FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of N-(l-oxopentyl)-N-[[2’-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-L-valine of Formula I.

BACKGROUND OF THE INVENTION
N-(l-oxopentyl)-N-[[2’(lH-tetrazol-5-yl)[l,-biphenyl]-4-yl]-methyl]-L-valines, generically known as Valsartan, is a nonpeptide, orally active, and specific angiotensin II antagonist acting on the ATi receptor subtype. Valsartan is used for the treatment of hypertension and is marketed as the free acid under the name DIOVAN®.
Ciba-Geigy has disclosed Valsartan and its pharmaceutically acceptable salts first time in US Patent No. 5,399,578.
US 5,399,578 describes two different processes for the preparation of Valsartan. One of the processes involves the reaction of 4-bromomethyl-2’-cyanobiphenyl (I) with L-valine methyl ester, followed by treatment with valeryl chloride to produce 2-amino-N-[(2’cyanobiphenyl-4-yl)methyl]-2-methyl-N-valerylpropionate (IV). Compound (IV) is treated with tri-n-butyltin azide to give N-(l-oxopentyl)-N-

[[2’-(lH-tetrazol-5-yl)[l,l’biphenyl]-4-yl]-methyl-L-valine methyl ester (V), which is then hydrolyzed under alkaline condition to give finally Valsartan. The process is as shown in Scheme-I below: SCHEME I:

This patent further describes a variant of the above method with use of the 2-cyano-4-formylbiphenyl instead of 4-bromomethyl-2’-cyanobiphenyl (I). The disadvantage of the above-mentioned methods is the use of toxic tributyl stannyl azide to build the tetrazol ring and high demands on safety in order to prevent an explosion due to the formation of hydrogen azide during the reaction.

According to US 5,399,578, Valsartan can also be prepared by reaction of 4-bromomethyl-2’-( 1 -triphenylmethyltetrazol-5-yl)biphenyl (VI) with L-valine benzyl ester to produce N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]-methy]-L-valine benzyl ester (VII), followed by treatment with valeryl chloride to produce N-(l-oxopentyl)-N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)[l,1’-biphenyl]-4-yl]-methyl]-L-valine benzyl ester (VIII). Compound (VIII) is deprotected under acidic conditions to produce N-(l-oxopentyl)-N-[[2’-(lH-tetrazol-5-yl)[l,r-biphenyl]-4-yl]-methyl]-L-valine benzyl ester (IX), which is then hydrogenated in presence of Pd/C catalyst to give finally Valsartan. The process is shown in scheme II, below: SCHEME II:


A major disadvantage of the above method is the fact that all the intermediates except the compound (IX) are oily substances, which cannot be crystallized. The final product is therefore, strongly contaminated with undesired compounds and required repeated crystallization, resulting in a significant loss of yield. Further the use of expensive hydrogenating catalysts like palladium charcoal for debenzylation is not viable for the commercial point of view.
WO 2004/101534 describes a variation to the above process of preparation of Valsartan, which involves isolation of N-[[2’-( 1 -triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methy]valine benzylester (VII) in the form of hydrochloride salt. The hydrochloride salt is further converted to Valsartan shown in the above method.
This process also suffers with major disadvantage of low yield and low purity of N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methy]valine benzylester (VII), which is the key intermediate in the preparation of Valsartan. The reason for such low yield is not described in any of the prior art. We have now found that the reason for the low yield is that the triphenylmethyltetrazol group is highly unstable towards the strong acidic conditions (hydrochloric acid) and under goes hydrolysis to generate undesired impurities, which gets carried forward as impurities in Valsartan (I). Removal of these impurities in the final stage is often proved to be difficult and requires repeated crystallizations, which finally results in the low yield of compound of Formula I.

In the process of the present invention, we have now found that, N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methy]valine methylester (X) can be purified by making its crystalline oxalic acid addition salt (Xa), and can be used as such to produce Valsartan of high purity and yield.
OBJECTIVE OF INVENTION
The main objective of the present invention is to provide a simple and cost-effective process for the preparation of Valsartan of high purity on commercial scale.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides a method for the preparation of N-(l-oxopentyl)-N-[[2’-(lH-tetrazol-5-yl)[l,1’-biphenyl]-4-yl]methyl]-L-valine of Formula I.

