FIELD OF THE INVENTION
The invention relates to an improved process for the preparation of Valsartan (1). It further relates to process for the purification of Valsartan (1).
BACKGROUND OF THE INVENTION
Valsartan is an orally active nonpeptide triazole-derived antagonist of angiotensin (AT) II. Chemically it is described as N-(1-oxopentyl)-N-[[2´-(1H-tetrazol-5-yl) [1,1´-biphenyl]-4-yl] methyl]-L-valine. Valsartan is sold under the brand name Diovan in the US and used in combination with hydrochlorothiazide, amlodipine or sacubitril as tablets. It is used for the treatment of hypertension and heart failure.
The synthesis of Valsartan (1) was reported in many patents and non-patent literature. The contents of which are hereby incorporated as reference in their entirety
US 7,659,406 patent discloses process of preparing Valsartan (1) by reacting N-[(2′-cyanobiphenyl-4-yl) methyl]-(L)-valine methyl ester (V) with the valeryl chloride (IV) to form (N-[(2′-cyanobiphenyl-4-yl)-methyl]-N-valeryl-(L)-valine methyl ester (III), which undergoes tetrazole formation to form intermediate (II). Intermediate (II) on hydrolysis yields Valsartan (I).
US 8,258,312 patent teaches preparation of Valsartan by treating intermediate (II) with tributyltin azide in presence of acid and isolating Valsartan. ‘312 does not

disclose the yield or the purity of the final compound. Moreover, tributyltin azide is a hazardous chemical and reactions using tributyltin azide leads to the formation of hydrogen azide which is explosive in nature, hence use in industrial scale is not advisable. This leads to an overall increase in the handling and production costs. Further, most of the intermediates formed in the disclosed process are oily in nature, making the process tedious, laborious and time consuming.
WO2004101534 application discloses preparation of Valsartan from N-[[2′-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] valine benzyl ester hydrochloride salt. The main disadvantage of this process is low yield and low purity of N-[[2′-(1-triphenylmethyltetrazol-5-yl) biphenyl-4-yl] methyl] valine benzyl ester as it is very instable at strong acidic conditions and may undergo hydrolysis to generate undesired impurities.
US 8,288,561 B2 patent discloses preparation of Valsartan using trityl benzyl valsartan ester intermediate. The oxalate salt of N-[(2′-(1-triphenyl methyl tetrazole-5-yl)biphenyl]-4-yl]methyl]-L-valine benzyl ester of formula with an

organic acid to obtain a compound of formula (IVB) was reacted with valeryl halide of formula (V) to form trityl benzyl valsartan of formula (VI), which on detritylating yielded benzyl valsartan of formula (VII). Intermediate (VII), on debenzylation yielded valsartan of Formula (I).
The main disadvantage with the above processes is the long duration of time for the completion of reaction and use of intermediates which are unstable, resulting in low yields and making the process tedious, which is not feasible for industrial scale. Hence, the present invention aims at providing an improved process for the preparation and purification of Valsartan (1) limiting the formation of impurities and resulting in increase in using safe and commercially viable reaction conditions which are applicable at large scales.
OBJECTIVE OF THE INVENTION
In one aspect, the present invention provides an improved process for the preparation of Valsartan (1).
In another aspect, the present invention provides a process for the purification of Valsartan (1).
In another aspect, the present invention provides Valsartan (1) with greater than 99.0 % purity by HPLC (High-performance liquid chromatography).

In another aspect, the present invention provides X-Ray powder diffraction pattern (XRPD) of Valsartan (1) as illustrated in figure 1.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of substantially pure Valsartan (1), with purity greater than 99.0 % by high-performance liquid chromatography (HPLC).
In one embodiment, the present invention provides an improved process for the preparation of pure Valsartan (1) as depicted in scheme-1.
a) reacting 4'-bromomethyl-2-biphenyl carbonitrile (8) with L-valine methyl ester hydrochloride (7) to yield (S)-methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-3-methylbutanoatehydrochloride (6);
b) reacting intermediate (6) with valeryl chloride (5) to form (S)-methyl 2-(N-((2'-cyanobiphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (4);
c) reacting intermediate (4) with sodium azide (3) and a suitable reagent to form (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2); and
d) converting (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2) to Valsartan (1) using a suitable base.
In another embodiment, the present invention provides purification process of Valsartan (1), comprising the following steps:
i. providing a solution of Valsartan (1) in a suitable base at a suitable
temperature;
ii. optionally, adding suitable solvent;
iii. adjusting pH of the reaction mass; and
iv. isolating pure Valsartan (1).
In another embodiment, the Valsartan (1) produced after purification, was having purity greater than 99.0 % by HPLC (High-performance liquid chromatography)

