DESC:Field of Invention
The present invention relates to a novel process for the preparation of neutral endopeptidase (NEP) inhibitors. More particularly, the present invention relates to a novel process for the preparation of Sacubitril or stereoisomers thereof. The present invention also relates to novel intermediates useful for the preparation of NEP inhibitors and preparation process thereof. Also the NEP inhibitors prepared from the present invention may be used in the preparation of medicaments useful for the treatment of disorders and conditions in which they are indicated.

Background of the Invention
The present invention is directed to a novel process for the preparation of NEP inhibitor, Sacubitril. The present invention also relates to compounds obtained from the novel process, useful as novel intermediates for the preparation of Sacubitril or stereoisomers thereof.
Neutral endopeptidase (NEP) also known as neprilysin, is a zinc-dependent metalloprotease that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptides such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), enkephalins, substance P, neurotensin, oxytocin, and bradykinin. Of these, ANP has several effects including vasodilation, natriuresis/diuresis as well as inhibition of cardiac hypertrophy and ventricular fibrosis. Thus, NEP plays an important role in blood pressure homeostasis and cardiovascular health. NEP inhibitors are thereby useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase, particularly cardiovascular disorders such as hypertension, renal insufficiency including edema and salt retention, pulmonary edema and congestive heart failure.
Sacubitril (AHU-377), a neprilysin inhibitor, is a prodrug which loses an ethyl group by hydrolysis to release the active metabolite, Sacubitrilat (LBQ657). Sacubitril is chemically known as (2R, 4S)-5-biphenyl-4-yl-4-(3-carboxy-propionylamino)-2methyl-pentanoic acid ethyl ester, having the molecular formula C24H29NO5 and represented by the following structure:

Currently, Sacubitril is marketed in combination with Valsartan in the form of film-coated oral tablets by Novartis Pharmaceuticals Corporation under the trade name, ENTRESTO®, indicated for the treatment of heart failure.
Processes for preparing NEP inhibitors are known in the art. US patent no. 5,217,996 describes biaryl substituted 4-aminobutyric acid amide derivatives useful as NEP inhibitors. US patent no. 5,217,996 discloses the process for preparing sacubitril, comprising hydrogenating N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester. However, a major drawback of the process is that the hydrogenation step is not very selective and yields N-t-butoxycarbonyl-(4S)-(pphenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester as an 80:20 mixture of diastereomers. Moreover, the process for preparing N-t-butoxycarbonyl-(4R)-(pphenylphenylmethyl)-4-amino-(2)-methyl(2)-butenoic acid ethyl ester requires D-tyrosine as starting material, which is an unnatural amino acid and is not readily available.
US patent no. 8,115,016 discloses a method for preparing sacubitril starting from pyroglutamic acid, which is a multiple stage reaction, difficult, and with low yields. International patent application WO2010/081410, describes a method for preparing an enantiomerically pure N-acyl biphenyl alanine compounds using chiral amines and resolution of the obtained diastereomeric mixtures. However, one main disadvantage of any chiral resolution of racemates compared to a direct asymmetric synthesis of one of the enantiomers is that the yield cannot reach more than 50% at maximum. Though epimerization of the undesired enantiomer and resubmission to resolution is possible in some cases, it generally requires additional processing steps, and thereby creating an additional burden.
International patent publication no. WO2009/090251 describes an alternative route for preparing the compound, N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester with improved diastereoselectivity when compared to that obtained in US patent no. 5,217,996. However, a disadvantage associated is that it is difficult process, tedious and commercially non-viable.
PCT publication no. WO 2011/035569 describes an alternative method for preparing an N-acylbiphenyl alanine. The desired product is obtained as racemic mixture under these conditions, with the associated disadvantages of non-stereoselective syntheses. In order to achieve stereoselective hydrogenations whilst using chiral metal catalysts, it is necessary to use an asymmetric ligand to induce selectivity. However, commonly used asymmetric ligands are often only accessible by complex synthetic routes and/or are very costly, therefore contributing significantly to the overall reaction costs.
International patent publications WO2012/025501, and WO2012/025502 also disclose processes for the preparation of sacubitril.
PCT publication no. WO2014/032627 describes synthesis of new intermediates of sacubitril comprising reacting epichlorohydrin with Grignard reagent, which is not economical.
International patent publication, WO2016/128924 describes synthesis of new intermediates for preparing sacubitril shown as below

