DESC:Field of the Invention
The present invention discloses a process for the preparation of Sacubitril and its novel intermediates.
Background of the invention
Sacubitril is an antihypertensive drug used in combination with valsartan. The combination is marketed under the brand name Entresto® by Novartis. It is used for the treatment of heart failure. Sacubitril is chemically known as N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester, compound of Formula I

US 5,217,996 & US 5,354,892 describe Sacubitril and the methods of preparation.
There are several known methods of the preparation of Sacubitril , which are described in various patents/patent applications : US 9,085,529; US 8,946,481; US 8,263,629; US 9,006,249; US 8,835,668; US 9,061,973; US 9,181,175; US 8,703,990; US 20150274650; US 20140142320; US 20150274642; US 20150166468; US 20150210632; US 20090326066; US 20130172572; CN 104557600; CN104860894 and CN 10500117. The reported processes for the preparation of Sacubitril suffer from many disadvantages which includes difficulty in achieving desired chiral purity, tedious & cumbersome work up procedures, multiple crystallizations or isolation steps, column chromatographic separations and purifications etc. All these disadvantages effect the overall yield as well as the quality of the final product.
In view of all these disadvantages, there is a significant need in the art to develop a novel process for the preparation of Sacubitril with good yield.
Summary of the Invention
In one aspect, the present invention relates to the novel intermediates of the formulae VI - XV, which are useful in the preparation of Sacubitril of formula (I)

In another aspect, the present invention provides a process for the preparation novel intermediate of Sacubitril of formula (V),

which comprises:
a) amine protection of compound of formula II

to give compound of formula III;

b) benzylating of compound of formula III to give compound of formula IV;

c) hydrolyzing of compound of formula IV to give compound of formula V;

d) converting of compound of formula V to novel intermediate of formula VI.
In another aspect, the present invention provides a process for the preparation of Sacubitril of formula I form intermediate of formula VI
a) reducing of compound of formula VI

to give compound of formula VII;

b) methylating of compound of formula VII to give compound of formula VIII;

c) converting of compound of formula VIII to compound of formula IX;

d) converting of compound of formula IX to compound of formula X;

e) deprotection followed by esterification of compound of formula X to give compound of formula XI;

f) converting of compound of formula XI to give compound of formula XII;

g) deprotecting of compound of formula XII to give compound of formula XIII;

h) converting of compound of formula XIII to give compound of formula XIV;

i) suzuki coupling of compound of formula XIV to give compound of formula XV;

j) converting compound of formula XV to give Sacubitril of formula (I).

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention relates to novel intermediates of formulae VI, VII, VIII, IX, X, XI, XII, XIII, XIV and XV which are useful in the preparation of Sacubitril of formula (I).

According to another aspect of the present invention, there is provided a process for the preparation of novel intermediate of formula (VI),

Scheme – 1 illustrates the process for preparation of novel intermediate formula (VI).

In step-a of the preparation, protection of D-Tyrosine Ester of formula (II) with amine protecting groups in the presence of base and solvent to give N-BoC.D-Tyrosine Ester of formula (III). The amine protecting groups are selected from carbobenzyloxy (Cbz), tert-Butyloxycarbonyl (BOC), benzoyl (Bz) or benzyl (Bn) and preferably using tert-Butyloxycarbonyl. The base used in the reaction is selected from trimethylamine, sodium hydroxide or potassium tert-butoxide and preferably using triethylamine. The solvent used in the reaction is selected from dichloromethane, dichloroethane or chloroform and preferably using dichloromethane. The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 35 °C. The duration of the reaction may range from 10 hours to 14 hours, preferably for a period of 12 hours.

In step-b of the preparation, benzylating N-BoC.D-Tyrosine Ester of formula (III) with benzyl bromide in the presence of base and solvent to give N-BoC-O-Bn-D-Tyrosine Ester of formula (IV) in the presence of base and solvent. The base used in the reaction is selected from potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate and preferably using potassium carbonate. The solvent used in the reaction is selected from dimethyl formamide or dimethyl acetamide and preferably using dimethyl formamide. The reaction temperature may range from 0 °C to ambient temperature and preferably at a temperature in the range from 25 °C to 35 °C. The duration of the reaction may range from 10 hours to 14 hours, preferably for a period of 12 hours.

In step-c of the preparation, Hydrolyzing of N-BoC-O-Bn-D-Tyrosine Ester of formula (IV) in presence of base and solvents to give N-BoC.O-Bn.D-Tyrosine of formula (V). The base used in the reaction is selected from potassium hydroxide or sodium hydroxide and preferably using sodium hydroxide. The solvents used in the reaction is selected from mixture of methanol and tetrahydrofuran. The reaction temperature may range from 20 °C to 35 °C and preferably at a temperature in the range from 25 °C to 35 °C. The duration of the reaction may range from 1 hour to 4 hours, preferably for a period of 3 hours.

