DESC:Field of the Invention
The specification discloses a process for the preparation of sacubitril or a pharmaceutically acceptable salt thereof and its novel intermediates.

Background of the invention
Sacubitril is an antihypertensive drug used in combination with valsartan. The combination is marketed under the brand name Entresto® by Novartis, is known for the treatment of heart failure. Sacubitril is chemically known as N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, compound of Formula I

Formula I

US Patent No. 5,217,996 & US 5,354,892 describe sacubitril and the methods of preparation.

There are several known methods of the preparation of sacubitril, which are described in various patents/patent applications no’s: US 9,085,529; US 8,946,481; US 8,263,629; US 9,006,249; US 8,835,668; US 9,061,973; US 9,181,175; US 8,703,990; US 20150274650; US 20140142320; US 20150274642; US 20150166468; US 20150210632; US 20090326066; US 20130172572; CN 104557600; CN104860894 and CN 10500117.

Summary of the Invention
One embodiment discloses a process for the preparation of compound of Formula IX

comprising the steps of:
a) reacting a compound of Formula II

with a compound of Formula III

wherein X is F, Cl, Br, I
to give a compound of Formula IV

;
b) oxidizing the compound of Formula IV to give a compound of Formula V ;
c) optionally, protecting the compound of Formula V with a suitable hydroxyl protecting group to give a compound of Formula VI

wherein Z is hydroxyl protecting group;
d) reacting the compound of Formula V or Formula VI with compound of Formula VII

to give a compound of Formula VIII

wherein Y is H or hydroxyl protecting group;
e) hydrogenating the compound of Formula VIII to give a compound of Formula IX; and
f) optionally, purifying the compound of Formula IX.

Another embodiment discloses the purification of compound of Formula-IX comprising the steps of:
a) hydrolyzing the compound of Formula IX to a compound of Formula X
;
b) crystallizing the compound of Formula X in presence of solvent; and
c) esterifying the compound of Formula X to obtain a compound of Formula IX.

One another embodiment discloses a process for the preparation of sacubitril of Formula I

comprising the steps of:
a) reacting the compound of Formula IX

with succinimide to give a compound of Formula XI
;
b) hydrolyzing the compound of Formula X to give a compound of Formula XII
; and
c) converting the compound of Formula XII into sacubitril of Formula I or a pharmaceutically acceptable salt thereof.

Another embodiment provides compounds of Formulae described as herein below.

Formula IV,

Formula V,

wherein Z is hydroxyl protecting group,
Formula VI,

wherein Y is H or hydroxyl protecting group,
Formula VIII

Formula IX.

Another embodiment discloses a process for the preparation of sodium salt of sacubitril of Formula I-a comprising the steps of:
a) dissolving sacubitril of Formula I

in a solvent in the presence of a base;
b) adding sodium source in a solvent to the solution obtained in step (a); and
c) isolating sodium salt of sacubitril of Formula I-a

Description of the Invention

The following definitions apply to terms as used herein:

The term "alkyl", unless otherwise specified, refers to a monoradical branched or unbranched saturated hydrocarbon chain having from 1 to 20 carbon atoms. This term can be exemplified by groups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, n-decyl or tetradecyl.

The term “aryl” means an aromatic carbocyclic moiety of up to 20 carbon atoms, which may be a single ring (monocyclic) or multiple rings (bicyclic, up to three rings) fused together or linked covalently. Any suitable ring position of the aryl moiety may be covalently linked to the defined chemical structure. Examples of aryl moieties include, but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, biphenyl, anthryl, phenanthryl, fluorenyl, indanyl, biphenylenyl, acenaphthenyl, acenaphthylenyl. In some embodiments, aryl groups have 6 to 20 carbon atoms.

The term "arylalkyl", unless otherwise specified, refers to alkyl-aryl linked through an alkyl portion (wherein alkyl is as defined above) and the alkyl portion contains 1-6 carbon atoms and aryl is as defined below. Examples of arylalkyl groups include benzyl, ethylphenyl, propylphenyl or naphthylmethyl.

The term “heterocyclyl” is intended to mean a 4-7 membered monocyclic saturated or partially unsaturated aliphatic ring or a 4-7 membered saturated or partially unsaturated aliphatic ring fused to a benzene ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen or sulphur. Suitable examples of such monocyclic rings include pyrrolidinyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, -tetrahydropyranyl, diazepanyl and azepanyl. Suitable examples of benzofused heterocyclic rings include indolinyl, isoindolinyl, 2,3,4,5-tetrahydro-1H-3-benzazepine or tetrahydroisoquinolinyl.