In the view of prior art cited above, there remains a need to develop an alternative process for the preparation of sacubitril which is robust, economical, industrially advantageous, to overcome the shortcomings of the prior art.
The present inventors have surprisingly found a novel, improved process for the synthesis of sacubitril or stereoisomers thereof and compounds obtainable from the process as novel intermediates for the synthesis of sacubitril. The novel process of the present invention is advantageous in that it avoids the use of expensive starting materials, provides compounds with high chemical purity and high stereoselectivity, suitable for industrial scale production under economically and environmentally favorable conditions.

Object of invention
An object of the present invention is to provide a novel process for the preparation of an NEP inhibitor, sacubitril or stereoisomers thereof.
Another object of the invention is to provide novel intermediates useful for the preparation of sacubitril or stereoisomers thereof.
It also an object of the invention to provide processes for preparing the novel intermediates of the present invention.
Further an object of the invention is to provide a novel, robust process for the preparation of sacubitril and novel intermediates thereof, overcoming the drawbacks of prior art.
Also an object of the invention is to provide a novel, economic process for the preparation of sacubitril and novel intermediates thereof, avoiding the use of expensive starting materials as observed in the prior art.
Another object of the present invention is to provide a novel cost-effective, industrially scalable process for the preparation of sacubitril and novel intermediates thereof, resulting in compounds with high enantiomeric and chemical purity.
Also an object of the invention is to provide a novel process for the preparation of NEP inhibitors, particularly sacubitril or stereoisomers thereof, and their use in the preparation of medicaments for the treatment of disorders and conditions influenced by inhibition of NEP.
Summary of Invention
The present invention provides a novel process for the preparation of a NEP inhibitor, sacubitril or stereoisomers thereof. Also provided are novel compounds useful as intermediates for the synthesis of sacubitril and preparation process thereof.
In first embodiment, the present invention provides a novel process for the preparation of sacubitril or stereoisomers thereof, represented by a compound of formula VIII,

Wherein the process comprises reacting a compound of formula VII or stereoisomers thereof, with a reducing agent, preferably with hydrogen and a transition metal catalyst.

In a second embodiment, the present invention provides a novel process for preparing a compound of formula VII or stereoisomers thereof, said process comprises coupling a compound of formula VI with succinic acid derivative, preferably with succinic anhydride.

In a third embodiment, the present invention provides a novel process for preparing a compound of formula VI or stereoisomers thereof, wherein the process comprises chemoselectively reducing a compound of formula V in the presence of sodium dithionate and a suitable solvent.

In a fourth embodiment, the present invention provides a novel process for preparing a compound of formula V or stereoisomers thereof, said process comprises reacting a compound of formula IV with an alkyl ester of methacrylic acid in the presence of an optically active organocatalyst.

In a fifth embodiment, the present invention provides a process for the preparation of a compound of formula IV, disclosed in “Indium-mediated one-pot synthesis of benzoxazoles or oxazoles from 2-nitrophenols or 1-aryl-2-nitroethanones” Tetrahedron 65 (2009) 8821–8831.
In a sixth embodiment, the present invention provides a novel compound of formula V or stereoisomers thereof.

In a seventh embodiment, the present invention provides a novel compound of formula VI or stereoisomers thereof.

In an eighth embodiment, the present invention provides a novel compound of formula VII or stereoisomers thereof.

In a ninth embodiment, the present invention provides a novel process for the preparation of NEP inhibitor, sacubitril and novel intermediates thereof, and their use in the preparation of medicaments for the treatment of disorders and conditions influenced by the inhibition of NEP.

