FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
An Improved Process for Preparation of N-[2'-(l-
triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryI-
(L)-valine benzyl ester, An Intermediate of Valsartan
APPLICANT:
CALYX CHEMICALS AND PHARMACEUTICALS LTD.
2, Marwah's Complex, Sakivihar Road, Sakinaka, Andheri (E), Mumbai-400 072, Maharashtra, India
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF INVENTION
The present invention provides an improved and commercially viable in-situ process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester, an intermediate of Valsartan (Formula I).

The present invention further provides an improved process for preparation of N-[2'-(1 -triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) by using water as a solvent.


The present invention also provides an improved process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester, an intermediate of Valsartan (Formula I) from N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula ID-BACKGROUND AND PRIOR ART
Valsartan, also known as (S)-N-(l-Carboxy-2-methyl-prop-l-yl)-N-pentanoyl-N-[2'-(lH-tetrazol-5-yl)bi phenyl-4-ylmethyl]-amine (Formula A), was first disclosed in US5399578.
Valsartan is an orally active specific angiotensin II antagonist acting on the ATI receptor subtype. Valsartan is prescribed for the treatment of hypertension and related conditions.
Number of methods for the preparation of Valsartan is known in the literature.
US 5399578 describes the process for preparation of Valsartan which starts with
i) alkylation of 4-bromomethyl-2'-(l-triphenylmethyl tetrazol-5yl)-biphenyl
with L-valine benzyl ester in dimethyl formamide ii) the alkylated product was acylated with valeroyl chloride in
dichloromethane iii) further the protecting group were removed to obtain valsartan.
Scheme I represents the reaction scheme of US5399578


WO2004101534 discloses a process for preparation of Valsartan via N-[(2'(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine benzyl ester. N-[(2'(l-triphenylmethyl-tetrazol-5-yl)biphenyl-4-yl)methyl]-(L)-valine benzyl ester is

prepared by alkylation of 4-bromomethyl-2'-(l-triphenylmethyltetrazol-5-yl)biphenyl with L-valine benzyl ester in presence of ethyl diisopropyl amine in solvent like acetonitrile. The alkylated product is isolated by converting it to its hydrochloride salt. The hydrochloride salt of alkylated product is further acylated with valeroyl chloride in presence of N, N-diisopropyl ethyl amine in solvent like toluene, the product obtained i.e. N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester is converted to Valsartan by removing of protective groups.
WO2006058701 discloses a process for preparation of Valsartan involves 3 steps
a) alkylation of 4-(bromomethyl) biphenyl-2-yl)-l-(triphenyl methyl) tetrazole with L-valine methyl ester HC1 is carried out in presence of sodium hydroxide and in solvent like dichloromethane.
b) acylation of the alkylated product by treating it with valeroyl chloride in presence of base like pyridine, preferably in solvent like tetrahydrofuran.
c) removing the protecting groups of the acylated product to obtain final product i.e. Valsartan.
The drawbacks of the processes disclosed above includes
i) the crude form of intermediate obtained in most of steps was carried forward in next step without purification. Hence, the final product i.e. Valsartan was therefore strongly contaminated and required multiple crystallization.
ii) the processes described are time consuming and industrially less feasible.
iii) hazardous chemicals like THF and pyridine are used.
iv) use of diisopropylethylamine, which is reported to lead to the formation of impurities.

Hence, there remains a need to provide an alternative to prior art process which overcomes the above drawbacks and is cost effective, feasible and industrially viable with high yield and purity, which is subject matter of the present invention.
OBJECT OF INVENTION
a) It is an object of the present invention to provide an improved, simple and cost-effective in-situ process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I) andN-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II).
b) It is another object of the present invention to provide an improved process for preparation of N-[2' -(1 -triphenylmethyl-tetrazol-5 -yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I) from N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) with reduced parameters and utility simplification.
c) It is yet another object of the present invention to provide commercially feasible process for the preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I) with good yield and purity.
d) It is yet another object of the present invention to provide commercially feasible process for the preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) with good yield and purity.