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1: illustrates the X-Ray powder diffraction pattern (XRPD) of amorphous Valsartan (1)
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment, the present invention provides an improved process for the preparation of pure Valsartan (1) as depicted in scheme- 1.
a) reacting 4'-bromomethyl-2-biphenyl carbonitrile (8) with L-valine methyl ester hydrochloride (7) to yield (S)-methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-3-methylbutanoatehydrochloride (6);
b) reacting intermediate (6) with valeryl chloride (5) to form (S)-methyl 2-(N-((2'-cyanobiphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (4);
c) reacting intermediate (4) with sodium azide (3) and tributyl tin chloride to form (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2); and
d) converting (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2) to Valsartan (1) using a suitable base.

Step a) involves coupling 4'-bromomethyl-2-biphenyl carbonitrile (8) with L-valine methyl ester hydrochloride (7) to yield (S)-methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-3-methylbutanoatehydrochloride (6). 4'-bromomethyl-2-biphenyl carbonitrile (8) may be dissolved in a suitable solvent and base and reacted with L-valine methyl ester hydrochloride (7) and heated to a suitable temperature. The reaction mass may be treated with a suitable acid and the product isolated from suitable solvents to yield (S)-methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-3-methylbutanoate hydrochloride (6).
Step b) proceeds with reacting intermediate (6) with valeryl chloride (5) to form
(S)-methyl 2-(N-((2'-cyanobiphenyl-4-yl) methyl) pentanamido)-3-
methylbutanoate (4). Intermediate (6) may be dissolved in a suitable solvent and reacted with valeryl chloride (5) in presence of a base and cooled to a suitable temperature 0-20 °C, preferably 0-5 °C. On completion of reaction, the organic layer may be extracted with a suitable acid and filtered to obtain (S)-methyl 2-(N-

((2'-cyanobiphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (4) in the filtrate , which was directly used in the next step.
Step c) proceeds with reacting intermediate (4) with sodium azide (3) and tributyl tin chloride to form (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2).To the intermediate (4) obtained in the step b) filtrate was treated with sodium azide and tributyl tin chloride and heated to 90-150 °C, preferably to 140-145 °C to obtain (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2) .
In another embodiment, step d) involves converting (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2) to Valsartan (1) using a suitable base and acid.
The suitable solvent used in the present invention for the preparation of Valsartan (1) may be selected from organic solvents comprising of protic or aprotic solvents, but not limited to water, methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane-1 ,2- diol, propane- 1 ,2 -diol , water , pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, 1 , 4- dioxane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate dimethylformamide, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, acetone, acetonitrile, propionitrile, isobutyronitrile or the mixtures thereof, preferably water , ethyl acetate, toulene, o-xylene, and dichloromethane were used in the present invention.
The base used in the present invention may be selected from but not limited to organic or inorganic bases, comprising of ammonia, dimethylamine, diethylamine, triethylamine, pyridine, piperidine, sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate , sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium methoxide, sodium ethoxide, potassium

methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, lithium tertiary butoxide and the like or mixtures thereof . Preferably, sodium bicarbonate, potassium bicarbonate and sodium hydroxide were used in the present invention.
The suitable acid used in the present invention may be organic or inorganic acid which can be selected but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid; preferably hydrochloric acid was used in the present invention.
In another embodiment, the present invention provides, a process for the purification of Valsartan (1), comprising:
i. providing a solution of Valsartan (1) in a suitable base at a suitable
temperature;
ii. optionally, adding suitable solvent;
iii. adjusting pH of the reaction mixture; and
iv. isolating pure Valsartan (1).
In another embodiment, purification of Valsartan (1) was done by providing a solution of Valsartan (1), in a suitable base and cooling the reaction mass to 0-30 °C, and the pH was adjusted using a suitable acid at 0-30 °C, preferably 15-20 °C. The solid formed was filtered and isolated from suitable solvent to yield pure Valsartan (1).
The suitable solvent used in the purification of Valsartan (1) may be selected from organic solvents comprising of protic or aprotic solvents, but not limited to water, methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, 2-butanol, tert-butanol, ethane-1 ,2- diol, propane- 1 ,2 -diol , pentane, n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and dimethyl ether, diethyl ether, diisopropyl ether, methyl tert-butyl ether, 1 ,2-dimethoxyethane, tetrahydrofuran, 1 , 4- dioxane, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate, dimethylformamide,

