FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
COMPLETE SPECIFICATION
(See section 10)
1. Title of the invention:' "Industrial process for preparation of Valsartan"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashta, India.
3. The following specification describes the invention:

FIELD OF INVENTION
The present invention relates to a novel and improved process for the preparation of Valsartan, an angiotensin II receptor antagonist for the treatment of hypertension. BACKGROUND OF THE INVENTION
Valsartan is a potent, nonpeptide, long-acting angiotensin II receptor that is especially useful in the treatment of cardiovascular ailments such as hypertension and heart failure. The chemical name of Valsartan is N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl) [1, 1'-biphenyl]-4-yl] methyl-L-valine. Valsartan is represented by following structure (Formula-I)

Formula-I
It has molecular formula C24H29N5O3 and molecular weight 435.52. Ciba-geigy has disclosed Valsartan and its pharmaceutically acceptable salts for the first time in US 5,399,578. This patent describes the process for the preparation of tetrazole in Valsartan. The process involves the reaction of 2-amino-N- [(2'-cyanobiphenyl-4-yl) methyl]-2-methyl-N-valerylpropionate with tri butyl tin azide in Xylene at reflux

temperature to give N- (l-oxopentyl)-N- [[2'-(lH-tetrazo]-5-yl) [1, 1'-biphenyl]-4-yl] methyl-L-valine methyl ester.
WO 2007/014412 describes the process for the preparation of tetrazole in Valsartan.
N-Valeryl-N- [(2'-cyanobipheny]-4-yl) methyl]-L-vaIine methyl ester was obtained
by multi step synthesis, which was reacted with sodium azide and tri ethyl amine
hydrochloride in Xylene to get (S)-N-(l-Methoxycarboxy-2-methyl-prop-l-yl)-N-
pentanoyl-N-[2'-(lH-tetrazol-5-yl)bipheny]-4-ylmethyl]-amine.
WO 2005/051929 relates to the conversion of aromatic nitriles to tetrazoles,
comprising treatment of the cyano compound with trialkyl tinchloride and sodium
azide in the presence of a phase transfer catalyst.
The preparation of several salts of Valsartan has been reported in WO 02/06253, WO
03/066606 and US 2003/0171414. WO 02/06253 discloses Valsartan salts including
sodium, potassium, magnesium and calcium salts; ammonium salts; and salts of
lysine and arginine in different solid state and hydrated forms. Mono and poly
hydrate Valsartan salts of magnesium and calcium are disclosed in US
2003/0171414.
US 2005/0101652 relates to salts of Valsartan especially various forms of Valsartan
salts of magnesium and calcium. WO 2005/049587 relates to Barium salt of
Valsartan.
The prior art processes for preparation of tetrazole of Valsartan involves lengthy
reaction time and tedious work up. Therefore there is a need for an improved

synthetic process having easy work up, cost effective and environmentally friendly
process.
Also, an effective and consistent purification process for salts need to be developed
in order to have Valsartan having purity more than 99.9 %.
SUMMARY OF THE INVENTION
One object of the present invention is to provide an industrially viable process for
preparation of tetrazole in presence of catalytic amount of water, without heating for
prolonged time and not involving tedious workup procedure.
Yet another object of the invention is to provide a simple process for purifying
Barium salt of Valsartan which leads to Valsartan having purity more than 99.9 % .
DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides a simple process of producing tetrazole of Valsartan
in pure form having easy work up, cost effective and environmentally friendly
process.
The present invention uses catalytic amount of water with sodium azide, tributyl tin
chloride in a suitable organic solvent such as toluene, o-Xylene, m-Xylene, p-Xylene
or its mixture. The temperature for the reaction is in the range of 80°C to 170°C,
preferably in the range of 140°C to 150oC. Time required for the completion of the
reaction is in the range of 6 hours to 16 hours, preferably in the range of 8 to 10
hours. It was invented by the present scientist that when tetrazole formation reaction

is carried out in absence of water, the time required for the completion of the
reaction is more than 40 hours which results in to impurity formation and hence yield
loss.
The invention describes the formation of pure of Barium salt by treating crude
Barium salt with N,N - Dimethyl formamide, further treatment with HC1 and
crystallization with EA and MDC and provides Valsartan having purity of 99.9 %
with excellent yield.
The wet crude Barium salt of Valsartan is heated using DMF to the temperature of
50 - 60°C to precipitate pure Barium salt.
The scheme is as follows

EXAMPLE-1
Preparation of Methyl ester of N-(1-oxopentyl)-N-[[2'-tetrazol-5-yl) [1, l'-biphenyl]-4-yI] methyl -L-valine
N-[(2'-cyanobiphenyl-4-yl) methyl]-N-valeryl-(L)-vaIine methyl ester in o-Xylene is azeotropically dried at temp 145 - 150°C and then cooled to 25 -30°C. Tri-n-butyl tin chloride, sodium azide and DM water is added and is heated at 145 - 150°C and maintained for 10 - 12 hours. After completion of reaction, it is cooled to 15 - 20°C, to get Methyl ester of N-(l-oxopentyl)-N-[[2'-(]H-tetrazol-5-yl) [1, l'-biphenyl]-4-yl] methyl -L-valine. Preparation of Barium salt of N-(l-oxopentyl)-N-[[2'-(lH-tetrazoI-5-yI) [1, l'-biphenyl]-4-yl] methyl -L-valine
Methyl ester of N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-yl) [1, l'-biphenyl]-4-yl] methyl -L-valine in o-Xylene is treated with aqueous sodium hydroxide solution and stirred at 15 - 20°C for 20 - 22 hours. On completion of reaction, layers are separated and aqueous layer pH is adjusted to 6.3 - 6.6 using dil. hydrochloric acid, washed with methylene chloride. Aqueous layer again adjusted to pH l - 2 using dil. hydrochloric acid, extracted with ethyl acetate and washed with sodium chloride solution. To the organic layer is added Barium hydroxide octahydrate and DM water at 25 - 30°C to precipitate solids, which is filtered, treated with N,N - dimethyl formamide at 50 - 60°C, seeded

with Barium salt to get Barium salt of N-(l-oxopentyl)-N- [[2'-(lH-tetrazol-5-yl )[1,1 '-biphenyI]-4-yI]methyl]-L-valine.
Preparation of N-(l-oxopenty])-N-[[2'-(1H-tetrazol-5-yJ) [1, r-biphenyl]-4-yl] methyl] -L-valine
Barium salt of N-(l-oxopentyl)-N- [[2'-(lH-tetrazol-5-yl) [1, 1'-biphenyl]-4-yl] methyl]-L-valine is treated with ethyl acetate and DM water, pH adjusted to 1.5-2 using dil. hydrochloric acid solution. Separate the layers and washed with sodium chloride solution, dried over sodium sulphate then treated with activated charcoal at 40 - 45°C and filtered through hyflo and micron filter, distilled off solvent under reduced pressure to 2.5 - 3 volumes. The solution is again filtered through micron filter to get clear filtrate, which is concentrated under vacuum to get residue, which is dissolved in ethyl acetate at 45 - 50°C. To the dissolved residue is added methylene chloride at 40 - 45°C. The clear solution obtained is cooled to 25 - 30 °C and stirred for 6 hours at 25 - 30 °C, cooled to -10 - -15°C, then stirred for 6 hours at -10 - -15 °C, filtered the solids, dried the solids in fluidized bed dryer at 50 - 60 °C to obtain pure Valsartan. The mother liquor is treated with Barium hydroxide and DM water to get solids, which is filtered, treated with N,N- dimethyl formamide at 50 - 60°C, seeded with Barium salt to get Barium salt of N-(l-oxopentyl)-N- [[2'-(lH-tetrazol-5-yl )[l,1'-biphenyl]-4-yl]methyl].-L-valine. This solids are again treated as per above process to get pure Valsartan.

We Claim:
1. A process for preparation of tetrazoie of Valsartan, comprising reacting N-[(2'-cyanobiphenyl-4-yI)methyl]-N-valeryl-(L)-valine methyl ester with Tri-n-butyl tin chloride ,sodium azide in the presence of catalytic amount of water, in a suitable organic solvent such as toluene, o-Xylene, m-Xylene, p-Xylene or mixture there of, to form Methyl ester of N-(l-oxopentyl)-N-[[2'-(lH-tetrazol-5-y!) [1, l'-biphenyl]-4-yl] methyl -L-valine, at 80°C to 170°C.
2. The process according to claim 1, the temperature of the reaction is 80°C to 170°C, most preferably 140-150 °C.
3. A process for preparation of Valsartan, comprising

a) condensing Methyl-N-((2'-cyanobiphenyl-4-yl)methyl)l-L-valinate hydrochloride with valeroyl chloride in the presence of base, to form N-[(2'-cyanobiphenyl-4-yI)methyl]-N-vaIeryl-(L)-valine methyl ester
b) reacting N-[(2'-cyanobiphenyl-4-yl)methyl]-N-vaIeryl-(L)-valine methyl ester with Tri-n-butyl tin chloride, sodium azide in the presence of catalytic amount of water, in toluene, o-Xylene, m-Xylene, p-Xylene or mixture there of, to form Methyl ester of N-(l -oxopentyl)-N-[[2'-(1H-tetrazol-5-yl) [1, 1 '-biphenyl]-4-yl] methyl -L-valine.
c) converting Methyl ester of N-(I-oxopentyI)-N-[[2'-(lH-tetrazol-5-yI) [1, 1'-biphenyl]-4-yl] methyl -L-valine to crude Barium salt of Valsartan, by treating it with Barium hydroxide

d) treating crude Barium salt of Valsartan with N,N- dimethyl formamide
e) converting Barium salt of Valsartan to pure Valsartan.
4. A process according to claim 3 gives Valsartan with purity 99.9%.
5. A process for preparing Valsartan as described in examples.