DESC:SALTS OF SACUBITRIL AND THEIR USE FOR THE PREPARATION OF AMORPHOUS TRISODIUM SACUBITRIL VALSARTAN

FIELD OF THE INVENTION
The present invention relates to salts of sacubitril and their use for the preparation of amorphous trisodium sacubitril valsartan. In particular, the present invention relates to benzhydryl piperazine salts of sacubitril and a polymorph of L-lysine salt of sacubitril, and their use for the preparation of amorphous trisodium sacubitril valsartan.

BACKGROUND OF THE INVENTION
Sacubitril valsartan trisodium hemipentahydrate complex, chemically known as Octadecasodiumhexakis(4-{[(1S,3R)-1-([1,1´-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4oxobutanoate)hexakis(N-pentanoyl-N-{[2´-(1H-tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate)-water (1/15) is being marketed in the name of Entresto® in USA for the treatment of hypertension and heart failure. Its chemical structure is represented by the following Formula I.

Formula I
U.S. Patent No. 8,877,938 discloses a process for the preparation of a crystalline form of trisodium sacubitril valsartan hemipentahydrate and an amorphous form of linked prodrug of sacubitril and valsartan.
PCT Publication No. WO 2016/125123 discloses a process for the preparation of amorphous form of trisodium sacubitril valsartan.
Chinese Publication No. CN 105693543 discloses various salts of sacubitril.
Chinese Publication No. CN 105461647 discloses a process for the preparation of amorphous a, ß and ? form of trisodium valsartan sacubitril.
In the pharmaceutical industry, there is a constant need to identify the critical physicochemical parameters such as novel salts a compound and their use in the preparation of a drug substance that affect the drug's performance such as solubility, stability, etc., which may play a key role in determining a drug's market acceptance and success.
Therefore, there exists a need in the art to develop novel salts of sacubitril which can be used for the synthesis of trisodium sacubitril valsartan. There also exists a need in the art to provide a process for the preparation of amorphous trisodium sacubitril valsartan having desired purity and yield.

SUMMARY OF THE INVENTION
A first aspect of the present invention provides benzhydryl piperazine salts of sacubitril of Formula II.

Formula II
Wherein, R, R1, and R2 are independently selected from the group comprising hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, CH2F, CHF2, and CF3.
In one embodiment, the present invention provides benzhydryl piperazine salts of sacubitril of Formula (II), which includes but not limited to benzhydryl piperazine, 4-chloro-benzhydryl piperazine, 4-methoxy-benzhydryl piperazine, 3,5-dichloro-benzhydryl piperazine, 3,4-dichloro-benzhydryl piperazine, 4-fluoro-benzhydryl piperazine, 4-methyl-benzhydryl piperazine or 4-trifluoromethyl-benzhydryl-piperazine. Preferably, the salt of sacubitril is benzhydryl piperazine i.e., 1-(diphenylmethyl)piperazine.
In another embodiment, the benzhydryl piperazine salt of sacubitril is characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Figure 1.
In yet another embodiment, the benzhydryl piperazine salt of sacubitril is further characterized by differential scanning calorimetry (DSC) thermogram substantially as depicted in Figure 2.

A second aspect of the present invention provides a process for the preparation of benzhydryl piperazine salts of sacubitril of Formula II, comprising the steps of:
a) treating sacubitril with benzhydril piperazine derivative of Formula III, and

Formula III
Wherein, R, R1, and R2 are independently selected from the group comprising hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, CH2F, CHF2, and CF3.
b) isolating benzhydryl piperazine salts of sacubitril of Formula II.

A third aspect of the present invention provides a process for the preparation of trisodium sacubitril valsartan, comprising:
a) treating benzhydryl piperazine salts of sacubitril of Formula II with an acid to obtain sacubitril free acid,
b) adding valsartan to the sacubitril free acid obtained in step a),
c) providing sodium ion source to step b), and
d) optionally isolating trisodium sacubitril valsartan.