which comprises;
i) treating N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methy]-
L-valine methyl ester (X)

iii) de-protecting the compound (XI) using anhydrous acidic reagent to produce N-(l-oxopentyl)-N-[[2’-(l-H-tetrazol-5-yl)[l,1’-biphenyl]-4-yl]methyl-L-valine methyl ester (V)

iv) treating the compound (V) with base in a solvent to produce N-(l-oxopentyl)-N-[[2’-(lH-tetrazol-5-yl)[l,l’-biphenyl]-4-yl]methyl]-L-valine (I).
DETAILED DESCRIPTION OF THE INVENTION
N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]-methy]valine methyl ester (X) is prepared according to the process described in US 5,399,578. Reacting N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methy]valine methyl ester (X) with a molar equivalent of oxalic acid or its hydrates selected from oxalic acid dihydrate in an organic solvent selected from alcohols such as ethanol, n-propanol, isopropanol, n-butanol, isobutanol, methylene chloride, ethylacetate or mixtures thereof, at a temperature of about -20°C to about 70°C. The product obtained is isolated by filtration and dried. The product obtained is purified in a solvent selected from chlorinated hydrocarbons such as methylene chloride,

chloroform, 1,2-dichloroethane, preferably methylene chloride to produce N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methy]valine methyl ester oxalate (Xa) in crystalline form. It has been observed that preparation of oxalic acid salt of Formula (X) results in greater than 98 % by HPLC analysis.
Treating N- [ [2’ -(1 -triphenylmethyl-tetrazol-5 -yl)biphenyl-4-yl]methy] valine methyl ester oxalate (Xa) with base selected from organic bases such as triethylamine, diethylamine, diisopropylethyl amine, butylammine or inorganic base such as aqueous solution of alkali metal carbonate such as sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, most preferably aqueous sodium carbonate and in a solvent selected from methylene chloride, ethylacetate, chloroform, carbon tetrachloride, ethylene dichloride, toluene, etc. The organic layer is separated and reacted with valeryl chloride in presence of base selected from diisopropylethylamine at a temperature of about 0°C to about 50°C and isolating N-[[2’-(1-triphenylmethyl-tetrazol-5-yl)[l,1’-biphenyl]-4-yl]-methyl]-N-valeryl-L-valine methyl ester (XI).
The protected tetrazolyl group of N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)[l,r-biphenyl]-4-yl] methyl]-N-valeryl-L-valine methyl ester (XI) is deprotected by using anhydrous acidic reagent selected from isopropanolic hydrochloride, methanolic hydrochloride, ethanolic hydrochloride to produce N-(l-oxopentyl)-N-[[2’-(l-H-tetrazol-5-yl)[l,r-biphenyl]-4-yl]methyl]-L-valine methyl ester (V), which is further converted to Valsartan using base hydrolysis.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
Example I:
Step A: Preparation of N-IP’-Cl-triphenylmethyl-tetrazol-S-yObiphenyM-
yl] methyl] L-valine methyl ester oxalate
L-Valinemethyl ester hydrochloride (132.2 g, 0.789 mole) was added to the mixture of l-triphenylmethyl-5-[4’-(bromomethyl)biphenyl-2-yl]tetrazole (400 g, 0.717 mole) and N,N-dimethylformamide (400 ml) at 20-30°C. Diisopropylethylamine (231.7 g) was added to the reaction mass at 20-30°C and heated to 45-50°C. The reaction mass was maintained for 16 h at 45-50°C and concentrated under reduced pressure. The reaction mass was dissolved in ethyl acetate (800 ml), washed with DM water (400 ml) followed by 10% w/w aqueous sodium chloride solution (200 ml) at 20-30°C. The organic layer was diluted with ethyl acetate (1200 ml) and treated with oxalic acid dihydrate (99.5 g, 0.789 mole) at 20-30°C. The reaction mixture was cooled to 0-5°C and stirred for 1 h at 0-5°C. The solid product was filtered washed with ethyl acetate and dried to yield N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]L-valine methyl ester oxalate (420 g).
Step B: Preparation of N-[[2’-(l-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl]methyl]-N-valeryl-L-valine methyl ester