Detailed description of the invention
The present invention is directed to a novel, cost-effective process for the preparation of sacubitril or stereoisomers thereof. Also, the present invention provides compounds obtainable from the said process as novel intermediates useful for the preparation of NEP inhibitors.
The general definitions used above and below, unless defined differently, have the following meanings, where replacement of one or more or all expressions or symbols by the more specific definitions can be made independently for each invention embodiment and lead to more preferred embodiments.
The term ‘’medicament’’ as used herein refers to a pharmaceutical composition comprising the NEP inhibitor, sacubitril prepared by the present invention, wherein the pharmaceutical composition may be used for human or non-human therapy of various diseases or disorders in a therapeutically effective dose.
The term "treatment" as used herein is defined as the management and care of a patient, e.g. a mammal, a human, for combating the disease, condition, or disorder and includes the administration of NEP inhibitors to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
The term “biaryl” as used herein refers to phenyl substituted by carbocyclic aryl as defined herein, ortho, meta or para being the point of attachment to the phenyl ring, advantageously para position.
The term "stereoisomers" as used herein refers to molecules of which one or more isomers exist and such isomeric molecules have the same molecular formula and sequence of bonded atoms (constitution), but which differ in the three dimensional orientations of their atoms in space. By way of example, enantiomers are two stereoisomers that are related to each other in that they are mirror images of each other, which are non- superimposable.
The term “chiral” refers to molecules which have the property of non-superimposability on their mirror image partner.
The term “organocatalyst” as used herein refers to a low molecular weight organic base which in catalytic amounts catalyze a chemical reaction.
In an embodiment, the present invention provides a novel process for preparing sacubitril or stereoisomers thereof, represented by a compound of formula VIII

Wherein the said process comprises the following steps:
1. Converting a compound of formula I in to a biaryl derivative of formula II,

2. Reacting the compound II with imidazole to form a compound of formula III,

3. Converting the compound of formula III in to a biphenyl nitro ketone compound of formula IV,

4. Reacting the compound IV with an alkyl ester of methacrylic acid to form a compound of formula V,

5. Subjecting the compound of formula V to selective hydrogenation using suitable reducing agent,

6. Reacting the compound VI with succinic anhydride to form a compound of formula VII, and

7. Reducing the compound VII using a transition metal catalyst to yield sacubitril, represented as formula VIII.

In another embodiment, the novel process of the present invention may be further explained by the following schemes:

The reaction may be carried out according to standard methods of organic chemistry, in particular reference is made to the methods described in “Copper catalyzed Gomberg–Buchmann–Hey reaction using aryldiazonium tosylate” Tetrahedron Letters 52 (2011) 4950–4953.
Scheme A describes a process for preparing a biaryl compound of formula II, wherein the said process comprises diazotizing para-amino benzoic acid (I) with para-toluene sulfonic acid (PTSA) and sodium nitrite in the presence of triethyl orthoformate (TEOF). The reaction is carried out in the presence of a copper catalyst, preferably copper (I) chloride and in the presence of an aromatic solvent such as benzene.
In another embodiment, the present invention relates to a process for preparing a compound of formula III, and subsequent conversion to biaryl ketone compound of formula IV.
The process for synthesis of biaryl nitro ketone compounds is described in “Indium-mediated one-pot synthesis of benzoxazoles or oxazoles from 2-nitrophenols or 1-aryl-2-nitroethanones” Tetrahedron 65 (2009) 8821–8831, the reference of which is herein incorporated in its entirety.
The biaryl nitro ketone compounds may be alternatively synthesized according to the embodiments of the invention, as described in scheme B.

As per scheme B, a biphenyl carboxylic acid compound (II) is reacted with thionyl chloride followed by imidazole in a suitable solvent at room temperature to form a biphenyl imidazole compound of formula III. Preferably, the solvent used is methylene chloride. The biphenyl imidazole is treated with nitromethane in the presence of suitable base and solvent to yield a biphenyl nitroketone compound of formula IV. Examples of solvents include without limitation, alcohols such as methanol, ethanol, propanol, halogenated hydrocarbons such as methylene chloride, organic sulfoxide such as dimethyl sulfoxide. Suitable bases may include alkali metal hydroxides, preferably sodium hydroxide.
According to the present invention, the compound of formula IV may be used as an intermediate for the synthesis of sacubitril or stereoisomers thereof.
In another embodiment, the present invention provides a process for the preparation of a novel compound of formula V, wherein the process may be explained in scheme C.