A fourth aspect of the present invention provides a L-lysine salt of sacubitril which is characterized by an XRPD pattern substantially as depicted in Figure 3.
In one embodiment, the L-lysine salt of sacubitril is further characterized by DSC thermogram substantially as depicted in Figure 4.

A fifth aspect of the present invention provides a process for the preparation of L-lysine salt of sacubitril, comprising:
a) treating sacubitril with L-lysine in a suitable solvent, and
b) isolating a L-lysine salt of sacubitril.

A sixth aspect of the present invention provides a process for the preparation of trisodium sacubitril valsartan, comprising:
a) treating L-lysine salt of sacubitril with an acid to obtain sacubitril free acid,
b) adding valsartan to the sacubitril free acid obtained in step a),
c) providing a sodium ion source to step b), and
d) optionally isolating trisodium sacubitril valsartan.

A seventh aspect of the present invention provides a process for the preparation of amorphous trisodium sacubitril valsartan, comprising:
a) treating trisodium sacubitril valsartan in non-polar solvent, and
b) isolating amorphous trisodium sacubitril valsartan.

In one embodiment of the seventh aspect, trisodium sacubitril valsartan or its hemipentahydrate is amorphous or crystalline.
An eighth aspect of the present invention provides use of benzhydryl piperazine salts of sacubitril for the preparation of trisodium sacubitril valsartan or its hemipentahydrate.
In one embodiment of the eighth aspect, trisodium sacubitril valsartan or its hemipentahydrate is amorphous or crystalline.
A ninth aspect of the present invention provides use of L-lysine salt of sacubitril for the preparation of trisodium sacubitril valsartan or its hemipentahydrate.
A tenth aspect of the present invention provides a process for the preparation of amorphous trisodium sacubitril valsartan, comprising:
a) reacting tromethamine salt of sacubitril with hydrochloric acid in ethyl acetate and water to obtain sacubitril free acid,
b) reacting sacubitril free acid with valsartan in presence of aqueous sodium hydroxide in toluene and methanol to provide trisodium sacubitril valsartan,
c) treating trisodium sacubitril valsartan in non-polar solvent, and
d) isolating amorphous trisodium sacubitril valsartan.

An eleventh aspect of the present invention provides a process for the preparation of crystalline trisodium sacubitril valsartan hemipentahydrate, comprising:
a) reacting tromethamine salt of sacubitril with hydrochloric acid in ethyl acetate and water to obtain sacubitril free acid,
b) reacting sacubitril free acid with valsartan in presence of aqueous sodium hydroxide in isopropyl alcohol and acetone to provide trisodium sacubitril valsartan,
c) treating trisodium sacubitril valsartan in acetone, and
d) isolating crystalline trisodium sacubitril valsartan hemipentahydrate.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the X-ray powder diffraction (XRPD) pattern of the benzhydryl piperazine salt of sacubitril.
Figure 2 depicts the differential scanning calorimetry (DSC) of the benzhydryl piperazine salt of sacubitril.
Figure 3 depicts the X-ray powder diffraction (XRPD) pattern of the L-lysine salt of sacubitril.
Figure 4 depicts the differential scanning calorimetry (DSC) of the L-lysine salt of sacubitril.
Figure 5 depicts the X-ray powder diffraction (XRPD) pattern of the amorphous trisodium sacubitril valsartan.
Figure 6 depicts the differential scanning calorimetry (DSC) of the amorphous trisodium sacubitril valsartan.