SUMMARY OF INVENTION
According to an aspect of the present invention, there is provided an improved in-situ process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester, an intermediate of Valsartan (Formula I)

Formula I
comprising the steps of,
a) reacting L-valine benzyl ester tosylate with N-triphenylmethyl-5-[(4'-
bromomethyl)biphenyl-2-yl]tetrazole (herein after referred as TTBB)
in presence of a first base in water at 50-80°C for 15-30 hours
b) extracting the reaction mixture of step a) with an aromatic solvent selected from toluene, xylene or mixture thereof
c) combining the organic extract of step b) with water and a second base and heating the mixture at 35-55°C for 0.5 to 2 hours
d) adding to the mixture of step c) an aromatic solvent selected from toluene, xylene or mixture thereof
e) cooling the mixture to 0-5°C and adding valeroyl chloride

f) raising the temperature of reaction mixture to 20-25°C and maintaining for 2-5 hours
g) recovering N- [2' -(1 -triphenylmethyl-tetrazol-5 -yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I).
According to another aspect of the present invention, there is provided an improved process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II)

comprising the steps of,
i) reacting L-valine benzyl ester tosylate with TTBB in presence of a base in
water at 50-80°C for 15-30 hours ii) extracting the reaction mixture of step i) with an aromatic solvent selected
from toluene, xylene or mixture thereof iii) cooling the organic extract of step ii) to 5-10°C and adding hydrochloric acid iv) stirring the mixture of step iii) at 5-10°C for 3-5 hours v) isolating N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-
valine benzyl ester hydrochloride (Formula II).

According to another aspect of the present invention, there is provided an improved process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I) from N-[2'-(1 -triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II), wherein Formula II is prepared by the process of the present invention as discussed above comprising the steps of,
A) treating N- [2' -(1 -triphenylmethyl-tetrazol-5 -yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) with a base in water and heating the mixture at 35-55°C for 0.5 to 2 hours
B) extracting the mixture of step A) with an aromatic solvent selected from toluene, xylene or mixture thereof
C) adding to the organic extract of step B) the base at temperature 10-15°C
D) cooling the mixture of step C) to 0-5°C and adding valeroyl chloride
E) raising the temperature of reaction mixture to 20-25°C and maintaining for 2-
5 hours
F) recovering N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-
valeryl-(L)-valine benzyl ester (Formula I).
DETAILED DESCRIPTION OF INVENTION
The present invention relates to an improved and commercially viable in-situ process for preparation of N-[2'-(1-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester, an intermediate of Valsartan (Formula I) with high purity and yield.


The in-situ process of the present invention for the preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester, an intermediate of Valsartan (Formula I) is as shown in the Scheme II below,


SCHEME II
The process of the present invention for the preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I) via N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) is as shown in the Scheme III below,


SCHEME III
According to first aspect of the present invention, there is provided an improved in-situ process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester, an intermediate of Valsartan (Formula I)


comprising the steps of,
a) reacting L-valine benzyl ester tosylate with TTBB in presence of a first base in water at 50-80°C for 15-30 hours
b) extracting the reaction mixture of step a) with an aromatic solvent selected from toluene, xylene or mixture thereof
c) combining the organic extract of step b) with water and a second base and heating the mixture at 35-55°C for 0.5 to 2 hours
d) adding to the mixture of step c) an aromatic solvent selected from toluene, xylene or mixture thereof
e) cooling the mixture to 0-5 °C and adding valeroyl chloride
f) raising the temperature of reaction mixture to 20-25°C and maintaining for 2-5 hours
g) recovering N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I).

According to another aspect of the present invention, there is provided an improved process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II)

comprising the steps of,
i) reacting L-valine benzyl ester tosylate with TTBB in presence of a base in
water at 50-80°C for 15-30 hours ii) extracting the reaction mixture of step i) with an aromatic solvent selected
from toluene, xylene or mixture thereof iii) cooling the organic extract of step ii) to 5-10°C and adding hydrochloric acid iv) stirring the mixture of step iii) at 5-10°C for 3-5 hours v) isolating N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-
valine benzyl ester hydrochloride (Formula II).
According to an embodiment of the present invention the molar ratio of L-valine benzyl ester tosylate used in step a) and step i) with respect to TTBB is in the range of 0.5 to 3, preferably 0.9 to 2.

