An Improved Process for the Preparation of Valsartan

Related Application:

This application claims the benefit of Indian patent application number 1204/CHE/2006 filed on July 10, 2006 which is incorporated herein by reference.

Field of the Invention:

The present invention relates to an improved process for the preparation of valsartan compound of formula-1, chemically known as N-(l-Oxopentyl)-N-[[2'-(lH- tetrazol-5-yl)[l, 1 '-biphenyl]-4-yl]methyl]-L-valine.

Formula- 1 This invention also relates to a novel process for the preparation of amorphous form of valsartan compound of formula-1.

Valsartan is an orally active specific angiotension II antagonist acting on the

ATI receptor subtype. Valsartan is prescribed for the treatment of hypertension.

Valsartan is marketed as the free acid under the name DIOVAN. DIOVAN is prescribed as oral tablets in dosages of 40 mg, 80 mg, 160 mg and 320 mg of valsartan.

Extensive pharmacological investigations have shown that the compound of formula-1 and its pharmaceutically acceptable salts, for example, have pronounced angiotensin II antagonist properties. As is known, angiotension II has strong vasoconstrictor properties, additionally stimulates aldosterone secretion and thus causes distinct sodium/water retention. The consequence of angiotensin II activity is manifested, inter alia, in an increase in blood pressure. The importance of angiotensin II antagonists is in suppressing the vasoconstrictor and aldosterone secretion stimulating effects caused by angiotension II by competitive inhibition of the binding of angiotension II to the receptors. The angiotension II antagonist properties of the compounds of the formula I

and their pharmaceutically acceptable salts can be detected in the angiotensin II binding test.

Background of the Invention: Valsartan and process for its preparation was first disclosed in U.S. Patent

5,399,578 and also in Bioorganic & Medicinal Chemistry Letters, Vol.4, No.l, pp 29-34, 1994. Two different processes were disclosed for the preparation of valsartan in the above said literatures which are schematically represented by scheme-A and scheme-B. Scheme-A:

In the above synthetic scheme-A, synthesis start with the methyl ester of L-valine (1) and bromo derivative (2), in this scheme-A important step is building of the tetrazol ring with tributyl stannyl azide. This patent also describes alternate process, using benzyl ester of L-valine instead of methyl ester of L-valine, whereas the benzyl group is removed by catalytic hydrogenation. This main disadvantage of this process is it involves the chromatographic techniques for separation and purification in many stages, hence this process is not recommendable for commercial synthesis.

Scheme - B;

The above described synthetic scheme-B has some advantages over the scheme-A. This synthetic scheme starts with the commercially available raw material and does not involve any chromatographic techniques for purification/separation. But most of the intermediates are oily nature which cannot be easily crystallized. Hence the necessity for the repeated crystallization makes the process not suitable for commercial scale. The starting compound of scheme-B, the bromo derivative in subsequent reaction with L- Valine benzyl ester provides a product of purity of only about 80%. Use of such intermediate, in turn, results in contaminated Valsartan, which has to be re-crystallized many times, which entails elevated economic costs. Hence this method is industrially not feasible.

The present invention provides an improved process for the preparation Cf valsartan through novel intermediate compounds, which avoids the all prior art problems. The present invention also provides a novel process for the preparation of amorphous form of valsartan compound of formula- 1.

Brief description of the Invention:

The present invention relates to an improved process for the preparation of valsartan compound of formula-1, chemically known as N-(l-Oxopentyl)-N-[[2'-(lH- tetrazol-5-yl)[l , 1 '-biphenyl]-4-yl]methyl]-L-valine.

Formula- 1

Accordingly the first aspect of the present invention is to provide an improved process for the preparation of valsartan compound of formula-1 which comprises of the following steps; a) Reacting the compound of formula-2 with a mixture of metal azide and alkyl tin halide in a suitable solvent gives the compound of formula-3, b) Reacting the 5-chlorovaleric acid compound of formula-4 with suitable thiophenol derivative compound in presence of a base in a suitable solvent gives corresponding 5 -phenyl thio valeric acid compound of general formula-5, which upon chlorination in presence of a suitable chlorinating reagent in a suitable solvent gives corresponding acid chloride compound of formula-5 followed by condensation with either the compound of formula-3 or optionally with silyl protected compound of formula-3 a in presence of a base in a suitable solvent gives corresponding compound of general formula-6, c) Desulfurisation of the compound of general formula-6 with a mixture of transition metal halide hydrate and reducing agent in presence of a base in a suitable organic solvent gives the valsartan compound of formula-1,

d) Purification of valsartan compound of formula- 1 in a suitable chloro solvent followed by ester solvents or in chloro solvent alone or in ester solvent alone or in a mixture of chloro and ester solvents gives high pure valsartan compound of formula- 1.