As per scheme C, a compound of formula IV is reacted with an alkyl ester of methacrylic acid in the presence of an organocatalyst and a suitable solvent to yield a compound of formula V or stereoisomers thereof.
In preferred embodiments of the invention, the alkyl ester of methacrylic acid is methyl, ethyl, more preferably ethyl methacrylate. Examples of organocatalyst include without limitation D or L-proline and proline derivatives such as D or L-prolinol, D or L-diphenylprolinol. In preferred embodiments of the invention, the organocatalyst is an optically active proline. Preferred solvent is an ethereal solvent, such as tetrahydrofuran. The reaction may be carried out at room temperature.
In another embodiment, the present invention provides a process for the preparation of a novel compound of formula VI or stereoisomers thereof, wherein the process may be explained in scheme D.

As per scheme D, a compound of formula V undergoes selective reduction of the nitro group in the presence of a reducing agent, preferably sodium dithionate in ethanol to yield a compound of formula VI.
In yet another embodiment, the present invention provides a process for the preparation of a novel compound of formula VII, said process may be described in scheme E.
Scheme E

According to scheme E, a compound of formula VI is coupled with succinic anhydride in the presence of a hydrocarbon solvent, preferably methylene chloride and a base such as dimethylamino pyridine (DMAP) to form a compound of formula VII or stereoisomers thereof.
In a further embodiment, the present invention provides a novel process for the preparation of a compound of formula VIII, sacubitril or stereoisomers, as may be described in scheme F.

As per scheme F, a compound of formula VII is hydrogenated in the presence of a transition metal catalyst in a suitable solvent to yield sacubitril.
Examples of transition metal catalysts include without limitation, palladium (Pd), platinum (Pt), rhodium (Rh), and nickel (Ni). The transition metal catalyst used comprises a transition metal on a solid support. Solid supports used are for example carbon, metal oxides (e.g. aluminium oxide, zirconium oxide, titanium oxide or silicon dioxide/aluminium oxide), sulfates (barium sulfate), carbonates (e.g. cesium carbonate and barium carbonate).
In preferred embodiments of the invention, the hydrogenation in scheme F is carried out using transition metal catalyst such as palladium supported on carbon (PdC).
Preferred solvents are, for example, alcohol solvents (e.g. methanol, ethanol or isopropanol), ether solvents (e.g. tetrahydrofuran, methyltetrahydrofuran or tetrahydrofuran/water), aromatic solvents (e.g. toluene) or ester solvents (e.g. ethyl acetate or isopropyl acetate). In more preferred embodiments, the solvent is ethanol.
In preferred embodiments of the invention, the reactions are carried out at room temperature, preferably at a temperature range of 20 to 25°C.
In some embodiments, the compounds of the present invention may be purified by one or more techniques known to a person skilled in the art. In preferred embodiments, the purification technique employed is recrystallization. It may be carried out using solvents such as, methanol, ethanol, isopropyl alcohol, acetonitrile, ethyl acetate, chloroform or mixtures thereof.
In other embodiments, the NEP inhibitor, Sacubitril prepared from the novel process of the present invention may be used for the preparation of medicaments, useful for the treatment of diseases and conditions for which it is indicated.
Preferred embodiments of the invention
In preferred embodiments, the present invention provides the novel compounds represented as follows:

The following scheme G, particularly describes the novel process of the present invention, without limiting the scope thereof.

Further the novel process for preparing sacubitril and novel intermediates thereof, according to the present invention are illustrated in the following examples. The following specific and non-limiting examples are to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.
Examples
Example 1: Preparation of 1-([1,1'-biphenyl]-4-yl)-2-nitroethan-1-one (IV) To a solution of sodium hydroxide (1.94 g, 0.0483 mol) in methanol (50 mL), is slowly added nitromethane (2.95 g, 0.0483 mol), the resulting solution is cooled to 10°C and stirred for 30 minutes. A solution of [1,1'-biphenyl]-4-yl(1H-imidazol-1-yl)methanone (III) in methanol (25 mL) is added drop wise at 10°C to the above solution and the reaction mass is stirred for about 8 hours at room temperature (RT). Around 70% of the solvent is distilled off, followed by addition of water (50 mL) to the reaction mass. Concentrated hydrochloric acid (1 mL) is added and the reaction mass is extracted with methylene chloride (3 ? 25 mL). The combined organic layers are dried over anhydrous sodium sulfate and the solvent is distilled completely under vacuum to obtain the title compound (8.93 g, 92%).
Example 2: Preparation of ethyl 5-([1,1'-biphenyl]-4-yl)-2-methyl-4-nitro-5oxopentanoate (V)
To a solution of compound IV (8 g, 0.0332 mol) in tetrahydrofuran (40 mL) obtained from example 1, is added optically active proline (0.76 g, 20 mol %) at room temperature and stirred for 30 minutes. The reaction mass is then cooled to 5°C and ethyl methacrylate (4.54 g, 0.04 mol) is added drop wise over a period of 4 hours. The reaction mass is stirred at 5°C for 24 hours. Tetrahydrofuran is distilled off under vacuum to obtain a residue. The residue is charged with methylene chloride (40 mL) and extracted with 1N hydrochloric acid (2 ? 20 mL). Proline is recovered from the aqueous layer. The organic layer is washed with brine (1 ? 20 mL) and dried over anhydrous sodium sulfate. The solvents are distilled off completely to obtain a residue which is then recrystallized from isopropyl alcohol to obtain the title compound as off white crystals (10.2 g, 87%).