In step-d of the preparation, reacting N-BoC.O-Bn.D-Tyrosine of formula (V) with Meldrum’s acid in presence of DCC, DMAP and solvent to give O-Benzyl –[(R)-tert-butyl 1-(2,2-dimethyl-4, 6-dioxo-1,3-dioxan-5-yl)-3-phenylpropan-2-yl carbamate of formula (VI). The solvent used in the reaction is selected from dichloromethane, dichloroethane or chloroform and preferably using dichloromethane. The reaction temperature may range from -5 °C to -10 °C. The duration of the reaction may range from 15 hours to 25 hours, preferably for a period of 20 hours.

In another aspect, the present invention provides a novel process for preparation of Sacubitril of formula (I) from novel intermediate of formula (VI), which comprises

Scheme – 2 illustrates the process for preparation of Sacubitril formula (I).

Wherein, the Protecting Groups P are: BOC, Pivolyl, Acetyl, Triflouroacetyl

In step-e of the preparation, reducing of O-Benzyl –[(R)-tert-butyl 1-(2,2-dimethyl-4, 6-dioxo-1,3-dioxan-5-yl)-3-phenylpropan-2-yl carbamate of formula (VI) with reducing agent in presence of acetic acid and solvent to give O-Benzyl–[(R)-tert-butyl 1-(2,2-dimethyl-4, 6-dioxo-1,3-dioxan-5-yl)-3-phenylpropan-2-yl carbamate of formula (VII). The solvent used in the reaction is selected from dichloromethane, dichloroethane or chloroform and preferably using dichloromethane. The reaction temperature may range from -5 °C to 0 °C. The duration of the reaction may range from 1 hours to 4 hours, preferably for a period of 2 hours.

In step-f of the preparation, methylating of O-Benzyl –[(R)-tert-butyl 1-(2,2-dimethyl-4, 6-dioxo-1,3-dioxan-5-yl)-3-phenylpropan-2-yl carbamate of formula (VII) with methyl iodide in presence of base and solvent to give 5-[2-(tert.butyloxy carbonyl)amino]-3-(4-benzyloxyphenyl)propyl)-2,2,5-trimethyl-1,3-dioxane-4,6 dione (VIII). The base used in the reaction is selected from potassium carbonate, sodium carbonate, potassium bicarbonate or sodium bicarbonate and preferably using potassium carbonate. The solvent used in the reaction is selected from dimethyl formamide or dimethyl acetamide and preferably using dimethyl formamide. The reaction temperature may range from 0 °C to 10 °C and preferably at a temperature in the range from 0 °C to 5 °C. The duration of the reaction may range from 1 hours to 4 hours, preferably for a period of 3 hours.

In step-g of the preparation, cyclizing of 5-[2(tert.butyloxy carbonyl)amino]-3-(4-benzyloxyphenyl)propyl)-2,2,5-trimethyl-1,3-dioxane-4,6 dione (VIII) with toluene to give tert.butyl (3R)-5-(4-benzyloxy phenyl)-3-methyl-2-oxo-propylidene carboxylate (IX). The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 35 °C. The duration of the reaction may range from 24 hours to 48 hours, preferably for a period of 48 hours.

In step-h of the preparation, hydrolyzing of tert.butyl (3R)-5-(4-benzyloxy phenyl)-3-methyl-2-oxo-propylidene carboxylate of formula (IX) with lithium hydroxide in presence of solvent to give O-Bn-(2R,4S)-4-aminoButyloxy Carbonyl-5-[4-(benzyloxy)phenyl]-2-methylpentanoic acid (X). The solvent used in the reaction is selected from tetrahydrofuran, diethyl ether, 1,4-dioxane or methyl tert-butyl ether and preferably using tetrahydrofuran. The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 30 °C. The duration of the reaction may range from 30 minutes to 2 hours, preferably for a period of 45 minutes.

In step-i of the preparation, deprotection and esterification of O-Bn-(2R, 4S)-4-aminoButyloxy Carbonyl-5-[4-(benzyloxy) phenyl]-2-methylpentanoic acid of formula (X) with ethanol in presence of hydrochloric acid and to give (2R,4S -4-amino-5-[4-(benzyloxy)phenyl]-2-methylpentanoate (XI). The reaction temperature may range from 10 °C to 35 °C and preferably at a temperature in the range from 25 °C to 35 °C. The duration of the reaction may range from 1 hours to 4 hours, preferably for a period of 3 hours.

In step-j of the preparation, protecting (2R,4S)-4-amino-5-[4-(benzyloxy)phenyl]-2-methylpentanoate of formula (XI) with protecting groups in presence of solvent and base to give (2R,4S)-5-(Phenyloxy benzyl)-4-Amino (2,2-dimethylpropionyl)-2-methylPentanoate (XII). The base used in the reaction is selected from trimethylamine, sodium hydroxide or potassium tert-butoxide and preferably using triethylamine. The solvent used in the reaction is selected from methyl acetate, ethyl acetate, isopropyl acetate or tert-butyl acetate and preferably using ethyl acetate. The reaction temperature may range from 20 °C to 40 °C and preferably at a temperature in the range from 25 °C to 35 °C. The duration of the reaction may range from 20 to 26 hours, preferably for a period of 24 hours.