The second aspect of the present invention is to provide an improved process for the preparation of valsartan compound of formula- 1 through novel imidazole intermediate compounds, which comprises of the following steps, a) Reacting the compound of formula-2 with a mixture of metal azide and alkyl tin halide in a suitable solvent gives the compound of formula-3, b) Reacting the 5-chlorovaleric acid compound of formula-4 with suitable imidazole derivative compound of general formula-7 in presence of a base in a suitable solvent gives corresponding 5-imidazolo valeric acid compound of general formula-S, which upon chlorination in presence of a suitable chlorinating reagent in a suitable solvent gives corresponding acid chloride compound of formula-8 followed by condensation with either the compound of formula-3 or optionally silyl protected compound of formula-3 a in presence of a base in a suitable solvent gives the compound of general formula-9, c) Desulfurisation of the compound of general formula-9 with a mixture of transition metal halide hydrate and reducing agent in presence of a base in a suitable organic solvent gives the valsartan compound of formula- 1, d) Purification of valsartan compound of formula- 1 in a suitable chloro solvent followed by ester solvents or in chloro solvent alone or in ester solvent alone or in a mixture of chloro and ester solvents gives high pure valsartan compound of formula- 1.

The third aspect of the present invention is to provide a novel process for the preparation of amorphous form of valsartan compound of formula- 1 which comprises of the following steps, a) Dissolving the valsartan compound of formula- 1 in a suitable ester solvent, b) Heating the reaction mixture to reflux, c) Stirring the reaction mixture at reflux temperature for 10-60 minutes, d) Bringing down the temperature of the reaction mixture to about 10-50°C and stirring for 1-5 hours,

e) Cooling down the reaction mixture to 0-5 ⁰ C and stirring for 2-3 hours, f) Isolating the product by filtration, g) Drying the compound under reduced pressure at 10-40 ⁰ C for 1-6 hours followed by 30-65 ⁰ C for 1-6 hours and finally at 40-80 ⁰ C for 20-25 hours gives amorphous valsartan.

Advantages of the present Invention:

• This process has an advantage that the condensation of 5-(phenyl thio) valeric acid compound of formula-5a with silyl protected compound of formula-3a gives highly pure N-(5-(phenylthio)-l-oxo-pentyl)-N-[[2'-(lH-tetrazol-5- yl)[l ₅ l'-biρhenyl]-4-yl]methyl]-L-valine compound of formula-6a.

• This process proceeds through the novel intermediate N-(5-(phenylthio)-l- oxo-pentyl)-N-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]me thyl]-L- Valine compound of formula-6a which in turn gives high yields of valsartan. • Provides novel imidazole intermediate compounds of general formula-8 and formula-9 for the preparation of valsartan.

• Provides a process starting from easily available raw materials

• Provides highly pure valsartan by purification of valsartan in chloro solvents followed by ester solvents. • The present invention is simple, commercially viable and eco-friendly process.

Detailed description of the Invention:

The present invention relates to an improved process for the preparation of valsartan compound of formula-1, chemically known as N-(l-Oxopentyl)-N-[[2'-(lH- tetrazol-5-yl)[l, 1 '-biphenyl]-4-yl]methyl]-L-valine.

Formula- 1

Accordingly the first aspect of the present invention is to provide an improved process for the preparation of valsartan compound of formula- 1, which comprises of the following steps; a) Reacting the compound of formula-2

Formula-2 with a mixture of metal azide like sodium azide and alkyl tin halide like tributyl tin chloride in a suitable solvent selected from non polar solvents like cyclohexane, n-hexane, ortho xylene, para xylene, meta xylene, mixture of xylenes, xylene, toluene, n-heptane, preferably xylene gives the compound of formula-3,

Formula-3 b) Reacting the 5-chlorovaleric acid compound of formula-4

Formula-4 with suitable thiophenol derivative in presence of a base like sodium methoxide, potassium tertiary butoxide, sodium hydride, preferably potassium tertiary butoxide in a suitable polar solvent like dimethyl sulfoxide, dimethylformamide, dimethylacetamide, preferably dimethylformamide gives