The term “heteroaryl” is intended to mean a 5-6 membered monocyclic aromatic or a fused 8-10 membered bicyclic aromatic ring containing 1 to 3 heteroatoms selected from oxygen, nitrogen and sulphur. Suitable examples of such monocyclic aromatic rings include thienyl, furyl, pyrrolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidyl, pyridazinyl, pyrazinyl and pyridyl. Suitable examples of such fused aromatic rings include benzofused aromatic rings such as quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, cinnolinyl, naphthyridinyl, indolyl, indazolyl, pyrrolopyridinyl, benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzoxadiazolyl, benzothiadiazolyl.

Various embodiments and variants of the present invention are described hereinafter.

One embodiment provides compounds of Formulae IV, V, VI, VIII, and IX or a salt, enantiomer, diastereomer, racemate or tautomer.

Another embodiment discloses a process for the preparation of compound of Formula IX according to scheme-1 below:

Scheme-1

The reaction of compound of Formula II with a compound of Formula III to give a compound of Formula IV can be carried out in a suitable solvent at a temperature of about 0°C to -10°C for a period of about 60 minutes.

The oxidation of compound of Formula IV is carried out in a suitable oxidizing agent and in a suitable solvent.

The suitable oxidizing agent may be one or more of peroxides; alkali or alkaline peroxides; peracids; hypohalite; perborates; N-oxides; permanganates; chromium compounds; ozone or oxygen. The peroxides is selected from hydrogen peroxide, alkali or alkaline peroxides is selected from sodium peroxide; peracids selected from peracetic acid, m-chloro perbenzoic acid, trifluoro peracetic acid, 2,4-dinitroperbenzoic acid, oxone or persulfuric acid; hypohalite is selected from sodium hypochlorite or sodium hypobromite; perborates is selected from sodium perborate; N-oxides is selected from pyridine-N-oxide or N-methylmorpholine-N-oxide; permanganates is selected from sodium permanganate or potassium permanganate; (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl, or (2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl or TEMPO; chromium compounds is selected from chromium trioxide, pyridinium chlorochromate, pyridinium dichromate, Collins reagent, Jones reagent or Sarett reagent.

Preferably the compound of Formula IV is oxidized to the corresponding aldehyde using a TEMPO mediated oxidation or with Des-Martin periodinane.

The compound of Formula V is protected with a suitable hydroxyl protecting groups to give a compound of Formula VI.

In general, hydroxyl protecting group is selected from ethers, esters or acid chloride. The ether is selected from methyl ether, methoxymethyl ether, methoxyethoxymethyl ether, benzyloxymethyl ether, tetrahydropyranyl ether, benzyl ether, p-methoxybenzyl ether or silyl ether; ester is selected from acetate, or pivaloate; acid chloride is selected from acetyl chloride or benzoyl chloride.

Alternatively, the compound of Formula V is proceeding to next step without the protection of hydroxyl group.

The compound of Formula V or VI is reacted with ethyl 2-(triphenylphosphoranylidene) propionate of Formula VII in a suitable solvent to give a compound of Formula VIII.

The compound of Formula VIII is hydrogenated to give a compound of Formula IX.

In a preferred embodiment, the hydrogenation of compound of Formula VIII carried out in presence of palladium/carbon.

In another preferred embodiment, the hydrogenation of compound of Formula VIII carried out in presence of transition metal catalysts, chiral ligands or combinations thereof. The transition metal catalyst comprises rhodium, iridium or ruthenium.

Suitable ligands for the organometallic complex generally are s-donor ligands, s-donor/p-acceptor ligands or s, p-donor/p-acceptor ligands. Suitable kind of ligand is selected from carbon monoxide, halides, phosphines, alkenyls, alkinyls, aryls or mixtures thereof.

Another embodiment discloses a process for the purification of compound of Formula IX according to scheme 2 below:

Scheme-2
The compound of Formula IX is subjected to hydrolysis in presence of a suitable solvent to give a compound of Formula X.

The compound of Formula X is subjected to crystallization in presence of suitable solvent.

The term "crystallization", as used herein, refers to a process by which a single diastereoisomer is preferentially crystallized out from a diastereoisomeric mixture, as defined herein.