N-[[2’-(l-Triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl] methyl]-L-valine methylester oxalate (150 g, 0.215 mole) was added to the mixture of toluene (450 ml) and DM water (300 ml), and basified with 10% w/w aqueous sodium bicarbonate solution (450 ml) at 20-30°C. The organic layer was separated and washed with DM water (150 ml) followed by saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and reacted with valeryl chloride (33.7 g) in the presence of N,N- Diisopropylethylamine (55.6 g) at 0-5°C. The reaction mixture was stirred for 3 h at 5-10°C and washed with DM water (150 ml), 10% w/w sodium carbonate solution (68 ml) followed by 10% w/w aqueous oxalic acid solution (40 ml). The organic phase was concentrated completely under reduced pressure to dryness to yield of N-[[2’-(l-triphenylmethyl-tetrazol-5-yl]biphenyl-4-yl]methyl]-N-valeryl-L-valine methyl ester as oil mass (141.3 g)
Step C: Preparation of N-(l-oxopentyl)-N-[[2’-(lH-tetrazol-5-yl)[l,l’-biphenyl]-4-yl]methyl]-L-valine methyl ester
N-[[2’-(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl]methyl]-N-valeryl-L-valine methyl ester (100 g) was added to the mixture of methanol (1 lit.) and isopropanolic hydrochloride (IPA .HC1, 2.75 g; 19% w/w) at 20-30°C and stirred for 5 h at 0-5°C. The reaction mass was cooled to 0-3°C and filtered off the solid by-product, trityl methyl ether.

The filtrate was concentrated completely under reduced pressure and dissolved in ethyl acetate (300 ml). The reaction mixture was treated with aqueous sodium carbonate solution (700 ml; 2.5% w/w) at 20-30°C and separated the aqueous layer. pH of the aqueous layer was adjusted to 8.0-8.3 with 10% w/w aqueous acetic acid and washed with ethyl acetate (100 ml) at 20-30°C. The aqueous layer was separated and acidified with 10% v/v aqueous acetic acid to pH 4.0. The solid product was filtered, washed with water and dried to yield N-(l-Oxopentyl)-N-[[2’-(lH-tetrazol-5-yl)[l,1’-biphenyl]-4-yl]methyl]-L-valine methyl ester (47 g).
Step D: Preparation of [N.(l-oxopenty)’N-[[2’-(lH-tetrazol-5-yl)[l,l’-biphenyl]-4-yl]methyl]-L-valine] (Valsartan)
N-l-Oxopentyl)-N-[[2’-(lH4etrazol-5-yl-[l,l’-biphenyl]-4-yl)methyl]-L-valine methyl ester (19 g) was added to DM water (76 ml) at 20-30°C and reacted with 22% w/v aqueous sodium hydroxide solution (38 ml) for 5h at 20-30°C. After completion of reaction, pH of the reaction mass was adjusted to 6.5 ± 0.2 with dilute HC1 and washed with ethyl acetate (40 ml). The aqueous phase was treated with activated carbon (1 g) at 20-30°C and acidified with dilute hydrochloric acid to pH 2.0±0.2 to precipitate the product.
The reaction mixture was cooled to 0-5°C, filtered the product, washed with water and dried under reduced pressure to yield 15.3 g of crude N-(l-oxopenty)-N-[[2’- (1 H-tetrazol-5-yl)[1,1 ‘-biphenyl]-4-yl]methyl]-L-valine (Valsartan) as a white

solid. The crude Valsartan was recrystallized from ethyl acetate to obtain pure Valsartan.
Example II:
Preparation of [N-(l-oxopenty)-N-[[2’-(lH-tetrazol-5-yl)[l,l’-biphenyl]-4- yl]methyl]-L-valine] (Valsartan)
N-l-Oxopentyl)-N-[[2MlH-tetrazol-5-yl)methyl ester (45 g) produced as per step (C) of Example I was reacted with 15% w/v aqueous barium hydroxide solution (528 ml) for 10 h at 20-30°C. After completion of reaction, the precipitated solid was filtered, treated with 10 % w/v dilute HC1 to pH 0.5 to 1.5 in DM water and isolated crude Valsartan. The crude Valsartan was dissolved in 2.5% w/v aqueous sodium carbonate solution (460 ml) at 20°C-30°C and pH was adjusted to 5-7 with 10% w/v hydrochloric acid and then washed with methylene chloride (90 ml). The aueous layer was acidified with 10% w/v hydrochloric acid and the product was extracted with ethylacetate (495 ml). The organic layer was separated and ethylacetate was distilled completely under reduced pressure at 20-60°C. The resulting solid mass was recrystallised from ethylacetate (225 ml), filtered at -15 to -20°C and dried to yield Valsartan (22 g, 99.7% purity by HPLC).