DESC:A Novel Process for the Preparation of an (2R, 4S)-4-(t-butoxycarbonyl amino)-5-(biphenyl-4-yl)-2-methyl pentanoic acid

Field of Invention
The present invention relates to a novel process for preparing an intermediate, (2R, 4S)-4-(t-butoxycarbonyl amino)-5-(biphenyl-4-yl)-2-methyl pentanoic acid, useful for the synthesis of Sacubitril/NEP inhibitors.

Background of the Invention
The present invention is directed to a novel process for the synthesis of biphenyl pentanoicacid derivatives. Such biphenyl pentanoic acid derivatives, are useful as intermediates in the preparation of NEP inhibitors/Sacubitril.
Neutral endopeptidase (enkephalinase; atriopeptidase; NEP) is a zinc-containing metalloprotease that cleaves a variety of peptide substrates on the amino side of hydrophobic residues. Substrates for this enzyme include, but are not limited to, atrial natriuretic peptide (ANP, also known as ANF), brain natriuretic peptide (BNP), met- and leu-enkephalin, bradykinin, neurokinin A, endothelin-1 and substance P. ANP is a potent vasorelaxant and natriuretic agent. Infusion of ANP in normal subjects resulted in a reproducible, marked enhancement of natriuresis and diuresis, including increases in fractional excretion of sodium, urinary flow rate and glomerular filtration rate. However, ANP has a short half-life in circulation, and NEP in kidney cortex membranes has been shown to be the major enzyme responsible for degrading this peptide. Thus, inhibitors of NEP should increase plasma levels of ANP and, hence, are expected to induce natriuretic and diuretic effects.
Currently, the only NEP inhibitor approved for human use in the market is Sacubitril. It has been approved in combination with valsartan in the form of oral. Film coated tablets in the United States. It is being marketed by Novartis Pharmaceuticals Corporation under the trade name, ENTRESTO®. According to the label approved by FDA, ENTRESTO® (Sacubitril and Valsartan) is a combination of a neprilysin inhibitor and an angiotensin II receptor blocker, indicated for the treatment of heart failure.
ENTRESTO contains a complex comprised of anionic forms of sacubitril and valsartan, sodium cations, and water molecules in the molar ratio of 1:1:3:2.5, respectively. Following oral administration, the complex dissociates into sacubitril (which is further metabolized to LBQ657) and valsartan. The complex is chemically described as Octadecasodiumhexakis(4-{[(1S,3R)-1-([1,1´-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)hexakis(N-pentanoyl-N-{[2´-(1H-tetrazol-1-id-5-yl)[1,1´-biphenyl]-4-yl]methyl}-L-valinate)—water (1/15).

Its empirical formula (hemipentahydrate) is C48H55N6O8Na3 2.5 H2O. Its molecular mass is 957.99 and its schematic structural formula is:

ENTRESTO acts by inhibiting neprilysin (neutral endopeptidase; NEP) via LBQ657, the active metabolite of the prodrug sacubitril, and blocks the angiotensin II type-1 (AT1) receptor via valsartan. The cardiovascular and renal effects of ENTRESTO in heart failure patients are attributed to the increased levels of peptides that are degraded by neprilysin, such as natriuretic peptides, by LBQ657, and the simultaneous inhibition of the effects of angiotensin II by valsartan. Valsartan inhibits the effects of angiotensin II by selectively blocking the AT1 receptor, and also inhibits angiotensin II-dependent aldosterone release.
U.S. Pat. No. 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. As a preferred embodiment U.S. Pat. No. 5,217,996 discloses N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester and a method for its preparation. In the preparation of said compound, N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester is hydrogenated in the presence of palladium on charcoal. A major drawback of said process is that such a hydrogenation step is not very selective and yields N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester as an 80:20 mixture of diastereomers.
Several dicarboxylic acid dipeptide neutral endopeptidase (NEP) inhibitors are further described in G. M. K sander et al., J. Med. Chem. 1995, 38, 1689-1700, “Dicarboxylic Acid Dipeptide Neutral Endopeptidase Inhibitors”. Among others, N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester and a method for its preparation are disclosed.
Other processes for preparing NEP inhibitors are known in the art.
U.S. pat. No. 8,946,481 describes a process for preparing (S)-(t-butoxy carbonyl amino)-5-(biphenyl-4-yl)-pentanoic acid ethyl ester.
Furthermore, the invention relates to products obtainable by said process and their use in the production of NEP inhibitors. Moreover use of transition metal catalyst in the preparation NEP inhibitors or prodrugs thereof.
U.S pat. No 9,206,116 described using a methods for preparation and their use in the preparation of NEP inhibitors, particularly the preparation of N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino(2R)-Methyl-1-butanoic acid ethyl ester, in the preparation of N-t-butoxy carbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-(2)-butanoic acid ethyl ester and a method for its preparation are disclosed.
U.S pat. No. 9,085,529 describes process for producing useful intermediates for the manufacture of NEP inhibitors or prodrugs thereof, in particular inhibitors comprising N-(3- carboxyl-1-oxy-propyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester are disclosed. Wherein alternative hydrogenation step provides improved diastereo selectivity
U.S pat. No. 8,115,016 describes to provide an alternative reaction route in a process for producing NEP inhibitors or prodrugs thereof, in particular it was an object to provide an alternative reaction route in a process for producing N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methy- l butanoic acid ethyl ester, or salt thereof.
U.S pat. No. 8,716,495 describes an alternative reaction route in a process for producing NEP inhibitors, in particular it was an object to provide an alternative reaction route in a process for producing N-(3-carboxyl-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester. There exists a need to develop alternate processes for the preparation of NEP inhibitors and intermediates thereof, with greater purity, yield and better diastereomeric separation.
The present inventors have surprisingly found a novel process for the synthesis of an intermediate, (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoic acid, and use thereof for the synthesis of desired NEP inhibitors, more preferably Sacubitril.

Object of invention
An object of the present invention is to provide an alternative process for preparing NEP inhibitors or intermediates thereof. it was also an object to provide an alternative process, wherein the resulting compound (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoic acid can be provided in pure or even in crystalline form.
It is an object of the present invention to provide an alternative reaction route for preparing compound (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoic acid, preferably a reaction route which avoids the drawbacks of the prior art process.
An objects of the present invention can be achieved by providing a specific lactam as a key intermediate. Starting from that specific lactam, advantageous reaction routes producing the desired NEP-inhibitors and intermediates thereof are possible.
An object of the present invention can be achieved by using a specific catalyst in a hydrogenation step in the production of an NEP inhibitors, in particular a NEP inhibitor comprising an (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoic acid, most preferably gamma-amino delta-biphenyl-alpha methylalkanoic acid, or acid ester, backbone.
It is another object to provide a hydrogenation step in a process for producing NEP inhibitors or intermediates thereof, in particular NEP inhibitors comprising a gamma amino delta biphenyl alpha methylalkanoic acid, or acid ester, backbone. Wherein the hydrogenation step preferably having a better yield.
It is a still further object to provide a process for producing compound (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoic acid having a better diastereomeric ratio, wherein (2R)-(4S) configuration is preferred, in particular the diastereomeric ratio is desirably 50:50, preferably 55:45, particularly preferred 60:40
Yet another object of the invention we have now found to a process for producing (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoicacid, particularly in the production of NEP inhibitors with better purity as required, which is more efficient than the known prior art processes

Summary of Invention
The present invention is related to novel process for synthesis of biphenyl pentanoicacid derivatives which is useful for NEP inhibitors. Preferably a specific catalyst used in hydrogenation reaction. In particular a NEP inhibitor comprising a ?-amino-?-biphenyl-a-methyl alkanoicacid or acid ester, backbone
In one embodiment, the present invention provides a specific catalyst is used in hydrogenation reaction, therefore the subject matter of the present invention process for producing biphenyl pentanoicacid derivatives, preferably sacubitril.
In one embodiment, the present invention relates to intermediate (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoicacid,preferably carried out hydrogenation reaction in the presence of solvents are selected from alcohols preferably ethanol, methanol, isopropylacohol, butanol, most preferably is ethanol, the present invention provides the hydrogenation is carried out at a temperature about 25°c-30°c for 6 hrs.
In one embodiment the present invention provides, N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-butenoic acid ethyl ester is hydrogenated in the presence of transition metal catalyst on charcoal, to give N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester as a 75:25 mixture of diastereomers.
In another embodiment, the transition metal catalyst is selected from the group 7, 8, or 9 of the periodic table, therefore the transition metal catalyst comprises for example, Ruthenium (Ru), Rhodium(Rh), palladium(Pd), platinum(pt), preferably the transition metal catalyst comprises palladium.
In another embodiment, the present invention provides, N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-butanoic acid ethyl ester is under hydrolysis reaction in the presence of base, gives (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoicacid. Suitable bases are selected from an alkali metal hydroxides eg: sodium hydroxide, potassium hydroxide, preferable base is lithium hydroxide and preferable solvent is ethanol, the hydrolysis reaction is carried out at a temperature about 25°c-30°c for 2 hrs.
In another embodiment, the present invention provides, (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoicacid is under esterification reaction, in the presence of reagents, reacted with alcohol gives (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-butyl acetate.
In one embodiment, in esterification reaction, the alcohol is selected from tertiary butyl alcohol, the reaction is carried out at a temperature about 25°c-30°c, for 6 hrs.in this esterification reaction diastereomers are separated.
In another embodiment, the present invention provides, (2R)-(4S)-N-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-butyl acetate is under hydrolysis reaction in the presence of base, gives (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoicacid.
In one embodiment, the suitable bases are selected from alkali metal hydroxide for example sodium hydroxide, lithium hydroxide, potassium hydroxide. Preferable base is lithium hydroxide. Solvent selected from alcohol, preferable solvent is ethanol. The hydrolysis reaction is carried out at a temperature about 25°c-30°c, for 2 hrs.
In another embodiment, the present invention provides N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoicacid ethyl ester is under hydrolysis in the presence of base and solvent to give N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-pentenoicacid.
In one embodiment, suitable base is selected from alkali metal hydroxide for example lithium hydroxide, sodium hydroxide, potassium hydroxide, preferable base is lithium hydroxide. Preferable solvent is ethanol. The reaction is carried out at a temperature about 25°c-30°c, for 2 hrs.
In one embodiment, the present invention is provides, N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-pentenoicacid is hydrogenated in the presence of transition metal catalyst on charcoal to give (2R)-(4S)-N-t-butoxycarbonyl)-4-amino-2-methyl-pentanoic acid.
In one embodiment, the transition metal catalyst selected from the group 7, 8, or 9 of the periodic table. Therefore the transition metal catalyst comprises for example, Ruthenium (Ru), Rhodium (Rh), palladium (Pd), and platinum (pt), preferably the transition metal catalyst comprises palladium. Solvent is selected from the alcohol, more preferably ethanol.
In another embodiment, the present invention provides (2R)-(4S)-N-t-butoxycarbonyl)-4-amino-2-methyl-pentanoic acid is under esterification reaction, in the presence of reagents, reacted with alcohol give (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-butyl acetate. In esterification reaction the alcohol is selected from the tertiary butyl alcohol, the reaction is carried out at a temperature about 25°c-30°c, for 6 hrs.in this esterification reaction diastereomers are separated.
In one embodiment, the present invention provides, (2R)-(4S)-N-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-butyl acetate is under hydrolysis reaction in the presence of base, gives (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoicacid.
In one embodiment, the suitable bases are selected from alkali metal hydroxides for example sodium hydroxide, lithium hydroxide potassium hydroxide. Preferable base is lithium hydroxide. Solvent selected from alcohol, preferable solvent is ethanol. The hydrolysis reaction is carried out at a temperature about 25°c-30°c, for 2 hrs.
In one embodiment, the present invention provides N-t-butoxycarbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoicacid ethyl ester is under hydrolysis reaction in the presence of base, gives (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentenoicacid.
In another embodiment, the suitable bases are selected from alkali metal hydroxides for example lithium hydroxide, sodium hydroxide, potassium hydroxide. Preferable base is lithium hydroxide. Solvent selected from methanol, ethanol, and propanol. Preferable solvent is ethanol. The reaction is carried out at a temperature about 25°c-30°c. For 2 hrs.
In yet embodiment, (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentenoicacid is under hydrogenation reaction in the presence of transition metal catalyst on charcoal, to give (2R)-(4S)-N –t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoic acid. The transition metal catalyst is selected from the group 7, 8, or 9 from the periodic table. Therefore the transition metal catalyst comprises for example, Ruthenium (Ru), Rhodium (Rh), palladium (Pd), and platinum (pt), preferably the transition metal catalyst comprises palladium. Solvent is selected from the alcohol, more preferably ethanol.
In another embodiment, diastereomers are separated in column purification, having a better diastereomeric ratio, the diastereomeric ratio is desirably 50:50, preferably 55:45, and particularly preferred 60: 40.

Detailed description of the invention
The present invention relates to process for the preparation of compound (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid according to formula (1), or salts thereof


As defined herein, process for the preparation and their use in the preparation of NEP inhibitors, particularly in the preparation of (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described.
The term ‘’NEP inhibitors’’ as used herein refer to compounds particularly useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase. In the preferred embodiments of the invention, the NEP inhibitor is Sacubitril.
The term ‘’angiotensin receptor blockers’’ as used herein refers to compounds which modulate the renin-angiotensin system, useful in the treatment of hypertension. In the preferred embodiments of the invention, the angiotensin receptor blocker is valsartan.
The term ‘’prodrug’’ as used herein refers to a pharmacological substance which is administered in an inactive form. Once administered, the prodrug is metabolised in the body in vivo into the active compound.
The term ‘’active pharmaceutical ingredients’’ as used herein refers to an angiotensin receptor blocker and neutral endopeptidase inhibitor.
The term ‘’diastereomers’’ as used herein refers a type of a stereo isomers. Diastereomers occurs when two or more stereoisomers of a compound have different configurations at one or more of the equivalents stereo centers and are not mirror images of each other.
In an embodiment, the present invention relates to process for the preparation of (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid, which comprises following steps:
Step 1: hydrogenation of about 1-1.5 moles of N-t-butoxycarbonyl (4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester in the presence of 5% palladium on
Scheme 1:

charcoal, in 10 volumes of ethanol. This reaction carried out at a temperature of about 25°-30°c, and maintained for 8-9 hrs. to give 1-1.5 moles of N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-butanoic acid ethyl ester.
Step 2: Hydrolysing the product of step 1 using 1-1.5 moles of lithium hydroxide in 10 volumes of ethanol. This reaction carried out at a temperature of about 25°c-30°c, and maintained for 2 hrs, to give (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid.
Step 3: esterification the product of step 2 using 1.5 moles of DCC, 1.1 moles of DMAP, 5 volumes of tertiary butyl alcohol. This reaction carried out at a temperature of about 25°c-30°c, and maintained for 6 hrs, to give (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-butyl acetate.
Step 4: hydrolyzing the product of step 3 using 1-1.5 moles of lithium hydroxide in 10 volumes of ethanol. This reaction carried out at a temperature of about 25°c-30°c, and maintained for 2 hrs, to give (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid.

In another embodiment, the present invention relates to process for the preparation of (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid, wherein the process comprise following steps
Step 1: hydrolysing of N-t-butoxy carbonyl (4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester using 1-1.5 moles of lithium hydroxide in 10 volumes of ethanol. The reaction carried out at a temperature of about 25°c-30°c and maintained for 2 hrs, to give N-t-butoxy carbonyl (4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid.
Step 2: hydrogenation the product of stage 1 using 5% palladium on charcoal, in 10 volumes of ethanol. This reaction carried out at a temperature of about 25°c-30°c and maintained for 6 hrs, to give (2R)-(4S)-N-t-butoxy carbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoic acid.
Step 3: esterification the product of stage 2 using 1.5 moles of DCC, 1.1 moles of DMAP, 5 volumes of tertiary butyl alcohol. This reaction carried out at a temperature of about 25°c-30°c and maintained for 6 hrs, to give (2R)-(4S)-N-butoxy carbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl butyl acetate.

Scheme 2

Step 4: hydrolyzing the product of stage 3 using 1-1.5 moles of lithium hydroxide 10 volumes of ethanol. This reaction carried out at a temperature of about 25°c-30°c and maintained for 2 hrs, to give (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid.
Scheme 3:
In another embodiment, the present invention relates to process for the preparation of (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid, wherein the process comprises the following steps
Step 1: hydrolysing of N-t-butoxy carbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoicacid ethyl ester using lithium hydroxide in ethanol. This reaction carried out at a temperature of about 25°c-30°c and maintained for 2 hrs, to give N-t-butoxy carbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl pentenoic acid.
Step 2: hydrogenation the product of step 1 using 5% palladium on charcoal in ethanol.
Step 3: product obtained in step 2, is subjected to column purification to yield desired diastereomers, in the ratio of 55: 45.

Without wishing to be bound by theory, the inventors have discovered a novel process for the preparation of (2R, 4S)-4-(t-butoxycarbonyl amino)-5-(biphenyl-4-yl)-2-methyl pentanoic acid with different approaches followed by separation of the isomers. The methods may also be exploited in order to achieve the continuous purification and isolation of the isomers.
The foregoing descriptions of chemicals are not intended to be exhaustive. Those skilled in the art will be aware of many other substances that are useful in the practice of the application, and the use of such substances is specifically included in this application.
Certain specific aspects and embodiments are more particularly described in the following examples, being provided solely for purposes of illustration, and the scope of the application is not to be limited thereto.
Example 1:
a) Preparation of N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-butanoic acid ethyl ester: About 10.0 g of N-t-butoxycarbonyl (4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester was charged in an autoclave vessel, followed by addition of ethanol (500 mL) and 5% Pd/C (4.7 g). The pressure of the vessel was raised to 4.0 kg/cm2 and reaction was maintained at a temperature of 25-30°C for 6 hours. The reaction mass filtered through Hyflo®. The filtrate was distilled to remove the solvent completely under vacuum at a temperature of 40°C to give the title compound (11.0 g)
b) Preparation of (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid: To the compound obtained from step a) was added ethanol (60 mL) and lithium hydroxide (1.0 g) at room temperature (RT) and stirred for 4 hours. The solvent was distilled off at 40°C and the residue obtained was charged with water. The pH of the solution was adjusted to neutral using acetic acid and extracted with ethyl acetate. The organic layer was separated and solvent was distilled off completely to give the title compound (11.0 g)
c) Preparation of (2R)-(4S)-N-t-butoxycarbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-butyl acetate: To the compound obtained from step b) was added dichloromethane (50 mL) and nitrogen gas was passed through. To the above, dimethylaminopyridine (2.0 g), N,N’-dicyclohexyl carbodiimide (5.0 g) was added at room temperature, followed by addition of tert-butyl alcohol (30 mL). The reaction mixture was stirred for 5 hours at RT. After completion of the reaction, the solvent was distilled off completely, cooled to RT. The residue obtained was charged with ethyl acetate and filtered through Hyflo®. To the filtrate, was added ethyl acetate (20 mL) and water (50 mL). Aqueous layer was extracted with ethyl acetate (2 ? 20 mL). Combined organic layers were subjected to distillation to remove the solvents completely at 40°C to obtain a crude compound (9.0 g). The crude compound was purified by column chromatography to give the title compound (1.5 g).
d) Preparation of (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid: To the compound obtained from step c) was added ethanol (15 mL), stirred for 5 minutes. Lithium hydroxide (0.1 g) was added to the above mixture and stirred for 3 hours at RT. The solvent is distilled off completely under vacuum and water (30 mL) was added to the residue obtained. The pH is adjusted to neutral using acetic acid. The reaction mass was extracted with ethyl acetate (30 mL). Organic layer was dried with sodium sulfate and the solvents were distilled completely under vacuum to yield the title compound (0.5 g).

Example 2:
a) Preparation of N-t-butoxy carbonyl (4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid: In a 250 mL RBF, was charged N-t-butoxycarbonyl (4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester (20.0 g), lithium hydroxide (3.0 g), ethanol (70 mL) and stirred for 6 hours at RT. After the completion of reaction, the solvent is distilled off completely at 40°C and cooled to RT. The residue obtained was charged with water (100 mL) and pH adjusted to neutral with acetic acid, followed by addition of ethyl acetate (50 mL). Aqueous layer was extracted with ethyl acetate (2 ? 50 mL). The organic layers were combined, dried over sodium sulfate and the solvent was distilled completely under vacuum to give the title compound (15.0 g).
b) Preparation of (2R)-(4S)-N-t-butoxy carbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoic acid: To the compound obtained from step a) in an autoclave vessel, was added ethanol (500 mL) and 5% Pd/C (2.0 g) at RT and stirred for 5 minutes. The hydrogen gas pressure was raised up to 5.0 kg/cm2 at 25-30°C for 5 hours. The reaction mass was filtered through Hyflo®. The filtrate was distilled to remove the solvent completely under vacuum to yield 13.0 g of compound, which was further purified by column chromatography to give the title compound (5.0 g).
c) Preparation of (2R)-(4S)-N-butoxy carbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl butyl acetate: To the compound obtained from step b) was added dichloromethane (30 mL) and nitrogen gas was passed through. To the above, dimethylaminopyridine (1.0 g), N,N’-dicyclohexyl carbodiimide (2.0 g) was added at room temperature, followed by addition of tert-butyl alcohol (10 mL). The reaction mixture was stirred for 5 hours at RT. After completion of the reaction, the solvent was distilled off completely, cooled to RT. The residue obtained was charged with ethyl acetate and filtered through Hyflo®. To the filtrate, was added ethyl acetate (10 mL) and water (20 mL). Aqueous layer was extracted with ethyl acetate (2 ? 10 mL). Combined organic layers were subjected to distillation to remove the solvents completely at 40°C to obtain a crude compound (4.0 g). The crude compound was purified by column chromatography to give the title compound (0.8 g).
d) Preparation of (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid: To the compound obtained from step c), was added ethanol (10 mL), lithium hydroxide 0.05 g), stirred for 3 hours at RT. The solvent was distilled off completely under vacuum and cooled to RT. The residue obtained was charged with water (20 mL0 and pH adjusted to neutral using acetic acid. The reaction mass was extracted with ethyl acetate (15 mL). The organic layers were combined and the solvent was distilled completely to give the title compound (0.3 g).

Example 3:
a) Preparation of N-t-butoxy carbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl pentenoic acid: In a 250 mL RBF, was charged N-t-butoxycarbonyl (4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester (20.0 g), lithium hydroxide (3.0 g), ethanol (70 mL) and stirred for 6 hours at RT. The solvent is distilled off completely at 40°C and cooled to RT. The residue obtained was charged with water (100 mL) and pH adjusted to neutral with acetic acid. Aqueous layer was extracted with ethyl acetate (2 ? 50 mL). The organic layers were combined and the solvent was distilled completely under vacuum to give the title compound (15.0 g).
b) Preparation of (2R)-(4S)-N-t-butoxy carbonyl-(p-phenylphenylmethyl)-4-amino-2-methyl-pentanoic acid: To the compound obtained from step a) was added ethanol (200 mL) and 5% Pd/C (2.0 g) at RT, stirred for 5 minutes. The hydrogen gas pressure was raised up to 5.0 kg/cm2 at 25-30°C for 5 hours. The reaction mass was filtered through Hyflo®. The filtrate was distilled to remove the solvent completely under vacuum to yield 13.0 g of compound, which was further purified by column chromatography to give the title compound (5.0 g).

The invention having been disclosed in connection with the foregoing embodiments, additional variations will now be apparent to persons skilled in the art. Various modifications and variations to the above described route of synthesis may be possible to obtain highest possible purity of the compound and also can be made without departing from the scope of the invention.
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 and as the device herein described may be varied in various parts, all without departing from the scope of the invention, it is to be understood that all matter hereinbefore set forth or shown in the accompanying 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.
Further the present invention has be illustrated in the different schemes (ROS 1, 2 & 3). The following specific and non-limiting steps for functioning need to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.
,CLAIMS:We Claim,
1. A process for the preparation of (2R, 4S)-4-(t-butoxycarbonyl amino)-5-(biphenyl-4-yl)-2-methyl pentanoic acid, comprising:
(a) Hydrogenating N-t-butoxycarbonyl (4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester using 5% Pd/C in the presence of a solvent to yield N-t-butoxycarbonyl-(4S)-(p-phenylphenylmethyl)-4-amino-2-methyl-butanoic acid ethyl ester,

(b) Subjecting the compound obtained in step (a) to hydrolysis using lithium hydroxide,

(c) Esterifying the compound obtained from step (b) with tertiary butyl alcohol in the presence of a condensing agent and base,

(d) Hydrolysing the compound obtained in step (c) using lithium hydroxide in the presence of a solvent to yield (2R, 4S)-4-(t-butoxycarbonyl amino)-5-(biphenyl-4-yl)-2-methyl pentanoic acid.

2. A process for the preparation of (2R, 4S)-4-(t-butoxycarbonyl amino)-5-(biphenyl-4-yl)-2-methyl pentanoic acid, comprising:
(a) Hydrolysing N-t-butoxy carbonyl (4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester using lithium hydroxide in the presence of a solvent,

(b) Hydrogenating the compound obtained in step (a) using 5% Pd/C in the presence of a solvent,

(c) Esterifying the compound obtained from step (b) with tertiary butyl alcohol in the presence of a condensing agent and base,

(d) Hydrolysing the compound obtained in step (c) using lithium hydroxide in a solvent to yield (2R, 4S)-4-(t-butoxycarbonyl amino)-5-(biphenyl-4-yl)-2-methyl pentanoic acid.

3. A process for the preparation of (2R, 4S)-4-(t-butoxycarbonyl amino)-5-(biphenyl-4-yl)-2-methyl pentanoic acid, comprising:
(a) Hydrolysing N-t-butoxy carbonyl-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoicacid ethyl ester using lithium hydroxide in a solvent,

(b) Hydrogenating the compound obtained in step (a) using 5% Pd/C in the presence of a solvent,

(c) Subjecting the compound obtained in step (b) to column purification to yield (2R, 4S)-4-(t-butoxycarbonyl amino)-5-(biphenyl-4-yl)-2-methyl pentanoic acid as a 60: 40 mixture of diastereomers.
4. A process according to claims 1-3, wherein the solvent used is ethanol.
5. A process according to claims 1-3, wherein the condensing agent is dicyclohexyl carbodiimide and the base is 4-dimethylaminopyridine.