dichloromethane, dichloroethane, chloroform, carbon tetrachloride acetone, methyl ethyl ketone, methyl isobutyl ketone, acetonitrile or the mixtures thereof, preferably water and dichloromethane were used in the present invention.
The base used in the purification may be selected from but not limited to organic or inorganic bases, comprising of ammonia, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, triethylamine, triisopropyl amine, tributylamine, tertbutyl amine, pyridine, piperidine , sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate , sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tertiary butoxide, potassium tertiary butoxide, lithium tertiary butoxide, sodium hydride, potassium hydride, lithium hydride , sodium amide, potassium amide, lithium amide and the like or their mixtures. Preferably, sodium hydroxide was used in the present invention.
The suitable acid used in the present invention may be organic or inorganic acid which can be selected from but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid; preferably hydrochloric acid was used in the present invention.
In another embodiment the present invention provides process for the preparation of 4'-bromomethyl-2-biphenyl carbonitrile (8) by reacting 4'-methylbiphenyl-2-carbonitrile (9) with bromine in the presence of hydrogen peroxide.

In an embodiment, the purification process of the present invention provides Valsartan (1) having a purity greater than 99.0% as determined by HPLC.
In another embodiment, the present invention provides pure Valsartan (1) having optical rotation between -69.0⁰ to -64.0⁰.
In an embodiment, the purification process of the present invention provides Valsartan (1) having water content by Karl Fischer method less than 2% (w/w), preferably less than 1.5% (w/w) HPLC.
The Valsartan (1), obtained after purification was having total impurities less than 1.0 % (w/w), preferably less than 0.5% (w/w) and each single known impurity, more specifically the related Compound A impurity , related Compound B impurity, related compound C impurity is controlled less than 0.20% (w/w); preferably less than 0.15% (w/w).

In another embodiment, Valsartan (1), obtained from the purification is having X-Ray powder diffraction (XRPD) pattern as shown in figure 1 and is amorphous.
The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
EXAMPLE-1: Preparation of (S)-methyl 2-((2'-cyanobiphenyl-4-yl)
methylamino)-3-methylbutanoate hydrochloride (6)
100 g of 4'-bromomethyl-2-biphenyl carbonitrile (8) was dissolved in 700 mL of ethyl acetate. To this, sodium carbonate solution and 80 g of L-valine methyl ester hydrochloride (7) were added. The reaction mass was heated to 50-55 °C. The aqueous layer was separated and washed with ethyl acetate. The organic layer was then distilled off, and reaction mass was cooled to 25-30 °C with addition of 600

mL of toluene. Further 100 mL of concentrated hydrochloric acid was added to the reaction mass at 15-20 °C. and filtered. The solid so obtained was washed with toulene and dried under vacuum to yield (S)-methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-3-methylbutanoate hydrochloride (6). Yield: 99%; Purity: 97%.
EXAMPLE-2: Preparation of (S)-methyl 2-(N-((2'-cyanobiphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (4)
100g of (S)-methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-3-methylbutanoate hydrochloride (6) was dissolved in o-Xylene and added to a solution of 115g of potassium carbonate in 300 mL of water. The reaction mass was cooled to 0-5 °C and 50g of valeryl chloride was added. On completion of reaction, the aqueous layer was extracted with ethyl acetate. The total organic layer was washed with hydrochloric acid and sodium chloride solution, separated to yield (S)-methyl 2-(N-((2'-cyanobiphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (4), in the filtrate which was directly used in the next step.
EXAMPLE-3: Preparation of (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2)
155g of tributyl tin chloride and 30 g of sodium azide (3) was added to the filtrate obtained in example 2, containing intermediate (4). The reaction mass was heated to 140-145 °C. The reaction mass was cooled to 25-30 °C and filtered to obtain (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2), which was directly used in the next step.
EXAMPLE-4: Preparation of Valsartan (1)
The intermediate (2) obtained in example 3, was added to a solution of 85 g of sodium hydroxide dissolved in 870 mL of water. The reaction mass was cooled to 15-20 °C. On completion of the reaction, organic and aqueous layers were separated. The aqueous layer was washed with 100 mL of dichloromethane and layers separated. 500 mL of water was added to the aqueous layer and cooled to 10-

