Improved process for the preparation of (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid
Priority
This application claims priority of our provisional patent application filed on July 15th 2016 entitled "Improved process for the preparation of (2R, 4S)-S-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid" bearing the application number 201641024217.
Field of the Invention
The present invention relates to a novel process for preparing (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid from D-Phenylalanine compound, which is an intermediate of biaryl substituted 4-amino-butyric acid amide derivatives. Specifically the present invention relates to an improved process for preparing intermediate compounds and their conversion to N-(3-carboxyl-1 -oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methyl butanoic acid ethyl ester.
Background of the Invention
Biaryl substituted 4-amino-butyric acid amide derivatives are useful as neutral endopeptidase (NEP) inhibitors, e.g. as inhibitors of the ANF-degrading enzyme in mammals, so as to prolong and potentiate the diuretic, natriuretic and vasodilator properties of ANF in mammals, by inhibiting the degradation thereof to less active metabolites. These compounds are thus particularly useful for the treatment of conditions and disorders responsive to the inhibition of neutral endopeptidase (EC 3.4. 24.11), particularly cardiovascular disorders, such as hypertension, renal insufficiency including edema and salt retention, pulmonary edema and

congestive heart failure. By virtue of their inhibition of neutral endopeptidase. these compounds ' may also be useful for the treatment of pain, depression and certain psychotic conditions. Other potential indications include the treatment of angina, premenstrual syndrome, Meniere's disease, hyperaldosteronism, hypercalciuria. ascites, glaucoma, asthma, inflammations and gastrointestinal disorders such as diarrhea, irritable bowel syndrome and gastric hyperacidity.
US 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. Specifically, the NEP inhibitors such as Sacubitril, and chemically known as 4-{[(2S, 4R)-l-(4-Biphenylyl)-5-ethoxy-4-methyl-5-oxo-2-pentanyl] amino}-4-oxobutanoic acid and represented by the following structure.

US Pat. No. 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-(4R)-(p-phenylphenylmethyl)-4-amino-2-methyl-2-butenoic acid ethyl ester is hydrogenated in the presence of palladium on charcoal to give N-t-butoxycarbonyt-(4S)-(p-phenylphenylmethyl)-4-amino-2-methylbutanoic acid ethyl ester as a 80:20 mixture of diastereomers, which further converted to the desired compound.
US 8,017,378 discloses the preparation of optically active biphenylalanine compound or salt or ester, which is a key intermediate for the preparation of biaryl substituted 4-amino-butyric acid

amide derivatives. N-substituted-L-amino acid and N-substituted-D-amino acid ester are produced by hydrolysis of racemic N-substituted-DL-amino acid ester by using protease in the presence of a weak base as a pH controlling reagent.
The preparation of L-Phenylalamne, N-[(l,l-dimethylethoxy)carbonyl]-4-iodo-, methyl ester from phenylalanine disclosed in the Journal of organic chemistry 1994, 59, 4206-4210, it discloses the preparation of N-substituted-L-amino acid ester from L-iodophenylalanine.
The synthesis of R-biphenyla!aninol, is a key intermediate compound of biaryl substituted 4-amino-butyric acid amide derivatives, has been reported by several synthetic methods. However, these are based on the use of expensive raw materials (D-Tyr; J. Med. Chem. 1995, 38, 1689) or rely on an (enzymatic) resolution of the corresponding racemic ester (EP1980622), which makes them less attractive from a commercial point of view. In addition, synthetic routes based on asymmetric hydrogenation of theN-acyl dehydroamino acid derivatives are known (Adv. Synth. Cat. 2003. 345. 308). The disadvantage of this approach is that the required hydrolysis of the N-acetyl group is time consuming and may give rise to erosion of enantiomeric excess.
Typically, synthetic methods to prepare the above mentioned bipheny! alanine derivatives in enantiomerically pure form use expensive starting materials such as non-natural D-tyrosine. Moreover, said methods require the use of trifluoromethanesulfonic anhydride, which is also expensive, to activate the phenolic hydroxyl in order to carry out the aryl coupling reaction leading to the desired biphenyl structure. One exampfe of such a synthetic approach is described in the J. Med. Chem. 1995,38, 1689-1700. The following Scheme 1 illustrates one of these methods:

The preparation of N-acyl derivatives of bipheny] alanine as described in the prior art references have few disadvantages which is difficult to be used on an industrial level.because of the rather critical conditions.
Therefore, there is a strong need to develop inexpensive methods to prepare R-biphenylalaninol and to develop an improved and commercially viable process for the preparation of N-acyl derivatives of biphenyl alanine and related intermediates useful in the preparation for biaryl substituted 4-amino-butyric acid amide derivatives which act as NEP inhibitors, preferably of enantiomerically pure N-acyl derivatives of biphenyl alanine and related intermediates, which synthesis can be used on a commercial scale and which avoids the above mentioned drawbacks of the prior art processes.

Objective of the invention
The main object of the present invention is to provide a new process for preparing N-acyl derivatives of biphenyi alanine and related intermediates such as (R) biphenyl alaninol or (R) phenyl alanine derivative which are key intermediates and useful in the preparation of NEP inhibitors. Preferably, the main object of the present invention is to provide a new process for preparing enantiomerically pure 3-biphenyl-2-aminopropan-l-ol or (R ) phenyl alanine derivatives and their conversion to N-acyl derivatives of biphenyl alanine followed by conversion to NEP inhibitors such as biaryl substituted 4-amino-butyric acid amide derivatives.
Summary of the invention
The main aspect of the present invention is to provide a new process for the preparation of (2R3 4S)-5-(Bipheny)-4-y])-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid of formula (!) from intermediate compounds of Formula (VI) or Formula (Vllb). The compound of formula (I) as obtained by the present invention is enantiomer pure and stable which can further converted to the required Biaryl substituted 4-amino-butyric acid amide derivatives.

Whereas X is a leaving group such as F, CI, Br, 1 and boronic acid; Pr is amine protecting group; and R is H, alkyl, benzyl and phenyl;
Drawings
Sheet (1 of 4)
Shows the PXRD values of compound of Formula (IX)

Sheet (2 of 4)
Shows the PXRD values of compound of Formula (VII)
Sheet (3 of 4)
Shows the PXRD values of crystalline form A compound of Formula (I)
Sheet (4 of 4)
Shows the PXRD values of crystalline form B compound of Formula (I)
Description of the Invention
In one aspect of the present invention, the new preparation process of compound of formula (I), using the intermediate compound. (R)-tert-butyl (!-([!, l'-biphenyl]-4-yl)-3-hydroxypropan-2-yl)carbamate of Formula (VI), which is depicted by the following structure.

whereas, Pr is amine protecting group
In another aspect of the present invention, the new preparation process of compound of formula (I), using the intermediate compound, (R)-2-pentanoic acid ((([1, I'-di methyl ethoxy] carbonyl) amino)-5-(4-iodo phenyl)-2-methyl ethyl ester of Formula (VUb), which is depicted by the following structure.

whereas, R, X and Pr as defined above;
According to the present invention, the preparation process of compound of Formula (VI) is prepared from the compound of Formula (VII).
According to the present invention, optionally the preparation process of compound of Formula (VI lb) is prepared by the intermediate compound of Formula (VII). which is depicted by the following structure.
whereas, X and Pr as defined above;
According to the present invention, optionally the preparation process of compound of Formula (VII) is prepared from the compound of Formula (X). which is depicted by the following structure.

In another embodiment, the new process of the present invention for the preparation of intermediate compound of Formula (VI), prepared from the starting compound of the (D)-phenyl alanine of compound of Formula (X).
According to the present invention, the compound of Formula (VI) preparation process can be depicted by the following Synthetic Scheme-2

Whereas "X" is a leaving group such as F. CI, Br, I and boronic acid; "Pr" is amine protecting group and "R" is any alkyl of Ci-io, aryl. hetero aryl etc.
The novel process of the present invention for the preparation of intermediate compound of Formula (VI) can be briefly explained by the following procedure which comprising.
(i) conversion of the compound of Formula (X) to formula (IX) in the presence of organic solvent;
(ii) reacting the compound (IX) of step (i) with an alcohol, thionyl chloride in the presence of solvent to obtain the corresponding ester compound of Formula (IXa);
(iii) protecting the compound of Formula (IXa) of step (ii) with suitable protecting compound to obtain compound of formula (VIII);
(iv) reducing the compound of Formula (VIII) of step (iii) with a reducing agent in the presence of a solvent to obtain an alcohol compound of formula (VII). and
(v) reacting the compound of Formula (VII) of step (iv) with organic boronic acid or halobenzene in the presence of a catalyst in an organic solvent to obtain compound of Formula (VI).
According to the present invention, optionally protecting the compound of Formula (IX) of step (i) with suitable protecting compound to obtain compound of formula (lXb) and the compound of formula (IXb) esterified to obtain compound of formula (IXc), which further converted to form the compound of Formula (VI).
According to the present invention, the compound obtained by step (ii) and (iii) are optionally isolated.
According to the present invention, the compound of Formula (VII) optionally may be purified by conventional methods.
In another embodiment the compound of Formula (VII) the x-ray diffraction 20 values comprise here 8.1, 9.7, 11.7, 12.9, 13.8, 16.0, 16.2, 17.6, 19.1, 20.1, 20.7, 23.6, 24.5, 25.5 and 27.9.

In another embodiment, the present invention of compound of Formula (VI) also be prepared by another novel synthetic process, depicted by the following Synthetic Scheme-3

Scheme 3
Whereas "X" is a leaving group such as F, CI, Br, I and boronic acid; "Pr" is amine protecting group and "R" is any alky I of Cl-10, aryl, hetero aryl etc.
In another embodiment, the present invention of compound of Formula (VI) also be prepared by another novel synthetic process, depicted by the following Synthetic Scheme-4

wherein, "Pr" , "X" and "X^" defined as above;
In another embodiment, the present invention of compound of Formula (VI) also be prepared by another novel synthetic process, depicted by the following Synthetic Scheme-5

wherein, "Pr" defined as above;
In another embodiment, in the present invention the preparation of compound of Formula (I) can also be obtained from the intermediate compound of Formula (VII).
The compound of Formula (VII) prepared by the above depicted any of the synthetic process of schemes 2 & 3.
One more embodiment of the invention is process of conversion of compound of Formula (VII) to compound of Formula (I) by following methods.
The synthetic preparation process of compound of Formula (I) from compound of formula (VII), can be depicted by the following Synthetic Scheme-6

wherein," Pr" , "R" and "X" defined as above;
The novel process of the present invention for the preparation of compound of Formula (I) or Formula (III) from compound of Formula (VII) can be explained by the following procedure which comprising,
(i) conversion of the compound of Formula (VII) to formula (Vila) by oxidation process;
(ii) the compound (Vila) of step (a) converting to compound of Formula (VMb) by wittig reaction;

(iii) hydrolysis of step (ii) compound to obtain compound of Formula (Vile);
(iv) conversion of the compound of Formula (Vile) of step (iii) to compound of Formula (III) by coupling reaction, and
(v) converting the compound of Formula (III) as obtained by step (iv) to compound of Formula (I) by reduction.
According to the present invention, optionally, the compound of Formula (Vllb) converted to Formula (IV). and which converted to Formula (III) by hydrolysis reaction. The compound of Formula (HI) further converted to Formula (I).
One more embodiment of the invention is process of conversion of compound of Formula (VI) as obtained in any of the above mentioned process to compound of formula (I) by following methods.
The compound of Formula (VI) obtained by the above depicted any of the synthetic process of schemes 2. 3, 4 & 5.
The synthetic preparation process of compound of Formula (I) from compound of formula (VI), can be depicted by the following Synthetic Scheme-7

wherein, "Pr" defined as above:
One more embodiment of the invention is process of conversion of compound of Formula (X) to compound of Formula (I) by following methods.

The synthetic preparation process of compound of Formula (1) from compound of formula (X), can be depicted by the following Synthetic Scheme-8

The process of the present invention for the preparation of compound of Formula (I) can be briefly explained by the following procedure which comprising,
(i) conversion of the compound of Formula (X) to formula (IX) by reacting, compound of formula (X) with halogen in the presence of a halogenating agent, acids, and an organic solvent, and optionally purifying the obtained compound (IX) by conventional methods;
(ii) reacting the compound (IX) of step (i) with an alcohol, thionyl chloride in the presence of solvent to obtain the corresponding ester compound of Formula (lXa);
(iii) protecting the compound of Formula (IXa) of step (ii) with suitable protecting compound in the presence of base to obtain compound of formula (VIII):
(iv) reducing the compound of Formula (VIM) of step (iii) with a reducing agent in the presence of a solvent to obtain an alcohol compound of formula (VII),
(v) conversion of the compound of Formula (VII) to formula (Vila) by using oxidation agent in a suitable solvent in suitable temperature;
(vi) the compound (Vila) of step (v) converting to compound of Formula (VMb) by wittig reaction;
(vii) conversion of the compound of Formula (Vllb) to compound of Formula (IV) by coupling reaction,
(viii) hydrolysis of compound of Formula (JV) of step (vii) to obtain compound of Formula (III);
(ix) converting the compound of Formula (III) as obtained by step (viii) to a compound of Formula (II) by reduction in the presence of Transition metal catalyst in an organic solvent, and
(x) purification of compound of Formula (I) in the presence of organic solvents and their mixtures.
According to the present invention, the compounds obtained by step (ii), (iii), (v), (vii) and (ix) are optionally isolated.

According to the present invention, wherein, the halogen of step (i) is selected from Iodine. Fluorine, Bromine and the halogenating agent is selected from sodium iodate. potassium iodate, sodium periodate, N-bromosuccinamide. iodine. Potassium iodide, N-iodosuccinamide. or mixtures thereof.
According to the present invention, wherein, the acid of step (i) is selected from acetic acid, trifluoro acetic acid, sulfuric acid, fumaric acid and mixtures thereof.
According to the present invention, wherein step (i) the pH is adjusted to between 1 and 3 and preferably to between 2 and 3 and more preferably to between 2 and 2.5.
According to the present invention, wherein purification in step (i) is conducted by crystallization or slurring in suitable solvents selected from water, acetonitrile, dichloromethane, dichloroethane, hexane, heptane, ethylacetate, methylacetate, chloroform and their mixtures.
According to the present invention, the organic solvent used in step (ii) selected from group of alcoholic solvent such as methanol, ethanol. propanol. isobutanol, butanol and mixtures thereof.
According to the present invention, the protecting group used in step (iii) selected from Carbobenzyloxy (Cbz), p-nitro phenyl, p-Methoxybenzyl carbonyl (Moz or MeOZ), tert-Butyloxycarbonyl (BOC). acetyl, 9-Fluorenyimethyloxycarbonyl (FMOC), Tosyl (Ts) group, Benzoyl (Bz), Benzyl (Bn), Carbamate group thereof; wherein, the base is selected from triethylamine, diisopropylethylamine etc.
According to the present invention, the reducing agent'used in step (iv) is selected from Raney nickel, Lithium aluminium hydride, sodium borohydride, Diisobutylaluminium hydride -H (DIBAL-H), sodium cyanoborohydride, sodium triacetoxy borohydride. Lithium diisopropylamide (LDA), Lithium borohydride, vitride and or mixtures thereof.
According to the present invention, the solvent used in step (iv) selected from tetrhydrofuron, methanol, ethanol, propanol.
According to the present invention, the oxidation agent used in step (v) selected from a mixture of sodium hypochlorite, 2. 2. 6, 6-Tetramethylpiperidinyloxy (TEMPQ) or any other suitable oxidizing agents.

According to the present invention, in step (v) the solvent selected from isopropyl acetate, ethylacete, diisopropyt ehtylacetate, methyl acetate, dichloromethane. water and their mixtures.
According to the present invention, in step (v) the reaction temperature was maintained at < 20°C and more preferably the temperature between 0 and 10°C.
According to the present invention, in reaction of step (v) the addition of Sodium hypo chlorite solution below 2 hours and more preferably 1.0 to 1.5 hours.
According to the present invention, in step (v) the obtained compound (Vila) having the content of corresponding L-isomer at below 20% and more preferably below 5%.
According to the present invention, in step (vi) the witting agent selected from triphenyl phosphoniumylide.
According to the present invention, the catalyst used in step (vii) selected from group bis(tripheny]phosphine)palladium(ll) dichloride. palladium chloride; palladium acetate, tetrakis(triphenylphosphine)palladium. tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3) and tris(dibenzylideneacetone)dipalladium and thereof.
According to the present invention, the hydrolysis step (viii) the suitable hydrolyzing agent is selected from sodium hydroxide, lithium hydroxide, potassium hydroxide.
According to the present invention, the reduction step (ix), wherein the transition metal catalyst are selected from palladium on carbon, platinum on carbon, raney nickel, and wherein the organic solvent such as methanol, ethanoi, propanol, isobutanol, butanol and mixtures thereof.
According to the present invention, the purification step (x), wherein the organic solvent(s) is selected from Isopropyl acetate, heptane, ethyl acetate, hexane, ethyl format and their mixtures.
In one more embodiment of the invention the intermediate compounds as prepared according to the present invention, if required can be purified by conventional methods.

In another embodiment the compound of Formula (IX) the x-ray diffraction 20 values comprise here 4.4, 4.9, 8.8, 9.8, 13.2, 21.9, 26.6, 29.2 and 29.7 (±) 0.2° 2-theta.
In another embodiment the compound of Formula (VII) the x-ray diffraction 2G values comprise here 8.1, 9.7, 11.7, 12.9, 13.8, 16.0, 16.2, 17.6, 19.1, 20.1, 20.7, 23.6, 24.5, 25.5 and 27.9 (±) 0.2° 2-theta.
According to the present invention, wherein step (x) the method of preparation process of crystalline form A compound of Formula (I) is obtained from fast cooling of the reaction mass and the separated solid is filtered and dried.
According to the present invention, wherein step (x) the method of preparation process of crystalline form B compound of Formula (I) is obtained from slow cooling of the reaction mass and the separated solid is filtered and dried.
In another embodiment the crystalline form A compound of Formula (I) the x-ray diffraction 20 values comprise here 6.7, 8.4, 9.9, 10.6, 11.4, 13.6, 14.8] 16.6, 17.8, 18.1, 21.8 and 27.2 (±) 0.2° 2-theta.
In another embodiment the crystalline form B compound of Formula (I) the x-ray diffraction 2G values comprise here 7.7, 9.8, 12.0, 14.7, 15.6, 16.7, 18.0, 19.7, 21.2, 22.6, 24.0, 25.5, 26.4 and 29.0 (±) 0.2°2-theta.
In another embodiment, the compound of Formula (I) as obtained according to the above synthetic processes, further converted to the NEP inhibitor by an improved process.
In another embodiment, the compound of Formula (I) as obtained by any of the process of the present invention further converted to the desired NEP inhibitors of biaryl substituted 4-amino- . butyric acid amide derivatives.
The Following examples are illustrative of the present inventions and are not intended to limit the inventions.

EXAMPLES: Example: 1
Preparation of Carbamic acid, [(i/?)-2-hydroxy-1 -[(4-iodophenyl)methyI]ethyl]-, 1,1-di methyl ethyl ester of Formula (VII)
Step 1: Preparation of 4-(Iodo) - (D)-phenylalanine of Formula (IX)
Charged acetic acid (75ml) into round bottom flask and slowly added cone. Sulfuric acid (44.5g) at 25-45°C, followed by D-Phenylalanine (50g) and iodine (30.72g) and sodium iodate (12g) for 10-15 min at 25-35 °C. The reaction mixture was stirred at 70-75 °C for 3 to 4 hours. Cooled the reaction mixture to 40-50 °C and added water (500ml) and stirred the reaction mixture for 10 to 20 minutes at 25 to 35°C, then charged the dichloromethane (250ml) and stirred for 20 to 40 minutes at 25 to 35°C.
The Organic layer was separated and the aqueous layer pH was adjusted by drop wise addition of 10% sodium hydroxide solution at 40-60 °C and cooled to 30-35 °C and stirred for 30-45 minutes and filtered the solid and washed with water and acetonitrile (2*300 ml) and also washed with dichloromethane solvent and obtained wet material was dried at 70-90 °C for 6-8 hours to obtain the compound of formula (IX). Yield: 35-40(g}. *
Step 2:
Preparation of 4-(Iodo) - (D)-phenylalanine methyl ester of Formula (IXa)
Methanol (125ml) was added to the step lcompound (IX) (25g) at room temperature and cooled the mixture to 5-15 °C, at this temperature thionyl chloride (15.3g) was added, after addition completed, raised the temperature to 55-65 °C for 2-3hours. The reaction mixture was cooled to 10-20°C to get the reaction mass containing the compound of formula (IXa).

Step 3:
Preparation of (N-(l,l-dimethylethoxy carbonyl)-(D)-phenyIalanine)-4-(Iodo)-methyl ester of Formula (VIII)
To the above reaction mass of Formula (IXa) slowly added tri ethyl amine (34.8) below 35 °C and adjusted the pH not less than 8.00 and slowly added the di-tert-butyl dicarbonate (22.5g), toluene (250ml) and water (125ml) and heated the reaction mixture to 45-55 °C for 30-45 min and.separated the layers. The organic layer was distilled under vacuum below 80 °C and cooled the residue to 35 to 45 °C.
Step 4:
Preparation of Carbamic acid, [(1 R)-2 -hydroxy-1 -[(4-iodophenyl)methyl]ethyl]-, 1,1-dimethylethyl ester of Formula (VII)
To the above residue of Formula (VIII) was taken into Tetrahydrofuran (62.5ml) and this • solution was added slowly to the Lithium chloride (5.5g) and water mixture and to this slowly charged Sodium boro hydride in 10 equal lots for every 20-30 min interval at 20-35°C and maintained for 1-2 hours at 20-35°C. The organic layer was quenched with hydrochloric acid, Ethyl acetate and water and distilled off and obtained solid was filtered and washed with hexane and then dried under vacuum to obtain the compound of formula VII. Yield: 28-30(g).
Example: 2
Preparation of compound of Formula (VI lb)
To the above obtained compound of formula VII (50g), Sodium bicarbonate (NaHC03) (20. lg), Sodium bromide (NaBr) (25.9g), Water (300ml), Isopropyl acetate (750ml) were added while stirring at 25 to 35°C. Cooled the reaction mass to -2 to 5°C, then charged the 2, 2, 6, 6-Tetramethylpiperidinyloxy (TEMPO) (0.41g) and stirred for 10 to 15 minutes, to this slowly added the sodium hypochlorite solution (NaOCl), then stirred the mass for 20-30 minutes. After reaction completed, added sodium thiosulfate solution to the reaction mass at below 15 °C, the obtained organic layer was separated to obtain compound of formula (Vila). To the above obtained formula (Vila) compound, (Carbethoxyethylidene) triphenyl phosphorane (55.2g) was added and stirred the reaction mass for 30 to 60 minutes at 25 to 35°C. Then

distilled the mass completely under vacuum at below 55°C and cooled the residue upto 25°C. To this methanol and water was added and the solids were filtered and dried to obtain the compound of formula (Vllb). Yield (g): 45-50{g).
Example: 3
Preparation of compound of Formula (III)
Charged above obtained compound of Formula (Vllb) (20g), phenyl boronic acid (6.63g, 0.0092mols), sodium carbonate (9.23g) into Tetrahydrofuran (40ml), water (100ml) and toluene (120ml) was added at 25-30 °C with nitrogen purging for 30 to 45 mins. To this mixture palladium catalyst (0.2g) was added and then heated to 70-80 °C for 3-4 hrs. After reaction completed, the layers were separated. The organic layer was washed with water (20ml) and 2 % citric acid solution and then 2% sodium carbonate solution, activated. carbon, then distilled out the organic layer completely under vacuum to obtained residue compound of Formula (IV).
To the residue Methanol (180 ml) and Lithium hydroxide monohydrate (3.66g) were added at 25 to 35°C and stirred the reaction mass for 2 to 3 hours at 60 to 70 °C. After reaction completed, acetic acid and water mixture was added slowly at 50 to 65 °C and then cooled to 25 to 30 °C. The reaction mass was filtered and washed with mixture of methanol and water and suck dried for 15 to 30 minutes to obtain the compound of formula (III). Yield: 12-14(g).
Example: 4
Preparation of compound of Formula (I)
Charged the compound of formula (III) (20g) in to the Auto clave vessel at 25 to 35°C, to this 10 % Palladium /Carbon (1.2g) and methanol (240ml) were added, under nitrogen 5-6 Kg hydrogen pressure was applied and heated to 60 to 65°C for 8 to 10 hours. The mass was coole_d, filtered and washed with methanol. The filtrate was distilled completely under vacuum at below 50°C. To the above residue Isopropyl acetate (2 vol) and heptane (4 vol) were added at 25 to 45 °C and heated the reaction mass for 15 to 30 minutes at 75 to 85°C and then cooled the mass and stirred again for 60 to 90 minutes at 25 to 30°C. Filtered the precipitation and washed with heptane and dried for 45 to 60 minutes. Yield: 10-12 (g).

Claims
1. A process for the preparation of (2R, 4S)-5-(Biphenyl-4-yl)-4-[(tert-butoxycarbonyl) amino]-2-methylpentanoic acid of Formula (1) comprising.
(i) conversion of the compound of Formula (X) to formula (IX) by reacting, compound of formula (X) with halogen in the presence of a halogenating agent, acids, and an organic solvent, and optionally purifying the obtained compound (IX) by conventional methods;
(ii) addition of an methanol thionyl chloride at 0-20°C to the compound of formula (IX) as obtained in step (i) followed by stirring at 45-60°C for 2-4 hours to get the corresponding methyl ester compound of formula (IXa);
(iii) reacting the compound of Formula (IXa) of step (ii) with a suitable protecting group in the presence of a base at about 20-3 5°C to obtain compound of formula (VIII);
(iv) reducing the compound of Formula (VIII) of step (iii) with a reducing agent in the presence of a solvent and isolating the obtained alcohol compound of formula (VII):
(v) conversion of the compound of Formula (VII) to formula (Vila) by oxidation process in the presence of an oxidizing agent in a suitable solvent;
(vi) conversion of the compound (Vila) of step (v) to a compound of Formula (Vllb) by wittig reaction;
(vii) conversion of the compound of Formula (Vllb) to compound of Formula (IV) by coupling reaction using phenyl boronic acid;
(viii) hydrolyzing the compound of Formula' (IV) in the presence of a suitable hydrolyzing agent to obtain compound of Formula (111);
(ix) converting the compound of Formula (III) as obtained by step (viii) to a compound of Formula (II) by reduction in the presence of Transition metal catalyst in an organic solvent, and

(x) purifying the compound of Formula (II) of step (ix), in the presence of organic solvent and their mixtures to get the compound of formula (I).
2. The process of claim I of step (i), wherein the purification is carried out by crystallization or slurring in a suitable solvents, wherein the solvents is selected from isopropyl acetate, acetonitrile, ethylacete, dichloromethane, water and their mixtures.
3. The process of claim 1 of step (v). wherein the obtained compound (Vila) having the content of corresponding L- isomer at below 20%.
4. The process of claim 1 of step (v), wherein the solvent is selected from ethyl acetate, propyl acetate, diisopropyl acetate, isopropy acetate, water or mixture thereof.
5. The crystalline compound of claim 1 of step (iv), wherein the solid compound of Formula (VII) is characterized by a powder X-ray diffraction pattern having significant peaks at 8.1,9.7, 11.7, 12.9, 13.8, 16.0, 16.2, 17.6, 19.1,20.1,20.7,23.6,24.5,25.5 and 27.9 (±) 0.2° 2-theta.
6. The crystalline compound of claim I of step (x), wherein the solid crystalline form A of compound of Formula (I) is characterized by a powder X-ray diffraction pattern having significant peaks at 6.7, 8.4, 9.9, 10.6, 11.4, 13.6, 14,8, 16.6, 17.8, 18.1, 21.8 and 27.2 (±) 0.2° 2-theta.
7. The crystalline compound of claim 1 of step (x), wherein the solid crystalline form B of compound of Formula (1) is characterized by a powder X-ray diffraction pattern having

significant peaks 7.7, 9.8, 12.0, 14.7, 15.6, 16.7, 18.0, 19.7, 21.2, 22.6, 24.0, 25.5, 26.4 and 29.0 (±) 0.2° 2-theta.
8. A process for the preparation of compound of formula (Vila) from compound of Formula (VII) by oxidation reaction.
9. A process for the preparation of compound of formula (IV) from compound of Formula (Vllb) by coupling with phenylboronic acid.
10. A process for the preparation of Sacubitril from the compound of formula (1) as obtained by the process of claim 1.