 25 ° C to 35 ° C , preferably at 30 ° C
2. The process of claim 1 a., wherein the dipolar aprotic organic solvent is selected from the group like N, N Dimethyl formamide, acetonitrile, N-methyl pyrrolidone, Hexa methyl phosphorous triamide, N,N Dimethyl acetamide, preferably N,N dimethyl acetamide.
3. The process of claim la., wherein the inorganic base is selected from the group like anhydrous sodium carbonate, anhydrous potassium carbonate, preferably anhydrous potassium carbonate.
4. The process of claim la, wherein the catalyst used is selected from the halides of copper like cuprous chloride, copper bromide, cuprous iodide, preferably cuprous iodide.
5. The process of claim lc, wherein the base is selected from aqueous solution of alkali metal carbonate like sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bi carbonate, preferably aqueous sodium bicarbonate in solvent like methylene chloride, ethyl acetate, chloroform, ethylene dichloride, carbon tetra chloride, toluene, preferably methylene chloride

6. A process according to claim 1 d, wherein solvent used for acylation with valeryl chloride, is selected from toluene, methylene chloride, chloroform, carbon tetra chloride, ethylene dichloride, ethyl acetate, acetonitrile, preferably acetonitrile.
7. A process according to claim Id, wherein the inorganic base, for acylation with valeryl chloride is selected from the lithium carbonate, sodium carbonate, potassium carbonate, preferably anhydrous potassium carbonate.
8. The process of claim Id, where in the catalyst used for acylation with valeryl chloride, is selected from the halides of copper like cuprous chloride, copper bromide, cuprous iodide, preferably cuprous iodide.
9. A process according to claim le, wherein the detritylation is carried out in presence of catalytic quantity of organic acid reagent like chloro sulphonic acid, benzene sulphonic acid, methane sulphonic acid, glacial acetic acid, preferably chloro sulphonic acid.

10. A process according to claim If, wherein base used for ester hydrolysis is selected from aqueous alkali and alkaline earth metal hydroxides, such as sodium, potassium, or barium hydroxide, preferably sodium hydroxide.
11. A process according to claim 1, wherein valsartan produced, has less than 0.2% ((R) -N- Valeryl-N-( [2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]-methyl)-valine ,
12. A process according to claim 1, wherein valsartan produced, has less than 0.2% of ((S)-N-butyryl-N-{[2'-(l-H-tetrazol-5-yl)-biphenyl-4-yl]-methyl}-valine).
13.A process according to claim 1, wherein step f, the crude product is crystallized from ester solvent like ethyl acetate, propyl acetate, butyl acetate, preferably ethyl acetate, to give (S)-N- (1 -carboxy-2-methyl-prop-1 -yl)-N-pentanoyl-N-[2' -(1 H-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine, ( Valsartan , of Formula-I), having assay by HPLC 98 % to 102% and chiral purity is above 99.8%.

14. The process of preparing N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-
yl]methyl]-L-valine methyl ester malonate salt (XVIII), comprises,
reacting crude N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester with an equimolar quantity of malonic acid

15. The process of claim 14, wherein solvent used for the formation of malonate salt is selected from alcohols such as ethanol, n-propanol, isopropanol, isobutanol, methylene chloride, ethyl acetate or mixtures thereof, preferably ethyl acetate.
16. The process of claim 14, wherein the dried malonate salt is reacted with aqueous solution of an inorganic base like sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably aqueous sodium bicarbonate, which gives pure N-[t2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester, having HPLC purity more than 98%
17. The use of copper halide catalyst for coupling TTBB with L-valine methyl ester hydrochloride and for acylation with valeroyl chloride.
18. The malonate salt of N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-valine methyl ester (XVIII) obtained by reacting the crude product of step a. of claim 1 with malonic acid.


19. The process of claim 1, wherein Valsartan of formula I obtained is of amorphous form.
20. A process according to any of the preceding claims as substantially herein described
with reference to the examples.