5-phenyl thio valeric acid compound of general formula-5,

FormuIa-5

Wherein R is H or C ₁ -C ₄ alkyl or haloalkyl or halogen or aryl which upon chlorination in presence of a suitable chlorinating reagent like thionyl chloride, oxalyl chloride, phosphorous halides preferably oxalyl chloride in a suitable solvent selected from chloro solvents like methylene chloride, carbon tetrachloride, chloroform, preferably methylene chloride and catalytic amount of dimethylformamide gives an acid chloride compound, which upon condensation with compound of formula-3,

Formula-3 or optionally with silyl protected compound of formula-3 a with triniethyl silyl chloride, tertiary butyl dimethyl silyl chloride, hexamethyl disilazane, preferably tertiary butyl dimethyl silyl chloride in a suitable solvent selected from chloro solvents like methylene chloride, chloroform, carbon tetrachloride, preferably methylene chloride, in presence of an organic base like pyridine in a suitable solvent selected from ethereal solvents like tetrahydrofuran gives the compound of general formula-6,

Formula-6 Wherein R is H or C ₁ -C ₄ alkyl or haloalkyl or halogen or aryl

c) Desulfurisation of the compound of general formula-6 with a mixture of transition metal halide hydrate like Nickel chloride hexahydrate and reducing agent like sodium borohydride in presence of a base like sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide or activated Raney-Nickel in presence of a base, in a suitable organic solvent selected from alcoholic solvents like methanol, ethanol, preferably methanol gives the compound of formula- 1,

Formula- 1 d) Purification of valsartan compound of formula- 1 in a suitable chloro solvent like methylene chloride followed by in a suitable ester solvent like ethyl acetate, propyl acetate, methyl acetate, tertiary butyl acetate, preferably ethyl acetate or in chloro solvent alone or in ester solvent alone or mixture of both chloro and ester solvents gives high pure compound of formula- 1.

The second aspect of the present invention is to provides an improved process for the preparation of valsartan compound of formula- 1 through novel imidazole intermediate compounds,

Formula- 1 which comprises of the following steps a) Reacting the compound of formula-2 with a mixture of metal azide like sodium azide and alkyl tin halide like tributyl tin chloride in a suitable solvent

selected from non polar solvents like Cyclohexane, n-Hexane, ortho xylene, para xylene, meta xylene, mixture of xylenes, xylene, toluene, n-Heptane, preferably xylene gives the compound of formula-3, b) Reacting the 5-chlorovaleric acid compound of formula-4 with suitable imidazole thiol derivative compound of general formula-7 in presence of a base like sodium methoxide, potassium tertiary butoxide, sodium hydride, preferably potassium tertiary butoxide in a suitable polar solvent like dimethyl sulfoxide, dimethylformamide, dimethylacetamide, preferably dimethylformamide to give corresponding 5-imidazolo valeric acid compound of general formula-8 which upon chlorination in presence of a suitable chlorinating reagent like thionyl chloride, oxalyl chloride, phosphorous halides preferably oxalyl chloride in a suitable solvent selected from chloro solvents like methylene chloride, carbon tetrachloride, chloroform, preferably methylene chloride and catalytic amount of dimethylformamide gives an acid chloride compound, which upon condensation with compound of formula-3 or optionally with silyl protected compound of formula-3a with trimethyl silyl chloride, tertiary butyl dimethyl silyl chloride, hexamethyl disilazane, preferably tertiary butyl dimethyl silyl chloride in a suitable solvent selected from chloro solvents like methylene chloride, chloroform, carbon tetrachloride, preferably methylene chloride, in presence of an organic base like pyridine in a suitable solvent selected from ethereal solvents like tetrahydrofuran gives the compound of general formula-9, c) Desulfurisation of the compound of general formula-9 with a mixture of transition metal halide hydrate like Nickel chloride hexahydrate and reducing agent like sodium borohydride in presence of a base like sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, preferably sodium hydroxide or activated Raney-Nickel in presence of a base, in a _, suitable organic solvent selected from alcoholic solvents like methanol, ethanol, preferably methanol gives the compound of formula- 1, d) Purification of valsartan compound of formula- 1 in a suitable chloro solvent like methylene chloride followed by in a suitable ester solvent like ethyl acetate, propyl acetate, methyl acetate, tertiary butyl acetate, preferably ethyl acetate or in chloro solvent alone or in ester solvent alone or mixture of both chloro and ester solvents gives high pure compound of formula- 1.