According to another embodiment of the present invention the base used in step a), step c) and step i) is selected from organic or inorganic base wherein organic base like N,N-diisopropylethylamine or triethylamine are used and inorganic base like alkali metal carbonates or alkali metal bicarbonates are used. Preferably, base used in the said step is inorganic base such as alkali metal carbonates like sodium carbonate, potassium carbonate etc. and alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate etc., more preferably first base used in step a) and step i) is alkali metal bicarbonate like sodium bicarbonate or potassium bicarbonate and second base used in step c) is alkali metal carbonate like sodium carbonate or potassium carbonate.
The molar ratio of base used with respect to TTBB is in the range of 2 to 5, preferably it is 2 to 4.
According to another embodiment of the present invention, the molar ratio of the valeroyl chloride used in step e) with respect to TTBB is in the range of 0.9 to 3, preferably it is 1 to 2.
According to another embodiment of the present invention N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I) is prepared by in-situ preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester (Formula II). Thus, process of the present invention avoid isolation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester and minimizes the use of solvent.
According to further aspect of the present invention, there is provided an improved process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I) from N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester

hydrochloride (Formula II), wherein Formula II is prepared by the process of the present invention as discussed above comprising the steps of,
A) treating N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) with a base in water and heating the mixture at 35-55°C for 0.5 to 2 hours
B) extracting the mixture of step A) with an aromatic solvent selected from toluene, xylene or mixture thereof
C) adding to the organic extract of step B) the base at temperature 10-15°C
D) cooling the mixture of step C) to 0-5°C and adding valeroyl chloride
E) raising the temperature of reaction mixture to 20-25°C and maintaining for 2-
5 hours
F) recovering N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-
valeryl-(L)-valine benzyl ester (Formula I).
According to an embodiment of the present invention, the base used is selected from organic or inorganic base wherein organic base like N,N-diisopropylethylamine or triethylamine are used and inorganic base like alkali metal carbonates or alkali metal bicarbonates are used. The alkali metal carbonates like sodium carbonate, potassium carbonate and the like are used. The alkali metal bicarbonates are selected from sodium bicarbonate, potassium bicarbonate and the like. Preferably, base used is inorganic base such as alkali metal carbonates like sodium carbonate or potassium carbonate.
The molar ratio of base used with respect to N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) is in the range of 2 to 5, preferably it is 2 to 4.

According to another embodiment of the present invention, the molar ratio of the valeroyl chloride used in step D) with respect to N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) is in the range of 0.5 to 3, preferably it is 1 to 2.
The N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I) prepared by the process discussed in the present invention is converted to benzyl valsartan which is further used in preparation of Valsartan by the methods known in the art. One of such method of preparation of valsartan from benzyl valsartan is disclosed in our Indian patent application No. 331/MUM/2009 which is incorporated herein by reference.
The detail of the invention provided in the following example is given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES
Example 1:
Preparation of N-[2'-(l-triphenvlmethvl-tetrazol-5-Yr) biphenyl-4-vl)methyl-N-
vaIeryl-(L)-valine benzyl ester (in-situ)
Step 1:
To 500ml distilled water was charged 70gms of L-valine benzyl ester tosylate under
stirring at 25-30°C. The slurry obtained was continued to stir for 15 mins and then
50gms of sodium bicarbonate was added portion-wise followed by stirring at 25-30°C
for 30 mins. Further to the reaction mixture was added lOOgms of N-triphenylmethyl-
5-[(4'-bromomethyl)biphenyl-2-yl]tetrazole (TTBB). The reaction mixture was then
heated slowly to 65-70°C and was maintained at this temperature for 20-22 hours.
After the completion of reaction the reaction mixture was cooled to 30-35°C. To the
reaction mixture was added 500ml of toluene and the mixture was stirred for 30 mins.