Example 3: Preparation of ethyl 5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl-5oxopentanoate (VI)
To a solution of compound V (10 g, 0.0281 mol) obtained from example 2 in ethanol (80 mL) is added sodium dithionate (14.7 g, 0.0845 mol) in five portions at 50°C. The reaction mass is refluxed for 5 hours and cooled to room temperature. The insoluble matter is filtered and the filtrate is distilled to remove ethanol completely. The residue obtained is charged with methylene chloride (80 mL) and the organic layer is washed with water (2 ? 40 mL), and dried over anhydrous sodium sulfate. The solvents are removed under vacuum to obtain the title compound (7.21 g, 79%).
Example 4: Preparation of 4-((1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-1,5dioxopentan-2-yl)amino)-4-oxobutanoic acid (VII)
To a solution of compound VI (7 g, 0.0215 mol) obtained from example 3 and dimethylaminopyridine (0.262 g, 10 mol %) in methylene chloride (40 mL) is added succinic anhydride (2.15 g, 0.0215 mol) in three portions, stirred at room temperature for 8 hours. The reaction mass is washed with 1N hydrochloric acid (2 ? 30 mL) followed by washing with water (1 ? 30 mL). The organic layer is dried over anhydrous sodium sulfate and distilled completely under vacuum to yield the title compound (7.5 g, 82%).
Example 5: Preparation of Sacubitril (VIII)
A solution of a compound VII (7.0 g, 0.0165 mol) obtained from example 4 in ethanol (35 mL) is hydrogenated in the presence of 5% Pd-C (0.7 g) at room temperature and pressure of 5 kg/cm2 for 12 hours. The reaction mass is filtered over celite and the filtrate is boiled over activated charcoal (1 g) for 30 minutes. The reaction mass is again filtered over celite and distilled completely under vacuum to obtain the title compound (6.5 g, 96%).
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, a person skilled in the art will appreciate that certain changes and modifications may be practiced within the scope of the invention described.
Without being limited by theory, the processes according to the present invention may be advantageously used to prepare the complex compounds like Sacubitril and intermediates thereof. The proposed routes of the drug described in schemes A to G are such that it prevents the disadvantages of the prior art. It is envisaged that by providing the alternative routes of synthesis of compounds or related compounds or intermediates of the present invention, the shelf life or stability of the product is enhanced and the impurity content of the product is decreased or rather controlled during the preparation of intermediates, thereby contributing to the overall efficacy of the product.
From the foregoing it will be understood that the embodiments of the present invention described above are well suited to provide the advantages set forth, and since many possible embodiments may be made of the various features of this invention, all without departing from the scope of the invention, it is to be understood that all matter hereinbefore set forth or shown in the description and synthetic schemes is to be interpreted as illustrative and that in certain instances some of the features may be used without a corresponding use of other features, all without departing from the scope of the invention.
,CLAIMS:We Claim,
1. A process for the preparation of Sacubitril or stereoisomers thereof represented by a compound of formula VIII, wherein the process comprises hydrogenating a compound VII in the presence of a transition metal catalyst and suitable solvent.

2. A process according to claim 1, wherein the transition metal catalyst is selected from Palladium, Platinum, Rhodium and Raney nickel on a solid support and the solvent is selected from alcohols such as methanol, ethanol or isopropanol; ethers such as tetrahydrofuran, methyltetrahydrofuran or tetrahydrofuran/water; esters such as ethyl acetate or isopropyl acetate; and toluene.
3. A process for preparing a compound of formula VII or stereoisomers thereof, wherein the process comprises reacting a compound formula VI with succinic anhydride in the presence of a solvent such a methylene chloride, and a base such as dimethylamino pyridine.