The third aspect of the present invention is to provide a novel process for the preparation of amorphous form of valsartan compound of formula- 1 which comprises of the following steps; a) Dissolving the valsartan compound of formula- 1 in a suitable ester solvents like ethyl acetate, methyl acetate, propyl acetate, preferably ethyl acetate, b) Heating the solution to reflux temperature, c) Stirred the reaction mixture at reflux temperature for 10-60 minutes, d) Bringing the reaction mixture temperature to about 20-50 ⁰ C and stirring for 1-5 hours, e) Cooling down the reaction mixture temperature to -10 to 5 ⁰ C and stirring for

1-5 hours, f) Isolating the product by filtration, g) Drying the compound under reduced pressure for 1-6 hours at about 10-50 ⁰ C followed by at temperature about 30-65 ⁰ C for 1-6 hours and finally drying at a temperature of about 40-80 ⁰ C for 20-25 hours gives amorphous valsartan.

The compound of general formula-5, formula-6, formula-7 arid formul-8 are novel intermediate which are used in the preparation of valsartan. The process of the present invention is simple, environment friendly and suitable over the prior art references.

The present invention is schematically represented by the following schemes.

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples: Example 1:

Preparation of N-[[2'-(lH-tetrazoI-5-yl)[l,l'-biphenyl]-4-yI]methyI]-L- Valine compound of formula-3:

Added a solution of 200 grams of 2-cyano[l,l'-biphenyl]-4-yl]methyl]-L- Valine methyl ester hydrochloride compound of formula-2 in 1000 ml of xylene to the aqueous sodium bicarbonate solution (211 grams in 1000 ml of water) at 25-35°C. Stirred for reaction mixture for 30 minutes at 25-35°C. Separated the organic phase containing free base compound of formula-2. A solution of 125.6 grams of sodium azide in 400 ml water was cooled to 0-5 ⁰ C and added 630.8 grams ^' of tributyl tin chloride slowly at 0-5 ⁰ C. Stirred the reaction mixture for 90 minutes at 0-5 ⁰ C. Added 800ml of xylene to the above mixture and stirred for 20 minutes. Separated the organic phase and aqueous phases. Added the separated organic phase to the above obtained organic phase containing free base compound of formula-2. Heated the reaction mixture to 140-145 ⁰ C. Stirred the reaction mixture for 10 hours at 140-145 ⁰ C. Cooled the reaction mixture to 25-35 ⁰ C. Added aqueous sodium hydroxide solution (110 grams in 1100 ml of water) and stirred the reaction mixture for further 10 hours at 25-35°C. Separated organic and aqueous phases. Washed the aqueous phase twice with toluene. Added 200 ml of methylene chloride to the aqueous phase and adjusted the pH to 6.6 with acetic acid, and washed the aqueous phase with methylene chloride. Separated the organic and aqueous phases. Washed the aqueous phase with methylene chloride. Added 800 ml of methylene chloride to the aqueous phase and adjusted the pH of the aqueous phase to 5.2 with 20% acetic acid. Stirred the reaction mixture for 2 hours at 25-35 ⁰ C. Filtered the precipitated compound and washed with methylene chloride and finally washed with water. Dried the compound at 95-100 ⁰ C to get the title compound. Yield: 151 grams (77%)

Example 2:

Preparation of 5-phenyl thio valeric acid compound of formula-5a:

A solution of 100 grams of 5-Chlorovaleric acid compound of formula-4, 82.6 ml of thiophenol and 2000 ml of dimethylformamide is slowly added to a suspension of 120 grams of sodium hydride and 700 ml of dimethyl formamide at 25-35°C. Stirred the reaction mixture for 3 hours at 25-35°C. Quenched the reaction mixture with water slowly at a temperature of 25-35°C. Added 2400 ml of 20% sodium hydroxide solution drop wise at 25-35°C. Cooled the reaction mixture to 10-15 ⁰ C. Adjusted pH of the reaction mixture 2.5 with hydrochloric acid. Stirred the reaction mixture at 25-35°C for 90 minutes. Filtered the solid and washed with water. The semidried material taken in 1500 ml of cyclohexane and heated to reflux temperature, stirred the reaction mixture for clear solution. Cooled the solution to 25-35°C and stirred for 3 hours. Filtered the solid and washed with cyclohexane. Dried the solid at 40-45 ⁰ C under reduced pressure for 6 hours to get title compound of formula-5a.

