FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10) IMPROVED PROCESS FOR THE PREPARATION OF VALSARTAN
UNICHEM LABORATORIES LIMITED,
A COMPANY REGISTERED UNDER THE INDIAN COMPANIES ACT,
1956, HAVING ITS REGISTERED OFFICE LOCATED AT UNICHEM
BHAVAN, PRABHAT ESTATE, OFF S. V. ROAD, JOGESHWARI
(WEST), MUMBAI - 400 102, 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 VALSARTAN
FIELD OF THE INVENTION
The present invention relates to process for the preparation of intermediates of valsartan. particularly in situ preparation of compound of formula (XVI) [i.e. (N-[[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester] and its further conversion into valsartan, having chiral purity above 99.8%.
BACKGROUND OF THE INVENTION
Valsartan is chemically described as (S)-N- (l-carboxy-2-methylprop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine: of Formula (I)

It is a non-peptide, angiotensin II antagonist acting on the ATI receptor subtype. It is very much useful for the prophylaxis and treatment of diseases or the conditions, which may be inhibited by blocking the ATI receptor, such as high blood pressure and cardiac insufficiency. Valsartan, marketed as 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 is also well known.

Synthesis of Valsartan and its pharmaceutically acceptable salts has been disclosed by Ciba-Geigy in US Patent no. 5,399,578.
Various processes for the synthesis of valsartan and its intermediates are provided in US 6,271,375 (Marco V. et al; 2003) which relates to a process for direct ortho metalation of (tetrazole-5-yl) benzene useful for the preparation of 2-substituted-l-(tetrazole-5-yl) benzenes, intermediates for angiotensin II antagonists.
Also, the processes for the preparation of intermediates of Valsartan is described under U.S. Patent Application Publication Nos. 2006/0069268 (Donatienne D., et al) and 2009/0203921 (Ira S & et al; 2009) Al.
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 valeroyl chloride to get 2-amino-N- [2!-cyanobiphenyl-4-yl) methyl]-2-methyl-N-valeryl propionate (IV). Compound (IV) upon treatment with tri-n-butyi tin azide gives N- (l-oxopentyl)-N- [[2'-(lH-tetra2ol-5-yl)[l,1 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 environmental 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,l'-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,1-biphenyl]-4-yl]-methyI]-L-vaIine 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 in nature, as a result, 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'-(I-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 does not mention the chiral purity of Valsartan.
In US20060281801 (Ashok Kumar et al, 2006) , 4-bromomethyl-2'-cyanobiphenyl (11), and 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-yI)-N-pentanoyI-N-[2'-(lH-tetrazoI-5-yI)-biphenyI-4-yImethyl]-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-HI given below: -


VALSARTAN As already mentioned above, this '801 also involves the problem of handling sodium azide. At high temperatures such as 112- 115 °C, which is reflux temperature of toluene, this high temperature range may be hazardous and can cause explosion. The use of

tributyl tin chloride and sodium azide, in situ generates tributyl tin azide, which itself is hazardous and leads to tin contamination in the final product. 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, it is not commercially viable in large scale reactions.
WO 2008/004110 (Budidet, S R et al, 2008) involves reaction of l-triphenylmethyl-5-[4!-(bromomethyl)biphenyI-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'-(l-triphenylmethyltetrazole-5-yl]biphenyl-4-yl]methyl]-N-valeryl-L-valine methyl ester (XI), as an oily mass. It was detritylated using anhydrous IPA.HCl in methanol as a solvent at 0 -5° C to give N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)(l,1-bipheny]]-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.: -
SCHEMEIV-

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 does not describe the chiral purity of Valsartan, does not disclose the impurities, its percentage in the final product and 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, which is free from the afore mentioned disadvantages i.e. a process which can be undertaken on an industrial scale under milder/simpler conditions, is environment friendly, gives good yield and chiral purity. Thus, there exists a need for an improved process for the preparation of valsartan, which is safe, cost effective, 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 Valsartan with high yields and excellent enantiomeric purity
Another object of the present invention is to provide a simpler, cost effective and safe process for the synthesis of Valsartan.
Another object is to provide an efficient, eco-friendly, 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-y1-N-pentanoyl-N-[2'-(lH-tetrazole-5-y])-biphenyl]-4-ylmethy1]-amine,
(Valsartan, Formula-I)