In a another preferred embodiment, the compound of Formula X is treating with a chiral amine of Formula XV

wherein R1 and R2 are each independently selected from the group consisting of alkyl, an aryl, alkylaryl, a heterocyclyl, a heteroaryl, R3R4NC (=O)- or R5OC(=O)-;
wherein R3 and R4 are each independently selected from hydrogen or C1-7 alkyl; and R5 is C1-7 alkyl;
(*) means a chiral center with absolute stereochemistry (R) or (S);
to obtain the compound of Formula X.

The esterification of compound of Formula X to give a compound of Formula IX can be carried out in presence of esterifying agents.

In general, esterifying agent is selected from alkyl halides, thionyl halides, alcohols, dialkyl carbonates or dialkyl sulphate. More preferably the esterifiaction is carried out by using ethyl iodide in presence of cesium carbonate.

Another embodiment discloses a process for the preparation of sacubitril of Formula-I or a pharmaceutically acceptable salt thereof from the compound of Formula IX according to scheme-3 below:

Scheme-3

The compound of Formula IX is reacted with succinimide in presence of triphenyl phosphine and dialkyl azodicarboxylate in presence of a suitable solvent to give a compound of Formula XI.

In a preferred embodiment, dialkyl azodicarboxylate is diethyl azodicarboxylate and diisopropyl azodicarboxylate.

The compound of Formula XI is subjected to hydrolysis in presence of a suitable solvent to give a compound of Formula XII.

Another embodiment discloses a process for the preparation of sacubitril of Formula I or a pharmaceutically acceptable salt thereof from the compound of Formula XII according to scheme-4 below:

Scheme-4

The compound of Formula IX can be converted to sacubitril of Formula-I or pharmaceutically acceptable salt thereof according to the methods described in WO 2008/083967A2 and WO 2008/031567A1.

Another embodiment discloses a process for the preparation of sodium salt of sacubitril of Formula I-a

Comprising the steps of:
a) dissolving sacubitril of Formula I in a solvent in the presence of a base;
b) adding sodium source in a solvent to the solution obtained in step (a); and
c) isolating sodium salt of sacubitril of Formula I-a

The process involves dissolving sacubitril in a suitable solvent, followed by addition of solution of suitable base in suitable solvent at temperature of about -10°C to 10°C. Reaction mixture is stirred at temperature of about -10°C to 10°C for a period of 0.5 hour to 1 hour and filtered to obtain clear filtrate. Dropwise addition of solution of suitable sodium source in suitable solvent to the obtained clear filtrate at temperature of about -10°C to 10°C over a period of 0.5 hour to 1 hours.

The sodium source may be selected from one or more of sodium-2-ethylhexanoate, sodium hydroxide, sodium-2-ethyl-2-methylhexanoate, sodium 2-ethylbutanoate or sodium 2-methylpropanoate.

The base may be one or more of organic base or inorganic base. The organic base is selected from one or more of dimethylamine, diethylamine, triethylamine or ammonia. Inorganic base is selected from one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide or potassium t-butoxide.

Further, the process involves isolation of sodium salt of sacubitril. The reaction mixture is stirred for 0.5 hour to 1 hour followed by slow addition of solvent over the period of 15 minutes and continued stirring for 120 minutes at temperature of about 10°C to 20 °C. After completion of precipitation, sacubitril Sodium is collected by filtration of reaction mixture and washed with suitable solvent and dried under vacuum at temperature of about 35°C to 40 °C for period of 12 hours to obtain sacubitril sodium.

Another embodiment discloses sacubitril sodium of Formula I-a having purity more than 99 % when measured by HPLC.

In general, the hydrolysis of the embodiments can be carried out in presence of acid or base. The organic acid is selected from acetic acid, citric acid, formic acid, methanesulfonic acid, p-toluene sulfonic acid; the inorganic acid is selected from hydrochloric acid, or sulfuric acid; the organic base is selected from n-ethyldiisopropylamine, triethylamine, diethylamine, butylcyclohexylamine, diisopropylamine, dibutylamine, pyrrolidine, piperidine; and the inorganic base is selected from sodium carbonate, sodium hydroxide, potassium carbonate or potassium hydroxide.

If the hydrolysis is carried out with base, the obtained product is thereafter treated with acid in order to obtain the salt of the product.