Yield: 119 grams (77.3%)

Example 3:

Preparation of N-(5-(phenyIthio)-l-oxo-pentyI)-N-[[2'-(lH-tetrazol-5-yl)[l, l'- biphenyl]-4-yl]methyl]-L- Valine compound of formula-6a:

A solution of 25 grams of 5-phenylthio valeric acid compound of formula-5a, 375 ml of dichloromethane and 9.4 ml of N,N'-dimethyl formamide is cooled to 0-5 ⁰ C. Added 11.4ml of oxalyl chloride to the reaction mixture at 0-5 ⁰ C. Stirred the reaction mixture for 2.5 hours at 0-5 ⁰ C. Distilled the solvent completely under reduced pressure at below 50 ⁰ C. Cooled the residue to 25-35°C. Added 106 ml of tetrahydro furan to the residue and decanted the solution. Added the decanted solution to 26 grams of N-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-L-Vali ne compound of formula-3 in 106 ml of tetrahydrofuran at a temperature of about -5 to 0 ⁰ C. Added a solution of 9.5 ml of pyridine and 95 ml of tetrahydrofuran to reaction mixture at -5 to 0 ⁰ C. Stirred the reaction mixture for 2 hours. Quenched the reaction mixture with methanol and allowed the reaction mixture to attain a temperature of about 25-35 ⁰ C. Added 75 ml of water to the reaction mixture. Stirred the reaction mixture for 1 hour at 25-35°C. Cooled the reaction mixture to 0-5 ⁰ C. Adjusted the pH of the reaction mixture to 7.5 with 10% sodium carbonate solution.

Distilled the solvent completely under reduced pressure at below 50 ⁰ C. Cooled the residue to 25-35°C. Added 185 ml of ethyl acetate to the residue and cooled to 0-5 ⁰ C. Adjusted the pH of the reaction mixture to 2 with 2N hydrochloric acid at 0-5 ⁰ C. Filtered the un reacted N-[[2'-(lH-tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-L- Valine compound of formula-3. Separated the organic phase and aqueous phase from filtrate. Distilled the organic phase at below 45 ⁰ C under reduced pressure. Cooled the residue to 25 -35 ⁰ C. Added 50 ml of methylene chloride to the residue and distilled completely under reduced pressure at below 45 ⁰ C. Isolated the product using mixture of methylene chloride and hexanes as a solvent. Dried the compound at 30-35 ⁰ C to get title compound.

Yield: 25.5 grams (63.4%)

Example 4:

Preparation of N-(5-(phenylthio)-l-oxo-pentyl)-N-[[2'-(lH-tetrazol-5-yl)[l, l'- biphenyI]-4-yl]methyl]-L- Valine compound of formula-6a:

A solution of 25 grams of 5-phenylthio valeric acid compound of formula-5a, 375 ml of dichloromethane and 9.4 ml of N,N'-dimethyl formamide is cooled to 0-5 ⁰ C. Added 11.4ml of oxalyl chloride to the reaction mixture at 0-5 ⁰ C. Stirred the reaction mixture for 2 hours at 0-5 ⁰ C. Distilled the solvent completely under reduced pressure at below 50 ⁰ C. Added 106 ml of methylene chloride to the residue, this is methylene chloride solution-I. A solution of 26g of N-[[2'-(lH-tetrazol-5-yl)[l,l'- biphenyl]-4-yl]methyl]-L-Valine compound of formula-3, 12 grams of acetamide, 12.8 grams of hexamethyldisilazane and 300 ml of methylene chloride was heated to reflux. Stirred the reaction mixture for 4 hours at reflux. Cooled the reaction mixture to -6 to -8°C. Added the above obtained methylene chloride solution- 1 to this reaction mixture at -6 to -8°C. Stirred for 45 minutes at -6 to -8°C. Quenched the reaction mixture with water at 25-35°C. Adjusted pH of the reaction to 7.5 with 10% sodium carbonate solution. Separated the organic and aqueous phases. Distilled the solvent completely under reduced pressure at 50 ⁰ C. Cooled the reaction mixture to 25-35°C. Isolated the solid using mixture of methylene chloride and hexanes as solvent. Dried the compound at 30-35 ⁰ C to get title compound. Yield: 25.5 grams (63.4%)

Example 5:

Preparation of valsartan compound of formula-1:

Added 43.7 grams of Nickel chloride hexahydrate to a solution of 10 grams of N-(5-(phenylthio)-l-oxo-pentyl)-N-[[2'-(lH-tetrazol-5-yl)[l ₎ l'-biphenyI]-4-yl] methyl] -L- Valine compound of formula-6a and 600 ml methanol at 25-35°C. Cooled the reaction mixture to 0-5 ⁰ C. Slowly added a solution of 20.8 grams of sodiumborohydride and 600 ml of aqueous sodium hydroxide solution (50 grams in 600 ml water) to the above reaction mixture at 0-5 ⁰ C. Stirred the reaction mixture for 20 minutes at 0-5 ⁰ C. Filtered the reaction mixture to remove unwanted solid and washed with methanol. Distilled the filtrate completely under reduced pressure at below 50 ⁰ C. Cooled the residue to 25-35°C and added 100 ml of water. Adjusted the pH of the reaction mixture to 5.3 with 20% acetic acid solution. Extracted the reaction mixture with methylene chloride. Distilled the solvent at 40-45 ⁰ C under reduced pressure. Isolated the solid using cyclohexane. Dried the compound at 40-45 ⁰ C to get title compound.

Yield : 3.7 grams (46.2%)

Example 6:

Preparation of 5-(lH-benzo[d]imidazoI-2-yIthio)pentanoic acid compound of formula-8a:

This derivative compound was prepared as per the procedure described in example-2 using lH-benzoimidazole-2-thiol instead of thiophenol. This compound was isolated as a solid. Yield: 90 grams

Example 7:

Preparation of N-[5-(lH-benzo[d]imidazol-2-ylthio)pentanoyl]-N-[[2'-(lH- tetrazol-5-yl)[l,l'-biphenyl]-4-yl]methyl]-L- Valine compound of formula-9a:

This compound was prepared as per the procedure described in example-3 or examρle-4 using 5-(lH-benzo[d]imidazol-2-ylthio)pentanoic acid in place of 5-phenyl thio valeric acid. This compound was isolated as a solid. Yield: 21 grams

Example 8: Preparation of valsartan compound of formula-1:

This compound was prepared as per the procedure described in example-5 using N-[5-(lH-benzo[d]imidazol-2-ylthio)pentanoyl]-N-[[2'-(lH-tet razol-5-yl)[l,l'- biphenyl]-4-yl]methyl]-L- Valine in place of phenyl thio derivative compound of formula-6a. This compound isolated as a solid. Yield: 2.8 grams

Example 9:

Purification of valsartan compound of formula-1:

A solution of 50 grams of valsartan compound of formula-1 and 850 ml of methylene chloride is heated to reflux. Stirred the reaction mixture for 45 minutes at reflux temperature. Treated the above obtained solution with carbon. Cooled the reaction mixture to 0-5 ⁰ C and stirred for 2 hours. Filtered the precipitated solid and the semi dried solid was taken in 330 ml of ethyl acetate. Heated to reflux temperature and treated the obtained solution with carbon. Cooled the reaction mixture to 34-36°C and stirred for 2 hours followed by cooled the reaction mixture to 10-15 ⁰ C and stirred the reaction mixture for 60 minutes. Further cooled the reaction to 0-5 ⁰ C. Stirred the reaction mixture for 3 hours at 0-5 ⁰ C. Filtered the precipitated solid and washed with chilled ethyl acetate. Dried the compound under reduced pressure at a temperature of about 30-35 ⁰ C for 4 hours, then at 50-55 ⁰ C for another 4 hours and finally at 68-72 ⁰ C for 24 hours to get high pure valsartan compound of formula- 1.

Yield: 32 grams

Example 10:

Preparation of amorphous form of valsartan compound of formula-1 A solution of 55 grams of valsartan compound of formula-1 and 330 ml of ethyl acetate was heated to reflux temperature. Stirred the reaction mixture at reflux for 30 minutes. The solution was treated with carbon. Cooled the reaction mixture to 34-36 ⁰ C and stirred for 2 hours followed by cooled the reaction mixture to 10-15 ⁰ C and stirred for 60 minutes. Further cooled the reaction mixture to 0-5 ⁰ C. Stirred for 3 hours at 0-5 ⁰ C. Filtered the precipitated solid and washed with chilled ethyl acetate. Dried the compound under reduced pressure at a temperature of about 30-35 ⁰ C for 4 hours, then at 50-55 ⁰ C for another 4 hours and finally at 68-72°C for 24 hours to get amorphous form of valsartan. Yield: 40 grams (73%)