comprising:
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
b. crude product (N-[[2'-(l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl]methyl]-L-
valine methyl ester XIV) obtained in la) in situ acylated using valeroyl chloride
in presence of an inorganic base, cuprous halide and a phase transfer catalyst
c. deprotection of the trityl group of a compound N- [[2"-(l-
triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl
ester of Formula (XVI) obtained in step b) by catalytic quantity of organic
d. treating the compound N- (l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)(l,1'-
biphenyl]-4-yl]methyl-L-valine methyl ester of Formula (XVII) obtained in step
c), with an aqueous inorganic 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).
comprising:

a. coupling of l-triphenylmethyl-5-[4'-(bromomethyl)biphenyl-2-yl]tetrazo)e 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 at 25° C to 45 ° C ,
preferably at 30°C to 35°C
b. crude product (N-[{2'-l-triphenylmethyltetrazol-5-yl)biphenyl-4-yl)methyl)-L-valine
methyl ester XIV) obtained in la) in situ acylated using valeroyl chloride in presence of
an inorganic base, cuprous halide and a phase transfer catalyst at 0 to -10 ° C, preferably
at -5 ° C;
c. deprotection of the trityl group of a compound N- [[2'-(l-triphenylrnethyltetrazoI-5-yl)
biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester of Formula (XVI) obtained in
step b) by catalytic quantity of organic acid at 28 to 35 ° C , preferably at 30 to 32 ° C .
d. treating the compound N- (lo-xopentyl)-N-[[2'-(lH-tetrazo]-5-yl)(l,r-biphenyl]-4-
yI]methyI-L-vaIine methyl ester of Formula (XVII) obtained in step c), with an aqueous
inorganic base to produce (S)-N- (l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N- [2!-
(lH-tetrazole-5-yl)-biphenyl]-4-y]methy]]-amine, (Valsartan of Formula-I) at 25 ° C !o
35 ° C, preferably at 30 ° C
Further, the present invention relates to a novel in-situ process for the synthesis of intermediate of Valsartan, of Formula XVI, from TTBB (Formula-VI) and its further conversion to Valsartan (Formula-I), having chiral purity above 99.8%.
DETAILED DESCRIPTION OF THE INVENTION
The present invention (represented by Scheme V), relates to an improved process for preparation of an antihypertensive agent, (S)-N-(1-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'(lH-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine (i.e. Valsartan), which comprises selective reaction of 4-bromomethyI-2,-(l-triphenylmethyhetrazol-5-yl)biphenyl (TTBB) with L-valine methyl ester hydrochloride in dipolar aprotic organic

solvent, in presence of a base and a catalyst to produce the corresponding ester compound, that is in situ reacted with valeroyl chloride in presence of an inorganic base, a phase transfer catalyst, cuprous halide as a catalyst and a solvent to obtain methyl ester, (XVI), which is de-protected using organic acid to produce compound of formula (XVII), which is then hydrolyzed with an aqueous alkali solution to produce crude Valsartan. It is crystallized twice from a solvent like ethyl acetate to get Valsartan, having chiral purity above 99.8%.
In one aspect of the present invention is the processes for preparing the compound of Formula XVI, from TTBB (Formula-VI), having HPLC purity about 95 % and its further conversion to valsartan (Formula-I), having chiral purity above 99.8%.
In another aspect of the present invention is to provide process for synthesis of intermediate of valsartan, having Formula (XVI), in situ from TTBB (i.e. Formula VI). Further more aspect of the present invention is to provide a simpler, cost effective and industrially safe process for the synthesis of Valsartan, using the intermediate of Formula (XVI).
According to the present invention, the coupling of the TTBB with L-valine methyl ester hydrochloride is carried out in a solvent like N, N Dimethyl formamide, acetonitrile, N-methyl pyrrolidone, Hexamethyl phosphorous triamide, N,N Dimethyl acetamide, preferably N,N dimethyl acetamide, which is more economical to use, and in presence of commonly available, relatively cheaper inorganic base like anhydrous sodium carbonate. anhydrous potassium carbonate, lithium carbonate, preferably anhydrous potassium carbonate under nitrogen atmosphere at 25° C to 45 ° C , preferably at 30°C to 35°C and is completed in about 24 hours which is monitored on TLC & HPLC. The catalyst used in this coupling stage is like cuprous chloride , cuprous bromide or cuprous iodide , preferably cuprous iodide which helps to enhance the reaction rate