In general, suitable solvent for the processes of the embodiments may be one or more of alcohol, halogenated solvent, acetates, amides, ether, hydrocarbon, water or mixture thereof. The alcohol solvent selected from methanol, ethanol or isopropyl alcohol; the halogenated solvent selected from dichloromethane or chloroform; the ether selected from methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether or tetrahydrofuran; the amides selected from dimethyl acetamide or dimethyl formamide; the acetate selected from ethyl acetate, propyl acetate or butyl acetate; the hydrocarbon selected from toluene, n-hexane, benzene or heptane.

The embodiments of the specification are further illustrated by way of following examples, which do not limit the scope of the claims. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the claims.

Example 1: Preparation of (S)-1-([1, 1’-biphenyl]-4-yl)-propane-2, 3-diol (Formula IV)
A reaction flask was charged with R-(-)-glycidol [Formula II] (10 mmol) in diethyl ether (150 mL) followed by slow addition of 4-biphenyl magnesium bromide [Formula III] (11 mmol) at temperature of about 0°C to -10 °C. After completion of addition, the reaction mixture was gradually heated to temperature of about 25 °C to 35 °C and maintained at this temperature for 60 min. The reaction mixture was then quenched with 2N hydrochloric acid and extracted with diethylether and the aqueous layer was washed with diethyl ether. The combined organic layer was washed with water, then by brine solution and concentrated under vacuum to provide semisolid mass. The obtained semisolid mass was isolated and crystallized with isopropyl ether to provide the title compound.
Yield: 89%

Example 2: Preparation of (S)-3-([1, 1’-biphenyl]-4-yl)-2-hydroxypropanal (Formula V)
A reaction flask was charged with a mixture of (S)-1-([1,1’-biphenyl]-4-yl)-propane-2,3-diol [Formula IV] (10 mmol) , TEMPO (1 mmol), tetra butyl ammonium chloride (1 mmol), dichloromethane (100 mL) , 1M sodium bicarbonate solution (100 mL) and 0.5 M potassium carbonate solution. The reaction mixture was stirred at temperature of about 25 °C to 35 °C followed by addition of N-chlorosuccinimide (1.5 mmol) and stirred till the completion of reaction. After completion of the reaction, the organic layer was separated and the aqueous phase was extracted with dichloromethane (2x50 mL). The organic extracts were washed with brine (2x50 mL), dried over sodium sulphate and concentrated under vacuum. The residue obtained was then purified by column chromatography with ethyl acetate/hexane to provide title compound.
Yield: 83%

Example 3: Preparation of 5-biphenyl-4(S)-hydroxy-2-methyl-2-pentenoic acid ethyl ester (Formula VIII)
A reaction flask was charged with (S)-3-([1, 1’-biphenyl]-4-yl)-2-hydroxypropanal [Formula V] (10 mmol) in dichloromethane (100 mL) and added ethyl 2-(triphenylphosphoranylidene) propionate (15 mmol) at 0° C. The reaction mixture was heated at temperature of about 25 °C to 35 °C and stirred for 1 hour. To the reaction mixture 20% aqueous solution of citric acid (100 mL) was added and stirred. The aqueous phase was extracted with dichloromethane (2x50 mL). The combined organic extract washed with brine (2x50 mL), dried over sodium sulphate and concentrated under vacuum. The obtained residue was purified by column chromatography with ethyl acetate/hexane to provide the title compound.
Yield: 64%

Example 4: Preparation of 5-biphenyl-4(R)-hydroxy-2-methyl-2- pentanoic acid ethyl ester (Formula IX)
A reaction flask was charged with 5-biphenyl-4(S)-hydroxy-2-methyl-2- pentenoic acid ethyl ester [Formula VIII] (10 mmol) in ethanol (20 mL) and added 5% palladium on charcoal (20% w/w) followed by hydrogenation at 60 psi for 4 hours. After completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated to give 5-biphenyl-4(R)-hydroxy-2(R)-methyl-2-pentanoic acid ethyl ester as an 80:20 mixture of diastereomer. The obtained mixture of diastereomer was then separated by column chromatography method with ethyl acetate/Hexane to provide the title compound.
Yield: 74 %