The organic layer and aqueous layers were allowed to settle and were separated. The aqueous layer was extracted with 2 X 150 ml of toluene. Organic layers obtained were combined and washed with 2 X 200 ml water. The organic layer obtained was used in Step 2. Step 2:
To the organic layer obtained in Step 1 was added 95ml of water and a pre-prepared solution of potassium carbonate (49gms potassium carbonate dissolved in 500ml of water). The mixture was heated to 40-45°C for 1 hour and 500ml of toluene was added under stirring. The reaction mixture was further stirred for 40-45 mins at 40-45°C and then cooled to 30-35°C. The temperature of the reaction mixture was further slowly decreased to 0-5°C and 27gms of valeroyl chloride was added to it in 120 mins. The temperature of reaction mixture was then raised to 20-25°C followed by stirring for 3-4 hrs at this temperature. To the reaction mixture was then added 100ml of distilled water and stirred for 30 mins at 20-25°C. The organic and the aqueous layers were allowed to settle and were separated. To the organic layer was then added 200ml of 2N HC1 and the mixture was stirred for 30 mins, again the layers were separated and to the organic layer was added 150ml of 10% sodium bicarbonate. The mixture was stirred for 30 mins and layers were allowed to settle and were then separated. The organic layer thus obtained was washed with 100ml of water and then was distilled degassed under vacuum at 50-55°C to obtain N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester. Yield: 123-130gms Percentage Yield: 90-95%
Example 2:
Preparation of N-[2'-(l-triphenvlmethvl-tetrazol-5-vD biphenvl-4-vi)methvl-(L)-
valine benzyl ester hydrochloride
To 500ml of distilled water was added 70gms of L-valine benzyl ester tosylate under stirring at 25-30°C. The mixture was stirred for 15 mins and then to it was added

50gms of sodium bicarbonate portion-wise. The mixture was further stirred for 30 mins and to it was added lOOgms of N-triphenylmethyl-5-[(4'-bromomethyl)biphenyl-2-yl]tetrazole (TTBB) under stirring at 25-30°C. The reaction mixture was then heated slowly to 65-70°C and the temperature was maintained for 20-22 hours. After completion of the reaction, the reaction mixture was cooled to 30-35°C and 500ml of toluene was added to it. The mixture was stirred for 30 mins and the layers were allowed to settle and then the aqueous and organic layers were separated. The aqueous layer was extracted with 2 X 150 ml of toluene. Organic layers obtained were combined and washed with 2 X 200 ml water. The organic layer thus obtained was cooled to 5-10°C and slowly 80ml of 1:1 hydrochloric acid solution was added to it. The mixture was stirred for 4 hours at 5-10°C. The solid obtained was filtered and washed with 2 X 200ml of chilled toluene and 2 X 200ml of water. The solid was again washed with 100ml of chilled toluene, suck dried and then dried under vacuum at 5 0-55 °C for 10-12 hours to obtain N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride. Yield: 102gms Percentage Yield: 85%
Example 3:
Preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yD biphenyl-4-vDmethvl-N-valervHD-valine benzyl ester from N-[2'-(l-triphenvlmethyl-tetrazol-5-yD biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride
To 95ml of water was added lOOgms of N-[2,-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride and a pre-prepared solution of potassium carbonate (29gms potassium carbonate dissolved in 303ml of water). The mixture was heated to 40-45°C for 1 hour and then 300ml of toluene was added under stirring. The stirring was continued at 40-45°C for 40-45 mins the layers were then allowed to settled and separated. The aqueous layer was extracted with 200ml of toluene. Organic layers obtained were combined and washed with 100ml

water. To the organic layer was then added at 10-15°C potassium carbonate solution (39gms of potassium carbonate dissolved in 300ml of water). The mixture was then stirred for 30 mins at 10-15°C followed by cooling it further to 0-5°C. To this cooled solution was added 27gms of valeroryl chloride within 120 mins. After addition of valeroyl chloride the temperature was raised to 20-25°C and was stirred for 3-4 hours at this temperature. After completion of the reaction, 100ml of water was added to the reaction mixture and the mixture was stirred for 30 mins at 20-25°C. The layers were allowed to settle and then were separated. To the organic layer was added 200ml of 2N HC1 and the mixture was stirred for 30 mins. The layers were allowed to settle and then were separated. To the organic layer was then added 150ml of 10% sodium bicarbonate solution and the contents were stirred for 30 mins and layers were allowed to settle followed by separation of layers. The organic layer thus obtained was washed with water and was distilled degassed under vacuum at 50-55°C to obtain N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester. Yield: 112gms Percentage Yield: 80%