The resulting product, N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] valine methyl ester (XIV) is reacted in situ with valeroyl chloride, in the presence of a phase transfer catalyst, inorganic base and cuprous halide as a catalyst to get N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl)-N-valeryl-L-valine methyl ester of Formula (XVI).
The phase transfer catalyst may be selected from tetrabutyl ammonium bromide,
tetrapropyl ammonium bromide, tributyl benzyl ammonium bromide,
tetraethylammonium bromide, tetraoctyl ammonium bromide, tetrabutyl ammonium
hydrogen sulphate, benzyltrimethylammonium chloride, benzyl triethyl ammonium
chloride. tetrabutylarnmonium acetate, tetrabutylammonium iodide,
ethyltriphenylphosphonium bromide, and ethyltriphenylphosphonium iodide, preferably tetrabutylammonium bromide used as a phase transfer catalyst. The cuprous halide used for this reaction are like cuprous chloride, cuprous bromide, and cuprous iodide, preferably cuprous iodide which helps to facilitate this in-situ reaction. The required inorganic base for this reaction is selected from the lithium carbonate, sodium carbonate, potassium carbonate and preferably anhydrous potassium carbonate. The in-situ alkylation reaction may be carried out at a temperature between 0 to -10 ° C, preferably at -5 ° C.
The trityl-protecting group of N- [[2'-(l-triphenylmethyltetrazol-5-yl)[l,1-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 at 28 to 35 ° C , preferably at 30 to 32 ° C , for about 15 hours to produce N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-L-valine methyl ester (XVII).

Compound of Formula (XVII), may be isolated from reaction mixture by performing methods like layer separation, concentration, precipitation, filtration, decantation, distillation or a combination there of.
The methyl ester (XVII) formed in the present invention, which upon hydrolysis with a base selected from aqueous alkali and alkaline earth metal hydroxides, such as Jithium . sodium, potassium, or barium hydroxide, preferably sodium hydroxide is converted to crude Valsartan.
This crude product is crystallized twice from ester solvent like ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isopentyl acetate, butyl acetate, preferably ethyl acetate, to give (S)-N- (l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-f2'-(lH-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine (i.e. Valsartan of Formula-I ), having assay by HPLC 98 % to 102% and chiral purity above 99.8%
Valsartan product obtained as described above is dried by air drying in oven at 55° C for eight hours, passed through 100-mesh sieve and further re-dried at atmospheric pressure of about 70 to 75 ° C for about twenty hours The temperatures at which reactions and drying are carried out are very critical for obtaining high enantiomeric excess, as at higher temperature, valsartan has a 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.
Valsartan' obtained by this complies as per USP specification. Valsartan is in amorphous form and has OVI content well within the limits specified by the ICH guidelines.

The inventors have devised a telescopic approach to prepare Valsartan, wherein the number of steps have been reduced compared to a process reported in the literature related to Valsartan preparation
The substantial yield and purity improvement observed in the present invention lead to an efficient, safe, elegant, enantiomerically pure and commercially viable synthetic process for the preparation of valsartan.
According to another aspect of the present invention, 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, vaJsartan produced has less than 0.2% of ((S)-N-butyryl-N-{[2'-(l-H-etrazol-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. 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:


In the following section, the embodiments are described by way of examples to illustrate the process of invention. However, these do not limit the scope of the present invention. Several variants of these examples would be evident to persons ordinarily skilled in the art.

EXAMPLES Example 1
Preparation of N- [[2'-(l-triphenylmetbyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester (VLS-II )
In a three liter five necks RB flask, charged 500 ml of N, N, dimethyl acetamide at RT under nitrogen atmosphere. Charged 200 g of TTBB under stirring and stirred the reaction mass for ten minutes. Charged 126.6 g of freshly powdered anhydrous potassium carbonate, 10 g of cuprous iodide and stirred for five minutes at the same temperature. Charged 68 g of L- Valine methyl ester hydrochloride at RT and 300 ml of N,N Dimethyl acetamide, exotherm is observed. Temperature goes up by about 7 to 8 0 C. The reaction mass is stirred at 28 to 35 ° C for 24 hours. The progress of the reaction is monitored by TLC. A sample of the reaction mixture was also analyzed by HPLC. It showed unreacted TTBB 0.053 % and formation of coupled product VLS-I, 91.37 %. In the same reaction mass, charged first lot of 40 g of freshly powdered anhydrous potassium carbonate, followed by 25 g of Terra Butyl Ammonium Bromide (TBAB). Then, charged 5 g of cuprous iodide and the reaction mass is cooled to -5 ° C using (ice-salt) mixture. Start dropwise addition of first lot of 40 g of valeroyl chloride to the above solution at -5 ° C to -10 ° C in about twenty minutes, exothermic reaction is observed and stirred at -5 to 0 ° C for next ten minutes. Charged second lot of 20 g of freshly powdered anhydrous potassium carbonate, added second lot 20 g of valeroyl chloride to it during ten minutes and the reaction mass is stirred at -5 to 0 ° C for ten minutes. Charged third lot of 20 g of anhydrous potassium carbonate at 0 to -5 ° C, added third lot of 20 g of valeroyl chloride to it in ten minutes and the reaction mass is stirred at -5 ° C for fifteen minutes. Charged fourth lot of 10 g of freshly powdered anhydrous potassium carbonate, followed by 20 g of valeroyl chloride and reaction mass is stirred at -5 ° C for ten minutes. Charged fifth lot of 5 g potassium carbonate and 5 g of valeroyl chloride at -5 ° C and