Example 5: Preparation of 5-biphenyl-4(S)-succinimide-2(R)-methyl pentanoic acid ethyl ester (Formula XI)
A reaction flask was charged with a mixture of 5-biphenyl-4(R)-hydroxy-2(R)-methyl-2- pentanoic acid ethyl ester [Formula IX] (10 mmol), triphenylphosphine (15 mmol), succinimide (11 mmol) in toluene (100 mL). The reaction mixture was stirred and diisopropyl azodicarboxylate (15 mmol) under nitrogen was added to the reaction mixture at ambient temperature for over 30 to 60 minutes. The reaction mixture was stirred for about 8 to 10 hours at temperature of about 40°C to 45 °C. After completion of the reaction, the reaction mixture was concentrated under vacuum. To the crude residue obtained, isopropyl ether was added and stirred for 30 minutes, filtered and filtrate was concentrated under vacuum. Product obtained was purified by column chromatography using ethyl acetate/hexane to provide the title product.
Yield: 60%

Example 6: Preparation of 5-biphenyl-4(S)-amino-2(R)-methyl pentanoic acid (Formula XII)
A reaction flask was charged with 5-biphenyl-4(S)-succinimide-2(R)-methyl pentanoic acid ethyl ester [Formula XI] (10 mmol) in water (100 mL) followed by addition of sodium hydroxide solution (50 mL) at ambient temperature. The reaction mixture was stirred for about 4 hours at temperature of about 70°C to 90 °C. After completion of the reaction, reaction mixture was concentrated under vacuum to obtain residue. To the obtained residue, isopropyl ether was added and stirred for 30 minutes, filtered and filtrate was concentrated under vacuum. The residue obtained was purified by column chromatography using ethyl acetate/hexane to provide the title compound.
Yield: 67%

Example 7: Preparation of 5-biphenyl-4(S)-t-butoxycarbonylamino-2(R)-methyl pentanoic acid (Formula XIII)
A reaction flask was charged with a mixture of 5-biphenyl-4(S)-amino-2(R)-methyl pentanoic acid [Formula XII] (10 mmol) in anhydrous tetrahydrofuran (100 mL), 4-(dimethylamino) pyridine and Boc-Anhydride (11 mmol). The reaction mixture was stirred for about 6 to 8 hours at ambient temperature. After completion of the reaction, the mixture was concentrated under vacuum. To the obtained residue, dichloromethane and water were added. The reaction mixture was stirred and the organic layer was washed with aqueous potassium hydrogen sulphate followed by aqueous potassium bicarbonate and dried over sodium sulphate. The organic layer evaporated to provide the title compound.
Yield: 89%

Example 8: Preparation of (2R, 4S)-4-amino- 5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (Formula XIV)
A reaction flask was charged with 5-biphenyl-4(S)-t-butoxycarbonylamino-2(R)-methyl pentanoic acid (10 mmol) in ethanol (150 mL) and heated to temperature of about 50°C to 60 °C followed by addition of thionyl chloride (15 mmol) over a period of about 45 minutes. The reaction mixture was stirred further for 2 hours. The mixture was concentrated under vacuum to obtain the residue and suspended in cyclohexane (200 mL). Precipitated compound was collected by filtration and dried to provide title compound.
Yield: 79%

Example 9: Preparation of sodium salt of sacubitril of Formula (I-a)
A reaction flask was charged with a mixture of (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (10 mmol) in dichloromethane (50 mL), pyridine 15 (mL) and succinic anhydride (10 mmol). The reaction mixture was stirred for about 12 hours at temperature of about 25 °C to 35 °C and concentrated to obtain the residue. The obtained residue was dissolved in ethyl acetate, washed with 1N HCl solution followed by brine and dried over sodium sulphate. Organic layer was evaporated to obtain the residue. To the obtained residue 1N sodium hydroxide solution was added and stirred for about 8 to 10 hours at room temperature. Compound is then precipitated by addition of acetone to the reaction mixture, filtered, washed and dried to provide title compound.
Yield: 85 %
HPLC Purity: 99.5 %

Example 10: Preparation of sodium salt of sacubitril of Formula (I-a)
A reaction flask was charged with a mixture of (2R, 4S)-4-amino-5-biphenyl-4-yl-2-methylpentanoic acid ethyl ester hydrochloride (10 mmol) in dichloromethane (50 mL), pyridine 15 (mL) and succinic anhydride (10 mmol). The reaction mixture was stirred for about 12 hours at at temperature of about 25 °C to 35 °C and concentrated to obtain the residue. The residue was dissolved in ethyl acetate, washed with 1N HCl solution followed by brine and dried over sodium sulphate. Organic layer was evaporated to obtain the residue. To the obtained residue, solution of sodium-2-ethylhexanoate (40.4 gm; 0.243 moles) in dichloromethane (350 mL) was added dropwise over the period of about 60 minutes maintaining temperature at about 5°C to 10 °C. Reaction mixture was further stirred for a period of about 60 min, reaction mixture becomes turbid. To the reaction mixture, acetone (3000 mL) was added slowly over the period of about 15 min and continued stirring for period of about 120 min at temperature of about 10 °C to 20 °C. After precipitation, sodium salt of sacubitril was collected by filtration and washed twice with dichloromethane (200 mL). The isolated wet material was dried under vacuum at temperature of about 35°C to 40 °C for a period of about 12 hours to provide the title compound.
Yield: 86 %
HPLC Purity: 99 %