We claim
1. An improved in-situ process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester, an intermediate of Valsartan (Formula I)

comprising the steps of,
a) reacting L-valine benzyl ester tosylate with N-triphenylmethyl-5-[(4'-bromomethyl)biphenyl-2-yl]tetrazole (TTBB) in presence of a first base in water at 50-80°C for 15-30 hours
b) extracting the reaction mixture of step a) with an aromatic solvent selected from toluene, xylene or mixture thereof
c) combining the organic extract of step b) with water and a second base and heating the mixture at 35-55°C for 0.5 to 2 hours
d) adding to the mixture of step c) an aromatic solvent selected from toluene, xylene or mixture thereof
e) cooling the mixture to 0-5°C and adding valeroyl chloride at the same temperature
f) raising the temperature of reaction mixture to 20-25°C and maintaining for 2-5 hours

g) recovering N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I)
2. An improved process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II)

comprising the steps of,
i) reacting L-valine benzyl ester tosylate with N-triphenylmethyl-5-[(4'-
bromomethyl)biphenyl-2-yl]tetrazole (TTBB) in presence of a base in water at
65-70°C for 20-22 hours ii) extracting the reaction mixture of step i) with an aromatic solvent selected
from toluene, xylene or mixture thereof iii) cooling the organic extract of step ii) to 5-10°C and adding hydrochloric acid iv) stirring the mixture of step iii) at 5-10°C for 4 hours v) isolating N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-
valine benzyl ester hydrochloride (Formula II)
3. The process as claimed in claim 1 or 2, wherein the molar ratio of L-valine benzyl ester tosylate used in step a) and step i) with respect to TTBB is in the range of 0.5 to 3, preferably 0.9 to 2

4. The process as claimed in claim 1 or 2, wherein the base used in step a), step c) and step i) is inorganic base, preferably, selected from alkali metal carbonates like sodium carbonate, potassium carbonate or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate
5. The process as claimed in claim 1, 2 or 4, wherein the molar ratio of the base used in step a), step c) and step i) with respect to TTBB is in the range 2 to 5, preferably 2
to 4
6. The process as claimed in claim 1, wherein the molar ratio of valeroyl chloride used in step e) with respect to TTBB is in the range of 0.9 to 3, preferably 1 to 2
7. An improved process for preparation of N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I) from N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II)
comprising the steps of,
A) treating N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) with a base in water and heating the mixture at 40-45°C for 1 hour
B) extracting the mixture of step A) with an aromatic solvent selected from toluene, xylene or mixture thereof
C) adding to the organic extract of step B) the base at temperature 10-15°C
D) cooling the mixture of step C) to 0-5 °C and adding valeroyl chloride at the same temperature
E) raising the temperature of reaction mixture to 20-25°C and maintaining for 3-
4 hours

F) recovering N-[2'-(1 -triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-N-valeryl-(L)-valine benzyl ester (Formula I)
8. The process as claimed in claim 7, wherein the base used in step A) and step C) is inorganic base, preferably, selected from alkali metal carbonates like sodium carbonate, potassium carbonate or alkali metal bicarbonates like sodium bicarbonate, potassium bicarbonate
9. The process as claimed in claim 7 or 8, wherein the molar ratio of the base used in step A) and step C) with respect to N-[2'-(l-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) is in the range 2 to 5, preferably 2 to 4
10. The process as claimed in claim 7, wherein the molar ratio of the valeroyl
chloride used in step D) with respect to N-[2,-(l-triphenylmethyl-tetrazol-5-yl)
biphenyl-4-yl)methyl-(L)-valine benzyl ester hydrochloride (Formula II) is in the
range of 0.5 to 3, preferably 1 to 2.