stirred for next 30 minutes. The progress of the reaction is monitored by TLC. In TLC, Stage VLS-I was Jess than about 3%. The sample of the reaction mass is also sent for HPLC analysis for confirmation of results. It showed conversion to stage VLS-f I to be 84.81% and unreacted Stage VLS -I was 3%. Continued stirring for next thirty minutes. A sample was sent for inprocess HPLC analysis. Conversion is 84.81% and unreacted VLS-I was 3.0%. The reaction mass is slowly quenched in 3600 ml of water and stirred for next ten minutes. The reaction mass is extracted with 1080 ml of MDC. The organic layer is separated. The aqueous layer is back extracted with 800 ml of fresh MDC. The combined organic layer is washed with 2 x 1500 ml of water. The organic layer is washed with 600 ml of 10% sodium bicarbonate solution, followed by 300 ml 5% oxalic acid solution. The organic layer is washed with 800 ml of freshly prepared, saturated sodium chloride solution, dried over 30 g of anhydrous sodium sulphate, filtered and then distilled off under vacuum at 40 to 45 ° C to get 320 g of title compound, as light brown oily mass, having HPLC Purity = 88.65 % in quantitative yield,
Example 2
Preparation of N-(l-oxopentyl-(N-[[2'-(lH-tetrazol-5-yl)(l,1'-biphenyl)-4yl)methyl-L-valine methyl ester (XVII) ( VLS-III) :-
In a two liter five necked RB flask, methanol (1000 ml) was charged. To it, under
stirring, charged N- [[2'-(l-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl ester (320 g, 0.4625 mol) at RT. The reaction mass is heated to about 40 ° C to get clear solution and then cooled it to 10 to 15 ° C. A solution of chlorosulphonic acid (0.5 ml) in methanol (10 ml), was prepared separately and it is added to the flask in a drop wise manner, keeping the temperature at ] 0 ° C to ] 5 ° C in about 15 minutes and stirred at RT (28° C to'35 ° C, preferably at 30 ° C to 32 ° C), for the next fifteen to twenty hours. The progress of the reaction was monitored by TLC. [Mobile phase Ethyl acetate: n-Hexane, 20:80], A sample was sent for in process reaction monitoring by HPLC. (unreacted acylation product VLS-II was 0.22%). As the starting

material has completely reacted, the reaction mass is cooled to 0 to -5 ° C. The solid product, triphenyl methyl ether is filtered off on buchner, washed with chilled methanol (100 ml) and the filtrate is concentrated at 40 to 45° C on a rotary flash evaporator lo obtain 215 g of an oily residue. To it, charged 10% sodium carbonate solution (1546 ml) and stirred at RT for fifteen minutes to get a clear solution . Charged n-hexane (600 ml) and stirred at RT for fifteen minutes. The layers were separated. The aqueous layer is washed with additional n-hexane (600 ml). The pH of the aqueous layer is adjusted to 8.1 to 8.3 using 25% aqueous acetic acid. ( 220 ml of 25% aqueous acetic acid is required ). Now the aqueous layer is washed with 2 x 600 ml of n-hexane. The layers are separated. To the aqueous layer, ethyl acetate (600 ml) is added and its pH is adjusted to 4.5 to 5.0 using 25% aqueous acetic acid followed by glacial acetic acid and stirred at RT for ten minutes. (750 ml of 25% acetic acid, followed by 300 ml of glacial acetic acid are required for pH adjustment) and the layers were separated. The aqueous layer is re-extracted with 600 ml of ethyl acetate. Both the ethyl acetate layers are combined and washed with 2 x 1200 ml of warm water of about 40 -45 ° C, dried over 30 g of anhydrous sodium sulphate, distilled off the ethyl acetate under vacuum at 50 ° C to yield N- (l-oxopentyl)-N- [[2'-(lH-tetrazol-5-yl)(l,r-biphenyl]-4-yl] methyl-L-valine methyl ester (158 g), as an oily mass, in a quantitative yield, having HPLC purity 92.29 %, as measured by HPLC area percentage. It is also termed as VLS-III.
Example 3
Preparation of (S)-N-(l-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-
tetrazole-5-yI)-biphenyl]-4-yImethyl]-amine , (Valsartan , Formula-I)
In Two liter RBF, charged VLS-III (155 gms) and 341 ml of 22% sodium hydroxide
solution followed by 690 ml water. The reaction mass was stirred at RT ( 28 to 35 ° C).
for next fifteen hours. The progress of the reaction monitored by TLC. A sample was
sent for in process reaction monitoring by HPLC (Starting material was 0.14%). Charged
541 ml of n-Hexane and stirred for next ten minutes, followed by layer separation.