Example 11: Preparation of sodium salt of sacubitril of Formula (I-a)
A reaction flask was charged with sacubitril (100 gm; 0.243 moles) in dichloromethane (1000 mL) and cooled to temperature of about 0°C to 5 °C, followed by slow addition of solution of triethyl amine (29.5 gm; 0.292 moles) in dichloromethane (150 mL) at temperature about 0°C to 5 °C. Reaction mass was stirred at temperature of about 0°C to 5°C for a period of 30 minutes and filtered to get clear solution. The obtained filtrate was cooled to temperature of about 5°C to 10 °C followed by dropwise addition of solution of sodium-2-ethylhexanoate (40.4 gm; 0.243 moles) in dichloromethane (350 mL) over a period of 60 minutes maintaining temperature at 5 °C to 10 °C. Reaction mixture was further stirred for a period of 60 minutes. The acetone (3000 mL) was added to the reaction mixture slowly over the period of 15 minutes and continued stirring for period of 120 minutes at temperature of about 10°C to 20°C to get precipitate. The obtained precipitate was filtrated, washed with dichloromethane (200 mL). The isolated wet material was dried under vacuum at temperature of about 35°C to 40 °C for a period of 12 hours to get tile compound.
HPLC Purity: >99.9 %
,CLAIMS:1. A process for the preparation of compound of Formula IX

comprising the steps of:
a) reacting a compound of Formula II

with a compound of Formula III

wherein X is F, Cl, Br, I
to give a compound of Formula IV
;
b) oxidizing the compound of Formula IV to give a compound of Formula V ;
c) optionally, protecting the compound of Formula V with a suitable hydroxyl protecting group to give a compound of Formula VI

wherein Z is hydroxyl protecting group;
d) reacting the compound of Formula V or Formula VI with compound of Formula VII

to give a compound of Formula VIII

wherein Y is H or hydroxy protecting group;
e) hydrogenating the compound of Formula VIII to give a compound of Formula IX; and
f) optionally, purifying the compound of Formula IX.

2. The process of claim 1, wherein the compound of Formula IV is subjected to a TEMPO mediated oxidation or with des-martin periodinane.

3. The process of claim 1, wherein the compound of Formula VIII is subjected to hydrogenation in presence of palladium/carbon, or transition metal catalysts, or chiral ligands or combination of transition metal catalysts and chiral ligands.

4. The process of claim 1, wherein the purification of compound of Formula IX comprising the steps of:
a) hydrolyzing the compound of Formula IX to a compound of Formula X
;
b) crystallizing the compound of Formula X in presence of solvent ; and
c) esterifying the compound of Formula X to obtain a compound of Formula IX.

5. A compound selected from:
Formula IV,
Formula V,
Formula VI
wherein Z is hydroxyl protecting group,
Formula VIII
wherein Y is H or hydroxy protecting group,
Formula IX.

6. The process of claim 1, further comprising the steps of:
a) reacting the compound of Formula IX

with succinimide to give a compound of Formula XI
;
b) hydrolyzing the compound of Formula XI to give a compound of Formula XII
; and
c) converting the compound of Formula XII into sacubitril of Formula I or a pharmaceutically acceptable salt thereof.

7. The process of claim 6, further comprising the steps of:
a) dissolving sacubitril of Formula I

in a solvent in the presence of a base;
b) adding sodium source in a solvent to the solution obtained in step (a); and
c) isolating sodium salt of sacubitril of Formula I-a

8. The process of claim 7, wherein the sodium sources is sodium-2-ethylhexanoate.

9. The process of claim 7, wherein the steps (a) and (b) are carried out at low temperature of about -10° C to 10°C.

10. The process of claim 7, wherein the base is selected from one or more of an organic base or an inorganic base.