DETAILED DESCRIPTION OF THE INVENTION
Various embodiments and variants of the present invention are described hereinafter.
The term "about", as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term “solvent” or “suitable solvent”, as used herein, refers to a solvent which may include but not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene or xylene; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
The term “treating” as used herein, refers to dissolving, slurrying, stirring, or a combination thereof.
In a preferred embodiment of the second aspect, the treatment of sacubitril with benzhydryl piperazine derivative of Formula III is carried out in the presence of an organic solvent. Preferably, the organic solvent is ethyl acetate, n-heptane, or mixtures thereof.
The treatment of sacubitril with benzhydryl piperazine derivative of Formula III is carried out at a temperature of about 25°C to 80°C. Preferably, the reaction is carried out at a temperature of about 40°C to about 50°C.
The benzhydryl piperazine salt of sacubitril can be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof.
Sacubitril may be prepared by any of the methods known in the art, such as those described in U.S. Patent No. 5,217,996. The sacubitril used in step a) of second aspect and fifth aspect may be solid or in the form of a solution carried forward from the previous step(s).
In a preferred embodiment of the third aspect, the treatment of benzhydryl piperazine salts of sacubitril of Formula II with acid is carried out in the presence of a solvent.
The acid is selected from the group consisting of mineral acids or organic acids. The mineral acid is selected from the group comprising hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, boric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, or perchloric acid. The organic acid is selected from the group comprising formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, or an acidic ion exchange resin. Preferably, the acid is hydrochloric acid.
Preferably, the solvent is water, ethyl acetate, or mixtures thereof.
Preferably, the treatment of benzhydryl piperazine salts of sacubitril of Formula II with acid is carried out by dissolving or slurrying benzhydryl piperazine salts of sacubitril of Formula II in a solvent followed by the addition of acid.
The treatment of benzhydryl piperazine salts of sacubitril of Formula II with acid is carried out at a temperature of about 0°C to about 30°C. Preferably, the reaction is carried out at a temperature of about 10°C to about 20°C.
Sacubitril free acid obtained in step a) is optionally isolated or carried forward to the next step without isolation.
The addition of valsartan to sacubitril free acid is carried out in the presence of a solvent. Preferably, the solvent is toluene.
The sodium ion source is selected from the group comprising sodium hydroxide, sodium methoxide, sodium ethoxide, and sodium 2-ethylhexanoate. Preferably, the sodium ion source is sodium hydroxide.
Optionally, the trisodium sacubitril valsartan obtained in step d) is purified.
The trisodium sacubitril valsartan is optionally isolated by common isolation techniques such as extraction, crystallization, precipitation, filtration, decantation, centrifugation, or a combination thereof.
In a preferred embodiment of the fifth aspect, the treatment of sacubitril with L-lysine is carried out in the presence of an organic solvent. Preferably, the solvent is ethyl acetate.
Preferably, the treatment of sacubitril with L-lysine is carried out by dissolving or slurrying sacubitril in a solvent followed by the addition of L-lysine.
The treatment of sacubitril with L-lysine is carried out at the temperature of about 30°C to about 70°C. Preferably, the reaction was carried out at a temperature of about 40°C to about 55°C.
The L-lysine salt of sacubitril can be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof.
In a preferred embodiment of the present invention, the reaction of sacubitril free acid with benzhydryl piperazine or L-lysine may be carried out by directly contacting sacubitril free acid with benzhydryl piperazine or L-lysine.
In a preferred embodiment of the sixth aspect, the treatment of L-lysine salt of sacubitril with an acid is carried out in the presence of a solvent.
The acid is selected from the group consisting of mineral acids or organic acids. The mineral acid is selected from the group comprising hydrochloric acid, sulphuric acid, nitric acid, phosphoric acid, boric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, or perchloric acid. The organic acid is selected from the group comprising formic acid, acetic acid, trifluoroacetic acid, propionic acid, methanesulphonic acid, benzenesulphonic acid, p-toluenesulphonic acid, or an acidic ion exchange resin. Preferably, the acid is hydrochloric acid.
Preferably, the solvent is water, ethyl acetate, or mixtures thereof.
Preferably, the treatment of L-lysine salt of sacubitril with acid is carried out by dissolving or slurrying L-lysine salt of sacubitril in a solvent followed by the addition of acid.
The treatment of L-lysine salt of sacubitril with acid is carried out at a temperature of about 0°C to about 30°C. Preferably, the reaction is carried out at a temperature of about 10°C to about 20°C.
Sacubitril free acid obtained in step a) is optionally isolated or carried forward to the next step without isolation.
The addition of valsartan to sacubitril free acid is carried out in the presence of a solvent. Preferably, the solvent is toluene.
The sodium ion source is selected from the group comprising sodium hydroxide, sodium methoxide, sodium ethoxide, and sodium 2-ethylhexanoate. Preferably, the sodium ion source is sodium hydroxide.
Sodium ion source is added in solid form or in solution form dissolved in methanol or water. Preferably, the sodium ion source is dissolved in methanol prior to addition.
Optionally, the trisodium sacubitril valsartan obtained in step d) is purified.
In a preferred embodiment of the seventh aspect, step a) is carried out by dissolving trisodium sacubitril valsartan in a first non-polar solvent followed by the addition of a second non-polar solvent.
The non-polar solvent is selected from the group comprising pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane, and mixtures thereof. Preferably, the non-polar solvent is toluene, xylene, tert-butyl methyl ether, hexane, heptane, and mixtures thereof. More preferably, the non-polar solvent is toluene, n-heptane, or mixtures thereof.
Preferably, the first non-polar solvent is toluene and the second non-polar solvent is n-heptane.
The addition of second non-polar solvent leads to the precipitation of amorphous trisodium sacubitril valsartan.
The amorphous trisodium sacubitril valsartan can be isolated by common isolation techniques such as extraction, crystallization, precipitation, filtration, decantation, centrifugation, or a combination thereof.
The amorphous trisodium sacubitril valsartan contains water content below 5%, measured by Karl Fisher titration method.
In a preferred embodiment of the seventh aspect, the trisodium sacubitril valsartan of step a) is obtained by treating benzhydryl piperazine salts of sacubitril or L-lysine salt of sacubitril or calcium salt of sacubitril with acid to obtain sacubitril free acid, which is further reacted with valsartan and sodium ion source to afford trisodium sacubitril valsartan.
The calcium salt of sacubitril can be in crystalline or semi crystalline or amorphous form, which is prepared by the methods known in the art.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES:
Example-1: Preparation of benzhydryl piperazine salt of sacubitril
To a stirred solution of Ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride (10.0 g) in ethyl acetate (50 mL), triethyl amine (7.75 mL) and succinic anhydride (3.73 g) were added and stirred for 10 minutes at 0°C to 5°C. The temperature of the reaction mixture was raised to 30±3°C and stirred for 5 hours. To this mixture, water (50 mL) was added, cooled to 10°C to 15°C and adjusted pH to 2.0 with saturated aqueous hydrochloric acid. The reaction mixture was stirred for 15 minutes and layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined ethyl acetate layer was washed with saturated sodium chloride solution and dried over anhydrous sodium sulphate. The ethyl acetate layer was distilled under vacuum at 45°C to 50°C to obtain residue. To the obtained residue, ethyl acetate (50 mL) was added and stirred to get clear solution. To the clear solution, benzhydryl piperazine (7.2 g) was added, heated to 50°C and stirred for 1 hour. Subsequently, n-heptane (150 mL) was added to the reaction mixture and stirred for 30 minutes at 50°C. Thereafter, the reaction mixture was cooled to 30±3°C and stirred for 24 hours. The separated solid was filtered and washed with n-heptane (30 mL) and dried under vacuum to obtain desired product.
Yield: 18.0 g
HPLC Purity (by % area): 99.02%

Example-2: Preparation of amorphous trisodium sacubitril valsartan
To a stirred solution of benzhydryl piperazine salt of sacubitril (10.0 g) in water (100 mL) and ethyl acetate (50 mL), aqueous hydrochloric acid was added to adjust pH to 2.0 at 10°C to 15°C. The reaction mixture was stirred for 15 minutes and layers were separated. The aqueous layer was extracted with ethyl acetate (50 mL) and the combined ethyl acetate layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulphate. The ethyl acetate layer was distilled under vacuum at 45°C to 50°C to obtain residue. To the obtained residue, toluene (50 mL) was added and stirred to get clear solution. To the clear solution, valsartan (6.5 g) was added and stirred for 15 minutes at 25°C to 30°C. Subsequently, methanolic sodium hydroxide solution (1.8 g sodium hydroxide in 50 mL of methanol) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was filtered through hyflo® bed and washed hyflo® bed with methanol (10 mL). The filtrate was distilled under vacuum at 50°C to 60°C to afford residue. The obtained residue was dissolved in toluene (70 mL) under nitrogen atmosphere and slowly added n-heptane (210 mL). The reaction mixture was stirred for 2 hours at 30±3°C. The separated solid was filtered, washed with n-heptane (20 mL), and dried under vacuum to obtain amorphous trisodium sacubitril valsartan.
Yield: 11.5 g

Example-3: Preparation of L-lysine salt of sacubitril
To a clear solution of sacubitril (1.6 g) in ethyl acetate (16 mL), L-Lysine (0.57 g) was added at 25°C to 30°C. The reaction mixture was heated to 50°C stirred for 1 hour. The mixture was cooled to 30°C and stirred for 2 hours. The separated solid was filtered, washed with ethyl acetate (5.0 mL) and dried under vacuum at 50°C to obtain desired product.
Yield: 1.7 g
HPLC Purity (by % area): 99.29%

Example-4: Preparation of amorphous trisodium sacubitril valsartan
To a stirred solution of L-lysine salt of sacubitril (5.0 g) in water (50 mL), ethyl acetate (50 mL) was added and cooled to 10°C to 20°C. To this solution, concentrated hydrochloric acid (2.0 mL) was added to adjust pH to ~2.0 and stirred for 15 minutes. The layers were separated and aqueous layer was extracted with ethyl acetate (25 mL). The combined ethyl acetate layer was washed with water (50 mL), 10% aqueous sodium chloride (50 mL) solution and dried over anhydrous sodium sulphate. The organic layer was distilled under vacuum at 45°C to 50°C to obtain residue. The obtained residue was dissolved toluene (25 mL) and valsartan (3.90 g) was added. Subsequently, methanolic sodium hydroxide solution (1.08 g of sodium hydroxide dissolved in 25 mL of methanol) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was filtered through hyflo® bed and washed hyflo® bed with toluene (10 mL). The filtrate was distilled under vacuum at 55°C to 60°C to obtain residue. To the obtained residue, toluene (10 mL) was added and distilled to obtain residue. The obtained residue was dissolved in toluene (35 mL) under nitrogen atmosphere and slowly added n-heptane (100 mL). The mixture was stirred for 2 hours at 30±3°C. The separated solid was filtered, washed with n-heptane (20 mL) and dried under vacuum at 50°C for 10 to 12 hours.
Yield: 7.0 g

Example-5: Preparation of amorphous trisodium sacubitril valsartan
To a stirred solution of calcium salt of sacubitril (5.0 g) in water (50 mL), ethyl acetate (50 mL) was added and cooled to 10°C to 20°C. To this solution, concentrated hydrochloric acid (3.0 mL) was added to adjust pH to ~2.0 and stirred for 15 minutes. The layers were separated and aqueous layer was extracted with ethyl acetate (50 mL). The combined ethyl acetate layer was washed with water (50 mL), 10% aqueous sodium chloride (50 mL) solution and dried over anhydrous sodium sulphate. The organic layer was distilled under vacuum at 45°C to 50°C to obtain residue. The obtained residue was dissolved toluene (50 mL) and valsartan (5.06 g) was added. Subsequently, methanolic sodium hydroxide solution (1.39 g of sodium hydroxide dissolved in 50 mL of methanol) was added to the reaction mixture and stirred for 30 minutes. The reaction mixture was filtered through hyflo® bed and washed hyflo® bed with toluene (10 mL). The filtrate was distilled under vacuum at 55°C to 60°C to obtain residue. To the obtained residue, toluene (20 mL) was added and distilled to obtain residue. The obtained residue was dissolved in toluene (35 mL) under nitrogen atmosphere and slowly added n-heptane (90 mL). The mixture was stirred for 2 hours at 30±3°C. The separated solid was filtered, washed with n-heptane (20 mL) and dried under vacuum at 50°C for 10 to 12 hours.
Yield: 9.4 g

Example-6: Preparation of tromethamine salt of sacubitril
A stirred mixture of sacubitril hydrochloride (70 g) in ethyl acetate (350 mL) was cooled to 3±3°C and then triethyl amine (56.2 mL) was added at 3±3°C. To this mixture, succinic anhydride (22.1 g) was added at 3±3°C and stirred for 5 hours at 15±3°C. After completion of the reaction, water (350 mL) was added at 15±3°C followed by the addition of concentrated hydrochloric acid (25mL). The reaction mixture was stirred for 30 minutes and separated layers. The aqueous layer was extracted with ethyl acetate (210 mL) and the combined organic layer was washed with water (350 mL) and 10% aqueous sodium chloride solution (350 mL). The organic layer was distilled under vacuum at 45°C to 50°C to obtain residue. To the obtained residue, ethyl acetate (210 mL) was added and distilled at 45°C to 50°C. The obtained residue was dissolved in ethyl acetate (560 mL) and then tromethamine (24.4 g) was added. The reaction mixture was heated to 60±3°C and stirred for 3 hours at 60±3°C. The mixture was cooled to 30±3°C and stirred for 3 hours. The separated solid was filtered, washed with ethyl acetate (140 mL), and dried under vacuum at 50±3°C for 10 hours.
Yield: 102.0 g
HPLC Purity (by % area): 99.77%

Example-7: Preparation of crystalline trisodium sacubitril valsartan hemipentahydrate
A stirred mixture of tromethamine salt of sacubitril (75 g) in water (375 mL) and ethyl acetate (375 mL) was cooled to 15±5°C and then concentrated hydrochloric acid (18.8 mL) was added. The reaction mixture was stirred for 30 minutes and layers were separated. The aqueous layer was extracted with ethyl acetate (225 mL) and the combined organic layer was washed with 10% aqueous sodium chloride solution (375 mL). The organic layer was distilled under vacuum at 45°C to 50°C to obtain residue. The obtained residue was dissolved in isopropyl alcohol (375 mL) and then valsartan (62.3 g), and acetone (375 mL) were added. The mixture was cooled to 15±5°C, aqueous sodium hydroxide solution (16.9 g of sodium hydroxide in 37 mL of water) was added at 15±5°C and stirred for 30 minutes. The reaction mixture was filtered and the filtrate was distilled under vacuum at 45°C to 50°C to obtain residue. To the obtained residue, acetone (225 mL) was added and distilled at 45°C to 50°C. The obtained residue was dissolved in acetone (750 mL) and stirred for 2 hours at 50±3°C. The reaction mixture was cooled to 30±3°C and stirred for 2 hours. The separated solid was filtered, washed with acetone (75 mL), and dried under vacuum at 50±3°C for 12 hours.
Yield: 115.0 g
HPLC Purity (by % area): 99.91%

Example-8: Preparation of amorphous trisodium sacubitril valsartan
A stirred mixture of sacubitril tromethamine salt (75 g) in water (375 mL) and ethyl acetate (375 mL) was cooled to 15±3°C and then concentrated hydrochloric acid (20 mL) was added. The reaction mixture was stirred for 30 minutes and layers were separated. The aqueous layer was extracted with ethyl acetate (225 mL) and the combined organic layer was washed with water (375mL) and 10% aqueous sodium chloride solution (375 mL). The organic layer was distilled under vacuum at 45°C to 50°C to obtain residue. The obtained residue was dissolved in toluene (375 mL) and then valsartan (61.3 g), and methanol (375 mL) were added. The mixture was cooled to 15±3°C, aqueous sodium hydroxide solution (16.9 g of sodium hydroxide in 375 mL of methanol) was added at 15±5°C and stirred for 30 minutes. The reaction mixture was filtered and the filtrate was distilled under vacuum at 45°C to 50°C to obtain residue. To the obtained residue, toluene (150 mL) was added and distilled under vacuum at 45°C to 50°C. The obtained residue was dissolved in toluene (600 mL) at 58±3°C and slowly added to n-heptane (1500 mL). The reaction mixture was stirred for 2 hours at 30±3°C, the separated solid was filtered, washed with n-heptane (150 mL) and dried under vacuum at 50±3°C for 12 hours.
Yield: 115.0 g
HPLC Purity (by % area): 99.84%
,CLAIMS:We Claim:

1. A process for the preparation of benzhydryl piperazine salts of sacubitril of Formula II, comprising the steps of:
a) treating sacubitril with benzhydril piperazine derivative of Formula III, and

Formula III
wherein, R, R1, and R2 are independently selected from the group comprising hydrogen, halogen, C1-C6 alkyl, C1-C6 alkoxy, CH2F, CHF2, and CF3,
b) isolating benzhydryl piperazine salts of sacubitril of Formula II.

2. A process for the preparation of trisodium sacubitril valsartan, comprising:
a) treating benzhydryl piperazine salts of sacubitril of Formula II with an acid to obtain sacubitril free acid,
b) adding valsartan to the sacubitril free acid obtained in step a),
c) providing sodium ion source to step b), and
d) optionally isolating trisodium sacubitril valsartan.

3. L-lysine salt of sacubitril characterized by an XRPD pattern substantially as depicted in Figure 3 and/or DSC thermogram substantially as depicted in Figure 4.

4. A process for the preparation of L-lysine salt of sacubitril, comprising:
a) treating sacubitril with L-lysine in a suitable solvent, and
b) isolating a L-lysine salt of sacubitril.

5. A process for the preparation of trisodium sacubitril valsartan, comprising:
a) treating L-lysine salt of sacubitril with an acid to obtain sacubitril free acid,
b) adding valsartan to the sacubitril free acid obtained in step a),
c) providing a sodium ion source to step b), and
d) optionally isolating trisodium sacubitril valsartan.

6. The process according to claim 2 or 5, wherein the trisodium sacubitril valsartan is amorphous or crystalline.

7. A process for the preparation of amorphous trisodium sacubitril valsartan, comprising:
a) treating trisodium sacubitril valsartan in non-polar solvent, and
b) isolating amorphous trisodium sacubitril valsartan.

8. A process for the preparation of amorphous trisodium sacubitril valsartan, comprising:
a) reacting tromethamine salt of sacubitril with hydrochloric acid in ethyl acetate and water to obtain sacubitril free acid,
b) reacting sacubitril free acid with valsartan in presence of aqueous sodium hydroxide in toluene and methanol to provide trisodium sacubitril valsartan,
c) treating trisodium sacubitril valsartan in non-polar solvent, and
d) isolating amorphous trisodium sacubitril valsartan.

9. The process according to claim 7 or 8, wherein the non-polar solvent is selected from the group comprising pentane, cyclopentane, n-hexane, cyclohexane, n-heptane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, dichloromethane, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane, and mixtures thereof.
10. A process for the preparation of crystalline trisodium sacubitril valsartan hemipentahydrate, comprising:
a) reacting tromethamine salt of sacubitril with hydrochloric acid in ethyl acetate and water to obtain sacubitril free acid,
b) reacting sacubitril free acid with valsartan in presence of aqueous sodium hydroxide in isopropyl alcohol and acetone to provide trisodium sacubitril valsartan,
c) treating trisodium sacubitril valsartan in acetone, and
d) isolating crystalline trisodium sacubitril valsartan hemipentahydrate.