Charged the aqueous layer in RB flask, Charged 541 ml of MDC to it, stirred at RT for ten minutes. The layers were separated. Charged aqueous layer in to RB flask, added 540 ml of ethyl acetate to it and adjusted the pH of the reaction mass to 7.0- 7.1 using 25 ml of 7% HC1 solution. Layers were separated. Charged the aqueous layer in RB flask, washed with 540 ml of MDC and 540 ml of ethyl acetate and the layer separation was carried out. Charged the aqueous layer in to the three liter RB flask, charged 540 ml of ethyl acetate to it and adjusted the pH of the reaction mass to 1.5 to 2.0 using 750 ml of 7 % HC1. Stirred the reaction mass at RT for ten minutes and carried out the layer separation. The aqueous layer is back extracted with 400 ml of ethyl acetate. The combined ethyl acetate layer was washed with 2 x 1300 ml of warm water at 40 to 45 ° C. Carried out layer separation. The ethyl acetate layer was washed with 1100 ml of saturated brine solution. Organic layer is dried over 30 gm of anhydrous sodium sulfate. Ethyl acetate was distilled off under vacuum, at about 50 to 55 ° C to get oily mass. Oily mass is replenished with 3 x 75 ml of n-Hexane. White solid is obtained in the flask. Wt. of white solid = 130 gm. To this flask, charged 1000 ml of ethyl acetate, the reaction mass was heated to 50- 55 ° C to get a clear solution and stirred at this temperature for 15 minutes. Charged 15 g of activated carbon and stirred for fifteen minutes. Carbon is filtered off on a Celite bed. The filtrate is slowly cooled to RT under stirring, stirred at 32 ° C for two hours and the reaction mass is cooled to 0 to 5 ° C and stirred for two hours. The reaction mass is filtered off at 0 ° C. The solid is washed with 70 ml of chilled ethyl acetate. Wet wt. of crude valsartan is 160 g. It is dried at 55 to 60 ° C in air oven for about ten hours to give 87 g of crude valsartan, having HPLC purity 99.40 % This product was crystallized second time from ethyl acetate as follows. In a two liter capacity RBF, charged 564 ml of ethyl acetate, 87 gm of above prepared crude valsartan under stirring and the temperature was raised to 50 to 55 ° C. To the clear solution, charged 5 gm of activated carbon (Neutral grade), stirred at 55 ° C for ten minutes. The solution is filtered off while hot through a Celite bed, washed the celite bed with 50 ml of hot ethyl acetate. The filtrate was slowly cooled to RT under stirring,

stirred at 30 ° C for two hours. The reaction mass was cooled to 0 to 5 ° C, stirred at this temperature for next two hours. The reaction mass is filtered off on buchner at 0 ° C, washed with 2 x 50 ml of chilled ethyl acetate. Unload the wet cake in a glass tray. The product is dried in air drying oven at 55° C for eight hours. This material is passed through 100-mesh sieve, and further re dried at 70 to 75 ° C till constant weight. About twenty hours of drying at 70 to 75 ° C is required. Yield of pure valsartan was. 65 gm (HPLC purity 99.74%). The overall yield of the reaction from TTBB is 43.84%; The material complies as per USP ( chiral purity 99.91%, and all the other impurities are below 0.1%.) . XRPD of the product showed that it is in the amorphous form. All the likely residual solvents, (determined by GC method), like ethyl acetate, methylene chloride, isopropanol, n-Hexane, methanol, N,N-dimefhyl acetamide were well below the limits specified by ICH guidelines.