4. A process for preparing a compound of formula VI or stereoisomers thereof, wherein the process comprises selectively reducing the nitro group of compound of formula V using sodium dithionate and an alcoholic solvent such as ethanol.

5. A process for preparing a compound of formula V or stereoisomers thereof, wherein the process comprises reacting a compound of formula IV with an alkyl ester of methacrylic acid in the presence of an organocatalyst and a suitable solvent.

6. A process according to claim 5, wherein the alkyl ester of methacrylic acid is selected from methyl methacrylate and ethyl methacrylate; an organocatalyst is selected from (D/L)-proline, (D/L)-prolinol or (D/L)-diphenylprolinol; and solvent is preferably an ethereal solvent.
7. Compounds of formula V, VI, VII or stereoisomers thereof.

8. A process for the preparation of Sacubitril or stereoisomers thereof represented by a compound of formula VIII, wherein the process comprises the following steps:
(a) Diazotizing para-amino benzoic acid (I) with para toluene sulfonic acid (PTSA) and sodium nitrite in the presence of triethyl orthoformate in the presence of a copper catalyst and an aromatic solvent to form biphenyl-4-carboxylic acid (II), wherein the aromatic solvent is preferably benzene;

(b) Reacting biphenyl-4-carboxylic acid (II) with thionyl chloride followed by imidazole in a suitable solvent to form [1,1'-biphenyl]-4-yl(1H-imidazol-1-yl)methanone (III), wherein the solvent is preferably methylene chloride;

(c) Treating [1,1'-biphenyl]-4-yl(1H-imidazol-1-yl)methanone (III) with nitromethane in the presence of suitable base and solvent to form 1-([1,1'-biphenyl]-4-yl)-2-nitroethan-1-one (IV), wherein solvent is selected from alcohols such as methanol, ethanol, propanol, halogenated hydrocarbons such as methylene chloride, organic sulfoxide such as dimethyl sulfoxide, and a base is preferably an alkali metal hydroxide;

(d) Reacting a 1-([1,1'-biphenyl]-4-yl)-2-nitroethan-1-one (IV) with an alkyl ester of methacrylic acid in the presence of an organocatalyst and a suitable solvent to form ethyl 5-([1,1'-biphenyl]-4-yl)-2-methyl-4-nitro-5-oxopentanoate (V) or stereoisomers thereof,

Wherein the alkyl ester of methacrylic acid is selected from methyl methacrylate and ethyl methacrylate; an organocatalyst is selected from (D/L)-proline, (D/L)-prolinol or (D/L)-diphenylprolinol; and solvent is preferably an ethereal solvent;
(e) Selective reduction of the nitro group of ethyl 5-([1,1'-biphenyl]-4-yl)-2-methyl-4-nitro-5-oxopentanoate (V) using sodium dithionate and an alcoholic solvent such as ethanol to form ethyl 5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl-5-oxopentanoate (VI) or stereoisomers thereof;

(f) Reacting ethyl 5-([1,1'-biphenyl]-4-yl)-4-amino-2-methyl-5-oxopentanoate (VI) with succinic anhydride in the presence of a solvent such a methylene chloride, and a base such as dimethylamino pyridine to form 4-((1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-1,5-dioxopentan-2-yl)amino)-4-oxobutanoic acid (VII) or stereoisomers thereof; and

(g) Hydrogenating 4-((1-([1,1'-biphenyl]-4-yl)-5-ethoxy-4-methyl-1,5-dioxopentan-2-yl)amino)-4-oxobutanoic acid (VII) in the presence of a transition metal catalyst and suitable solvent to form Sacubitril (VIII) or stereoisomers thereof,

Wherein the transition metal catalyst is selected from Palladium, Platinum, Rhodium and Raney nickel on a solid support and the solvent is selected from alcohols such as methanol, ethanol or isopropanol; ethers such as tetrahydrofuran, methyltetrahydrofuran or tetrahydrofuran/water; esters such as ethyl acetate or isopropyl acetate; and toluene.