15 °C. The pH of the aqueous layer was adjusted to 7.0-7.5 with hydrochloric acid and extracted with dichloromethane. A 500 mL of ethyl acetate was then added to the aqueous layer and the pH of the aqueous layer adjusted to 1.0-2.0 using hydrochloric acid. The organic layer was collected and distilled off under vacuum. 450 mL of ethyl acetate was added to the concentrated. The reaction mass was then heated to 50-55 °C, cooled to -5 to 0 °C and filtered. The solid obtained was washed with ethyl acetate and dried to yield Valsartan (1). Yield: 66%; Purity: 99.5%.
EXAMPLE-5: Purification of Valsartan (1)
100g of Valsartan (1) was added to a solution of 18.5 g of sodium hydroxide dissolved in 1000 mL of water at 15-20 °C. 200 mL of dichloromethane was added to the reaction mass and layers separated. The aqueous layer was collected and filtered through micron filter and distilled. The reaction mass was then cooled to 15-20 °C and pH adjusted to 1.0-2.0 with hydrochloric acid. The solid formed was filtered, washed the solid with water and dried. Yield: 98%; Purity: 99.89% (HPLC).

We claim:
1. A process for the preparation of Valsartan (1) having purity greater than
99.0 % by HPLC comprising:
a) reacting 4'-bromomethyl-2-biphenyl carbonitrile (8) with L-valine methyl ester hydrochloride (7) in the presence of a base to obtain (S)-methyl 2-((2'-cyanobiphenyl-4-yl)methylamino)-3-methylbutanoatehydrochloride (6);
b) reacting (S)-methyl 2-((2'-cyanobiphenyl-4-yl) methylamino)-3-methylbutanoatehydrochloride (6) with valeryl chloride (5) in the presence of a base to form (S)-methyl 2-(N-((2'-cyanobiphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (4);
c) reacting (S)-methyl 2-(N-((2'-cyanobiphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (4) with sodium azide (3) and tributyl tin chloride to obtain (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2); and
d) hydrolyzing (S)-methyl 2-(N-((2'-(1H-tetrazol-5-yl) biphenyl-4-yl) methyl) pentanamido)-3-methylbutanoate (2) in the presence of a base to obtain Valsartan (1).

2. The process as claimed in claim 1, wherein the base used in step a), step b), step d) can be selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate , sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide.
3. The process as claimed in claim 1, wherein the solvent used in the present invention is selected form water, methanol, ethanol, n-propanol, iso-propanol, tetrahydrofuran, 1, 4- dioxane, methyl acetate, ethyl acetate, toluene, o-xylene and mixtures thereof.
4. A process for the purification of Valsartan (1), comprising:

a) providing a solution of Valsartan (1) in a base and solvent at 15-20 0C;
b) optionally, adding suitable solvent;
c) adjusting pH of the reaction mixture by using suitable acid; and
d) isolating pure Valsartan (1).

5. The process as claimed in claim 4, wherein the base used in step a) can be selected from sodium hydroxide, potassium hydroxide, lithium hydroxide and cesium hydroxide.
6. The process as claimed in claim 4, wherein the solvent used in step a) and step b) can be selected from methanol, ethanol, water, propanol, dichloromethane, tetrahydrofuran, ethyl acetate and mixtures thereof.
7. The process as claimed in claim 4, wherein the acid used in step c) can be selected form hydrochloric acid, hydrobromic acid and sulfuric acid.
8. The process as claimed in claim 4, wherein the Valsartan (1) is having purity greater than 99.0% and having one or more of the following: