FIELD OF THE INVENTION
The present invention relates to a process for preparation of sacubitril of Formula I or pharmaceutical acceptable salts thereof,
Formula I The present invention further provides a process for purifying sacubitril or its pharmaceutical acceptable salt.
BACKGROUND OF THE INVENTION
AHU-377, chemical name (2R, 4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2-methyl-pentanoic acid ethyl ester, also known as sacubitril is represented by the Formula I:
Formula I
It is a constituent of a drug for the treatment of hypertension and heart failure. AHU-377 (sacubitril) is disclosed in the patent US 5,217,996 and its process of preparation is subsequently disclosed in the literature (J. Med. Chem. 1995, 38, 1689-1700).
US 5,217,996 describes biaryl substituted 4-amino-butyric acid amide derivatives which are useful as neutral endopeptidase (NEP) inhibitors, e.g. as inhibitors of the

ANF-degrading enzyme in mammals. US 5,217,996 discloses N-(3-carboxyl-l-
oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid
ethyl ester as a preferred embodiment. In the preparation of said compound N-t-
butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid
ethyl ester of Formula (i) is hydrogenated in the presence of palladium on charcoal
to give N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-
methylbutanoic acid ethyl ester as a 80 : 20 mixture of diastereomers.
There are several other patent applications that discloses the preparation of the advanced intermediate of Formula 3 that is used in the preparation of sacubitril.
Formula 3
The above said patent applications include PCT applications such as 2017/009784, 2017/033212, 2017/141193, 2008/031567, 2008/083967, 2009/090251, 2011/088797, 2012/025502 and 2014/032627, and Indian patent application number 2647/DEL/2015 that discloses various processes for the preparation of advanced intermediate of Formula 3.

PCX application WO 2008/031567 discloses hydrogenation in presence of ligands such as Mandyphos ligand, Walphos ligand, Josiphos Solphos ligand.
PCX application WO2008/083967 discloses multistep process for the preparation
of N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-
butenoic acid ethyl ester through an intermediate, (S)-5-(biphenyl-4-carbonyl)pyrrolidin-2-one. Xhe said intermediate is converted to (S)-5-biphenyl-4-ylmethyl-l-(2,2-dimethylpropionyl)pyrrolidin-2- one followed by methylation, de-protection and ring opening to get (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid hydrochloride which is protected by Boc anhydride to get N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoicacid ethyl ester.
PCX application WO 2012/025502 discloses hydrogenation of N-protected-(4S)-(p-phenylphenylrnethyl)-4-amino-2-methyl-2-butenoic acid alkyl ester in presence of transition metal catalyst and chiral ligand.
Similarly, WO 2014/032627 and CN 105523964 discloses multistep process for preparation of advanced intermediate of Formula 3 of sacubitril. WO'627 discloses process of preparation of sacubitril by preparing (S)-l-([l,l'-biphenyl]-4-yl)-3-tert-butoxypropan-2-ol and converting it to (R)-l-(l-([l,l'-biphenyll-4-yl)-3-tert-butoxypropan-2-yl)pyrrolidine-2,5-dione followed by de-protection to get (R)-3-([l,l'-biphenyll-4-yl)-2-aminopropan-l-ol hydrochloride. Xhe compound so obtained is then reacted with boc anhydride to get N-protected compound which is then oxidized in presence of XEMPO and phosphorous ylide carbethoxyethylidene-triphenylphosphorane to form (R)-5-biphenyl-4-yl-4-tert-butoxycarbonylamino-2-methylpent-2-enoic acid which is used in preparation of sacubitril.
PCX application WO2017/009784 discloses preparation of sacubitril through an intermediate, ethyl (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2-methylpentanoate of Formula 3 or its acid addition salt wherein said intermediate is prepared by

esterification of (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2-methylpentanoic acid or its acid addition salt.
EP 555175 discloses the final step of chemical synthesis leading to sacubitril is represented by the reaction running in accordance with Scheme 1, wherein the advanced intermediate of Formula 3, reacts with succinic anhydride. The reaction results in crude sacubitril in the free carboxylic acid form.
Scheme-1:
Formula 3 Formula 1
Although there are several patent applications that discloses various processes for preparation of advanced intermediate of sacubitril and use of same for the preparation of sacubitril and its pharmaceutical acceptable salts, however, the prior published references discloses lengthy and complicated process for the preparation of sacubitril. Hence, there is always a need to develop an improved process of preparation of sacubitril which involves less number of steps and hence is economical at large scale production. In view of above, the present invention is focussed towards the manufacturing of sacubitril and its pharmaceutical acceptable salts wherein the process is simple and economically favourable.
OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved process for the preparation of sacubitril and/or its pharmaceutic al acceptable salts thereof.

Another object of the present invention is to prepare sacubitril and/or its pharmaceutical acceptable salts with high purity and use of said sacubitril or its pharmaceutical acceptable salts in preparation of valsartan sacubitril complex.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of sacubitril and/or its sodium salt thereof with high purity.
Accordingly, the present invention relates to a process for the preparation of
sacubitril or its sodium salt wherein said process comprises the steps of:
a) hydrolysis of ester compound of Formula V to give compound of Formula VI,

Formula V

Formula VI

;

b) deprotection and esterification of compound of Formula VI without isolation of intermediates, to give compound of Formula VII,


HCI.H2N

Formula VII

;

6

c) treatment of compound of Formula VII with succinic anhydride to give sacubitril of Formula I,

Formula 1

;

d) optionally purifying the sacubitril of Formula I; and
e) optionally converting the sacubitril of Formula I to its sodium salt.
In another aspect, the present invention relates to a process for the preparation of sacubitril or its sodium salt wherein said process comprises the steps of: a) oxidation of compound of Formula II in presence of oxidizing agent to give compound of Formula III,

Formula II

Formula III

;

b) condensation of compound of Formula III with ethyl 2-
(triphenylphosphoranylidene) propanoate in presence of metal halide to give compound of Formula IV,
7

Formula IV

;

c) hydrogenation of compound of Formula IV in presence of metal catalyst to give compound of Formula V,

Formula V

;

d) hydrolysis of ester compound of Formula V to give compound of Formula VI,

Formula VI

;

e) deprotection and esterification of compound of Formula VI without isolation of intermediates, to give compound of Formula VII,
8


HCI H2N
|(S)

Formula VII ;
e) treatment of compound of Formula VII with succinic anhydride to give sacubitril of Formula I,

Formula 1
f) optionally purifying the sacubitril of Formula I; and
g) optionally converting the sacubitril of Formula I to its sodium salt.
In another aspect, the present invention provides a process for the preparation of sacubitril sodium wherein said process comprises the steps of:
a) treating sacubitril of Formula-I with alcoholic or aqueous solution of sodium base in organic solvent;
b) distilling the organic solvent to get sacubitril sodium;
c) dissolving the sacubitril sodium in another organic solvent to get a solution; and
d) isolating the crystals and drying to get pure sacubitril sodium.
In one another aspect, the present invention relates to crystallization of sacubitril sodium comprising,
9

a) dissolving sacubitril sodium in organic solvent to get a solution;
b) optionally heating the solution at a temperature of 30-120oC;
c) cooling the solution to a temperature of 0oC to room temperature; and
d) isolating the crystals and drying to get sacubitril sodium.
DETAILED DESCRIPTION OF THE INVENTION
Drawings:
Fig. 1 represents X-Ray Powder Diffraction pattern of sacubitril sodium
Fig. 2 represents Differential Scanning Calorimetry of sacubitril sodium
Definitions:
The term “alkyl” as used in context of the present invention, refers to a straight or
branched chain alkyl group.
The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.
The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.
Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.
10

In one embodiment, the present invention relates to process of preparation of sacubitril or its sodium salt wherein said process comprises the steps of: a) oxidation of compound of Formula II in presence of oxidizing agent to give compound of Formula III, O


Formula II

Formula III

;

b) condensation of compound of Formula III with ethyl 2-
(triphenylphosphoranylidene) propanoate in presence of metal halide to give compound of Formula IV,

Formula IV

;

c) hydrogenation of compound of Formula IV in presence of metal catalyst to give compound of Formula V,
11

Formula V

;

d) hydrolysis of ester compound of Formula V to give compound of Formula VI,

Formula VI

;

e) deprotection and esterification of compound of Formula VI without isolation of intermediates, to give compound of Formula VII,


HCI.H2N

Formula VII ;
e) treatment of compound of Formula VII with succinic anhydride to give sacubitril of Formula I,
12


F ui uiuia x
f) optionally purifying the sacubiril of Formula I; and
g) optionally converting the sacubitril of Formula I to its sodium salt.
In another embodiment, the oxidizing agent is selected from the group comprising of Dess-Martin periodinone, oxalyl chloride in combination with dimethyl sulfoxide, 2-iodoxybenzoic acid, (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) in combination with sodium hypochlorite and so on.
In one another embodiment, the condensation of compound of Formula III with ethyl 2-(triphenylphosphoranylidene) propanoate is carried out in presence of metal halide selected from sodium bromide, potassium bromide, or potassium chloride.
In one another embodiment, the condensation of compound of Formula III with ethyl 2-(triphenylphosphoranylidene) propanoate is carried out in presence of base selected from the group comprising of hydroxides, carbonates and bicarbonates of alkali and alkaline earth metals and organic amines. Preferably the base is selected from the group comprising of sodium hydroxide, lithium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, cesium carbonate and the like.
Moreover, the condensation reaction is carried out in an organic solvent(s) selected from the group comprising of ethyl acetate, isopropyl acetate, propylene acetate, isobutyl acetate, butyl acetate, ethanol, methanol, isopropyl alcohol, tert-butyl
13

alcohol, n-butyl alcohol, methylene dichloride, chlorobenzene, tetrahydrofuran, dioxane, methyl tetrahydrofuran, toluene, dimethyl formamide, acetonitrile, acetone, methyl tert butyl ketone, methyl ethyl ketone, dichloroethane, dimethyl sulfoxide, N-methyl pyrrolidone, and mixture thereof. Preferably, the condensation reaction is carried out in presence of mixture of solvents such as isopropyl acetate and ethanol.
In further embodiment, the metal catalyst used for hydrogenation of compound of Formula IV is selected from palladium on carbon, palladium hydroxide, sodium borohydride and sulphuric acid. Moreover, the hydrogenation reaction is carried out in polar solvents selected from the group comprising of diglyme, tetrahydrofuran, methyl tetrahydrofuran, 1,4-dioxane, methanol, ethanol, water and mixture thereof.
In furthermore embodiment, the hydrolysis of ester compound of formula V is performed in presence of a base such as sodium hydroxide, potassium hydroxide, lithium hydroxide and polar solvent such as methanol, ethanol, tetrahydrofuran, methyl tetrahydrofuran, or mixture thereof.
The hydrolysed compound of Formula VI is Boc-deprotected and is esterified to get compound of Formula VII, in presence of thionyl chloride or oxalyl chloride in an organic solvent such as ethanol, methanol, isopropanol, butanol, t-butanol, n-heptane, hexane, and the like.
Moreover, compound of Formula VI can be prepared either by the process of the present invention or by any of the processes known from the prior published references.
In another embodiment, the reaction of compound of Formula VII with succinic anhydride is carried out in presence of base selected from dimethyl amino pyridine, triethyl amine, aniline, diisopropyl amine, diisopropyl ethyl amine, or mixture
14

thereof. The said reaction is carried in halogenated solvents such dichloromethane, chloroform, chlorobenzene, dichlorobenzene and the like.

as

In preferred embodiment, the sacubitril obtained as per the process of the present invention is directly converted to its pharmaceutical acceptable salts without any purification wherein the preferred salt is sacubitril sodium salt.
In another preferred embodiment, the sacubitril obtained as per the process of the present invention is optionally purified by crystallization in organic solvent to get crystallized sacubitril free base which is optionally converted to its pharmaceutical acceptable salts such as sacubitril sodium salt.
In further embodiment, the present invention provides crystallization of sacubitril of Formula I wherein the said product is isolated in different solvents at varied temperature conditions to get various polymorphic forms.
In a preferred embodiment, the present invention relates to a process for the
preparation of sacubitril or its sodium salt wherein said process comprises the steps
of:
a) hydrolysis of ester compound of Formula V to give compound of Formula VI,

Formula V

Formula VI

;

b) deprotection and esterification of compound of Formula VI without isolation of intermediates, to give compound of Formula VII,
15


HCI H2N
|(S)

Formula VII ;
c) treatment of compound of Formula VII with succinic anhydride to give sacubitril of Formula I,

Formula 1
d) optionally purifying the sacubitril of Formula I; and
e) optionally converting the sacubitril of Formula I to its sodium salt.
In another embodiment, the present invention provides a process for the preparation of sacubitril sodium comprising the steps of:
a) treating sacubitril of Formula-I with alcoholic or aqueous solution of sodium base in organic solvent;
b) distilling the organic solvent to get sacubitril sodium;
c) dissolving the sacubitril sodium in another organic solvent to get a solution; and
d) isolating the crystals and drying to get pure sacubitril sodium.
In further embodiment, preparation of sacubitril salt is carried out in organic solvent selected from the group comprising of alcohols such as ethanol, methanol,
16

isopropanol, butanol, t-butanol, isobutanol; esters such as ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, isopropylene acetate; ketones such as methyl ethyl ketone, acetone, methyl tert-butyl ketone; ethers such as tetrahydrofuran, methyl tetrahydrofuran, dioxane, diglyme; nitriles such as acetonitrile; hydrocarbons such as toluene, xylene, hexane, n-heptane, cyclohexane; halogenated solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixture thereof.
In furthermore embodiment, the base is selected from the group comprising of lithium hydroxide, potassium hydroxide, sodium hydroxide and sodium ethoxide.
In furthermore embodiment, the sacubitril salt is isolated by method selected from lyophihsation, filtration, evaporation under vacuum, centrifugation, or by any of the known conventional methods.
In one another embodiment, the present invention provides a process of preparation of sacubitril sodium wherein said process comprises the steps of:
a) treating sacubitril of Formula-I with ethanolic sodium hydroxide solution in ethanol;
b) distilling the ethanol to get sacubitril sodium;
c) treating the sacubitril sodium in a solvent system consisting of ethanol and heptane; and
d) isolating the crystals and drying to get pure sacubitril sodium.
In one more embodiment, the present invention provides the crystallization of sacubitril sodium comprising the steps of:
a) dissolving sacubitril sodium in organic solvent to get a solution;
b) optionally heating the solution at a temperature of 30-120°C;
c) cooling the solution to a temperature of 0°C to room temperature; and
d) isolating the crystals and drying to get pure sacubitril sodium.

In one embodiment, the organic solvent used for crystallization of sacubitril salt is selected from the group comprising of alcohols, ketones, halogenated solvents, ethers, hydrocarbons and mixture thereof.
Preferably, the organic solvent is selected from methanol, ethanol, chloroform, methyl ethyl ketone, acetone, methyl isobutyl ketone, isopropyl alcohol, methylene dichloride, carbon tetrachloride, tetrahydrofuran, methyl-tetrahydrofuran, dioxane, heptane, hexane, cyclohexane or mixture thereof.
In further embodiment, the sacubitril salt such as sacubitril sodium as obtained by the process of the present invention is characterized by purity of about 99.5% and above.
In further embodiment, the present invention provides crystallization of sacubitril salt such as sacubitril sodium wherein the said sacubitril sodium is crystallized in different solvents at varied temperature conditions to get various polymorphic forms.
In another embodiment, the present invention provides a crystalline form of sacubitril sodium characterized by X-ray powder diffraction peaks at about 3.13, 6.25, 7.26, 7.81, 9.29, 11.99, 12.47, 12.74, 12.97, 13.79, 15.58, 16.50, 16.89, 17.35, 17.65, 18.34, 19.97, 20.60, 21.56, 22.35, 22.70, 23.78, 24.14, 24.93, 26.25, 26.93, 27.74, 28.57, 31.48, and 35.80 ±O.2°20.
In another embodiment, the present invention provides a crystalline form of sacubitril sodium characterized by X-ray powder diffraction peaks as shown in Fig. 1
In further embodiment, is characterized by Differential Scanning Calorimetry (DSC) plot having peak onset at about 166.92°C and endotherm peak at about 173.0PC.

In another embodiment, the sacubitril or its sodium salt prepared as per the process of the present invention are used to form a complex with valsartan or its pharmaceutical acceptable salts to get valsartan-sacubitril complex or pharmaceutical acceptable salts thereof.
In one another embodiment, the sacubitril or its sodium salt prepared as per the process of the present invention is characterized by particle size distribution wherein, dw is 0.1 um to 200um.
In a preferred embodiment, the sacubitril or its sodium salt prepared as per the process of the present invention is characterized by particle size distribution wherein, dw is 2.0 um to 150um.
In still another embodiment, the present invention provides a pharmaceutical composition comprising valsartan sacubitril complex or its pharmaceutical acceptable salts wherein said valsartan sacubitril complex is prepared by using sacubitril or its sodium salt prepared as per the process of the present invention.
The present invention is explained below by way of examples. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.
EXAMPLES
EXAMPLE 1: Preparation of ethyl (2R,4SV5-(ri,r-biphenyll-4-vn-4-amino-
2-methylpentanoate hydrochloride (Formula VII)
Process 1: Charged (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methyl pentanoic acid of Formula VI in ethanol and added thionyl chloride at 25°C. Heated the reaction mas at a temperature of 60-75°C. After completion of reaction, distilled out the ethanol and isolated the crude compound. Charged acetonitrile and heated to 80°C followed by cooling at room temperature and filtration. Crystallized

the crude compound so obtained in ethyl acetate or acetonitrile to get pure ethyl (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride.
Process 2: Charged Ethanol (1.0V) and n-Heptane (2.0V) and added (2R, 4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methyl pentanoic acid of Formula VI and thionyl chloride(l .5 mol eq) at 25-30°C. Raised the temperature up to 60-70°C, stirred 2-4 hr at 60-70°C. After completion of reaction, distilled out the solvents and added n-Heptane (4.0V). Stirred the reaction mixture under nitrogen and filtered the solid followed by washing with n-heptane. Added ACN (5.0V) to the wet material so obtained and raised the reaction temperature up to 70-80°C. Cooled the reaction mass to RT and filtered followed by washing the solid with 1.0V of ACN to get ethyl (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride.
EXAMPLE 2: Preparation of Sacubitril (Formula I)
Process 1: Charged ethyl (2R,4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride of Formula VI in methylene dichloride and cooled the solution to 5-15°C. Added succinic anhydride and triethyl amine and stirred the reaction mass at 5-30°C till completion of reaction. After completion of reaction, quenched the reaction mas with IN hydrochloric acid. Distilled the solvents to get sacubitril crude compound.
Process 2: Charged ethyl (2R, 4S)-5-([l,l'-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride of Formula VI in methylene dichloride and cooled the solution to 5-15°C and added succinic Anhydride (1.16 m/e) and triethyl amine (1.45 m/e) at 0-10°C. Stirred 1-2 hrs at 5-10°C. After completion of reaction, quenched the reaction mass with IN HC1. Separated the layer and distilled out the organic layer to get sacubitril crude as oily residue with 85-95% yield.
EXAMPLE 3: Preparation of Sacubitril sodium salt

Process 1: Charged sacubitril of Formula I in ethanol and added sodium hydroxide ethanolic solution at room temperature. Stirred the reaction mass for 1 hr at room temperature. After completion of reaction, distilled off the ethanol to get crude mass. Crystallized the crude mass in ethanol and n-heptane to get pure sacubitril sodium salt with purity of 99.8%.
Process 2: Charged Sacubitril of Formula I in ethanol (4.5V) and added sodium hydroxide ethanolic solution at room temperature. Stirred the reaction mass for 1 hr at room temperature. After completion of reaction, distilled off the ethanol to get crude mass. Crystallized the crude mass in ethanol and cyclohexane to get pure sacubitril sodium salt.
Process 3: Charged sacubitril of Formula I in ethanol and added sodium hydroxide ethanolic solution at room temperature. Stirred the reaction mass for 1 hr at room temperature. After completion of reaction, distilled off the ethanol to get crude mass. Crystallized the crude mass in ethanol and n-heptane. Filtered the solid so obtained and charged acetone (7V) followed by stirring for 60-90 min. Filtered the product and added acetone again and stirred for 60-90 min at RT. Filtered the product and washed with acetone. Dried the crystals at 60-65°C to get sacubitril sodium with 60-70% yield.

WE CLAIM
1. A process for the preparation of sacubitril or its sodium salt comprising the steps
of:
a) hydrolysis of ester compound of Formula V to give compound of Formula VI,
Formula V Formula VI
b) deprotection and esterification of compound of Formula VI without isolation of intermediates, to give compound of Formula VII,
Formula VII ;
c) treatment of compound of Formula VII with succinic anhydride to give sacubitril of Formula I,

Formula 1
d) optionally purifying the sacubitril of Formula I; and
e) optionally converting the sacubitril of Formula I to its sodium salt.

2. The process as claimed in claim 1, wherein said hydrolysis of compound of Formula V is carried out in presence of base selected from sodium hydroxide, potassium hydroxide, lithium hydroxide; and in presence of polar solvent selected from methanol, ethanol, tetrahydrofuran, methyl tetrahydrofuran, or mixture thereof.
3. The process as claimed in claim 1, wherein said deprotection and esterification of compound of Formula VI is carried out in presence of thionyl chloride or oxalyl chloride.
4. The process as claimed in claim 1, wherein said compound of Formula VII is reacted with succinic anhydride in presence of solvent selected from dichloromethane, chloroform, chlorobenzene, or dichlorobenzene; and in presence of base selected from dimethyl amino pyridine, triethyl amine, aniline, diisopropyl amine, diisopropyl ethyl amine, or mixture thereof.
5. A process for the preparation of sacubitril sodium comprising the steps of:

a) treating sacubitril of Formula-I with alcoholic or aqueous solution of sodium base in organic solvent;
b) distilling the organic solvent to get sacubitril sodium;

c) dissolving the sacubitril sodium in another organic solvent to get a solution; and
d) isolating the crystals and drying to get pure sacubitril sodium.

6. The process as claimed in claim 5, wherein said organic solvent is selected from the group comprising of ethanol, methanol, isopropanol, butanol, t-butanol, isobutanol, ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, isopropylene acetate, methyl ethyl ketone, acetone, methyl tert-butyl ketone, tetrahydrofuran, methyl tetrahydrofuran, dioxane, diglyme, acetonitrile,, toluene, xylene, hexane, n-heptane, cyclohexane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride and mixture thereof.
7. The process as claimed in claim 5, wherein said process comprises the steps of:

a) treating sacubitril of Formula-I with ethanolic sodium hydroxide solution in ethanol;
b) distilling the ethanol to get sacubitril sodium;
c) treating the sacubitril sodium in a solvent system consisting of ethanol and heptane; and
d) isolating the crystals and drying to get pure sacubitril sodium.
8. A process for crystallization of sacubitril sodium comprising the steps of:
a) dissolving sacubitril sodium in organic solvent to get a solution;
b) optionally heating the solution at a temperature of 30-120°C;
c) cooling the solution to a temperature of 0°C to room temperature; and
d) isolating the crystals and drying to get pure sacubitril sodium.
9. The process as claimed in claim 1, wherein said sacubitril or its sodium salt is
used to prepare a complex with valsartan or its pharmaceutical acceptable salts to
get valsartan-sacubitril complex or pharmaceutical acceptable salts thereof.