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


comprising:
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.
b. crude product (N-[[2'-(]-tripher)y]methyJtetrazol-5-yl)biphenyl-4-yl]methyl]-L-
valine methyl ester XIV) obtained in la) in situ acylated using valeroyl chloride
in presence of an inorganic base, cuprous halide and a phase transfer catalyst
c. deprotection of the trityl group of a compound N- [[2'-(l-
triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl]-N-valeryl-L-valine methyl
ester of Formula (XVI) obtained in step b) by catalytic quantity of organic acid
d. treating the compound N- (l-oxopentyl)-N-[[2'-(lH-tetrazoI-5-yl)(l,1-biphenylj-
4-yl]methyl-L-valine methyl ester of Formula (XVII) obtained in step c); with an
aqueous inorganic base 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)
2. An improved process of claim 1 a), wherein the dipolar aprotic organic solvent comprises N,N Dimethyl formamide, Acetonitrile, N-methyl pyrrolidone, Hexa methyl phosphorous triamide, N,N Dimethyl acetamide, preferably N,N dimethyl acetamide.

3. An improved process la), wherein the inorganic base is selected from anhydrous sodium carbonate, anhydrous potassium carbonate, preferably anhydrous potassium carbonate, and catalyst selected from cuprous halides like cuprous chloride, cuprous bromide, cuprous iodide, preferably cuprous iodide
4. An improved process la), wherein the reaction temp is of 25° C to 45 ° C , preferably 30°C to 35°C
5. An improved process of claim lb), wherein the inorganic base selected from lithium carbonate, sodium carbonate, potassium carbonate, preferably anhydrous potassium carbonate, and copper halides are like cuprous chloride, cuprous bromide, cuprous iodide, and preferably cuprous iodide.
6. An improved process of claim lb), wherein the phase transfer catalyst selected from the group such as tetrabutyl ammonium bromide, tetrapropyl ammonium bromide. tributyl benzyl ammonium bromide, tetraethylammonium bromide, tetraoctyl ammonium bromide, tetrabutyl ammonium hydrogen sulphate, benzyltrimethylammonium chloride, benzyl triethyl ammonium chloride. Tetrabutylammonium acetate, tetrabutylammonium iodide, ethyltriphenylphosphonium bromide, ethyltriphenylphosphonium iodide, preferably tetrabutylammonium bromide
7. An improved process of claim lb), wherein the reaction is carried out at 0 to -10 °C, preferably at -5 ° C;
8. An improved process of claim lc), wherein the detritylation is carried out in presence of catalytic quantity of organic acid reagent selected from the group such as chloro sulphonic acid, benzene sulphonic acid, methane sulphonic acid, glacial acetic acid, preferably chloro sulphonic acid.
9. An improved process of claim lc), wherein the detritylation is carried out at 28 to 35 ° C , preferably at 30 to 32 ° C .
10. An improved process according to claim 1d), 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. An improved process according to claim 1d), wherein the hydrolysis is carried out at 25 ° C to 35 ° C, preferably at 30 ° C
12. An improved process according to claim 1, wherein valsartan obtained has less than 0.2% of ((R) -N- Valeryl-N- ([2'-(lH-tetrazol-5-yl)-biphenyl-4-yl]-methyl)-valine)
13. An improved process according to claim 1, wherein valsartan obtained has less than 0.2%of((S)-N-butyryl-N- {[2'-(l-H-tetrazol-5-y])-biphenyl-4-y]]-methy]}-valine)
14. An improved process according to claim 1, wherein the crude product is crystallized twice from ester solvent like ethyl acetate, propyl acetate, isopropyl acetate, t-butyl acetate, isopentyl acetate, butyl acetate, preferably ethyl acetate, to give (S)-N- (1-carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazole-5-yl)-biphenyl]-4-ylmethyl]-amine (i.e. Valsartan of Formula-I), having assay by HPLC 98 % to 102% and chiral purity above 99.8
15. An improved process according to claim 1, wherein valsartan is dried by air drying in oven at 55° C for eight hours, passed through 100-mesh sieve and further re-dried at atmospheric pressure of about 70 to 75 ° C for about twenty hours
16. An improved process according to claim 1, wherein valsartan produced with high enantiomeric purity of 99.8%.
17. An improved process according to claim 1, wherein Valsartan obtained is amorphous form.
18. A process according to any of the preceding claims substantially is herein described with reference to the examples.