In step-k of the preparation, deprotecting (2R,4S)-5-(Phenyloxy benzyl)-4-Amino (2,2-dimethylpropionyl)-2-methylPentanoate (XII) with palladium on carbon in presence of solvent under pressure of 1-5 Kg H2 gm/Cm2 to give (2R,4S)-5-(Phenyl)-4-Amino (2,2-dimethylpropionyl)-2-methylPentanoate of formula (XIII). The solvent used in the reaction is selected from methanol, ethanol, n-propanol or isopropanol and preferably using methanol. The reaction temperature may range from 25 °C to 50 °C and preferably at a temperature in the range from 25 °C to 40 °C. The duration of the reaction may range from 20 to 26 hours, preferably for a period of 24 hours.

In step-l of the preparation, reacting of (2R, 4S)-5-(Phenyl)-4-Amino (2,2-dimethylpropionyl)-2-methylPentanoate (XIII) with Triflic anhydride in presence of solvent to give triflate derivative of formula (XIV). The solvent used in the reaction is selected from dichloromethane, dichloroethane or chloroform and preferably using dichloromethane. The reaction temperature may range from 25 °C to 50 °C and preferably at a temperature in the range from 25 °C to 40 °C. The duration of the reaction may range from 1 to 2 hours, preferably for a period of 2 hours.

In step-m of the preparation, coupling of triflate derivative of formula (XIV) with phenyl Boronicacid in presence of base, ligand and solvent to give Ethyl (2R)-4-Amino(2,2-dimethylpropionyl)-5-biphenyl-4-yl-2-methyl pentanoate which on deprotection to get Ethyl (2R)-4 Amino -5-biphenyl-4-yl-2-methyl pentanoate (XV). The ligand used in the reaction is selected from tetrakis triphenyl phosphine palladium, Bis (triphenyl phosphine) palladium (II) chloride, Bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) palladium, palladium acetate, cuprous bromide or racemic Binap, preferably using tetrakis triphenyl phosphine palladium. The base used in the reaction is selected from trimethylamine, sodium hydroxide, potassium tert-butoxide, sodium carbonate or potassium carbonate and preferably using potassium carbonate. The solvent used in the reaction is selected from tetrahydrofuran, toluene or methyl tert-butyl ether, preferably toluene. The reaction temperature may range from 85 °C to 100 °C and preferably at a temperature in the range from 90 °C to 95 °C. The duration of the reaction may range from 13 to 16 hours, preferably for a period of 15 hours.

In step-n of the preparation, reacting of Ethyl (2R)-4 Amino-5-biphenyl-4-yl-2-methyl pentanoate (XV) with succinic anhydride in presence of base and solvents to give N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (I). The base may be an inorganic base organic base. Examples of suitable inorganic bases include alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, and alkaline alkoxides. Examples of suitable organic bases include pyridine, triethylamine, and N,N-diisopropylethylamine. Examples of suitable halogenated solvent include dichloromethane, trichloroethylene, carbon tetrachloride, or methyl chloroform. The reaction temperature may range from 35 °C to 70°C and preferably at a temperature in the range from 40 °C to 70 °C. The duration of the reaction may range from 15 to 18 hours, preferably for a period of 17 hours.

EXPERIMENTAL PROCEDURE

Example 1: Preparation of O-Benzyl – [(R)-tert-butyl 1-(2,2-dimethyl-4, 6-dioxo-1,3-dioxan-5-yl)-3-phenylpropan-2-yl carbamate [Formula (VI)]

Step-a: Preparation of compound formula N-BoC.D-Tyrosine Ester [Formula (III)]
D-Tyrosine Ester (100 grams, 0.51 moles) was dissolved in methylene dichloride (1000 mL) added trimethylamine (1.02 moles) and BoC anhydride (0.56 moles) at 0-5 °C. Raised the mass temperature to room temperature and maintained for 12 hours at 25-35 °C. DM water (0.5 Litre) was added to the reaction mixture and adjusted PH to 3-4 with 10 % Aqueous HCl Solution. Separated the organic layer and washed with 10% NaCl Solution (0.5 Litre). Distilled off organic layer Completely under vacuum below 50 °C and finally Isolated with n-Hexane (0.5 Litre) to get N-BoC.D-Tyrosine Ester, yellow color Solid, (Yield: 80 %).
1H NMR (d ppm, DMSO): 1.33 (9H, d), 2.69-2.88(2H, m), 3.59(3H, s), 4.03-4.11 (1H, m), 5.06(2H, s), 6.64-6.67(2H, d), 6.99-7.02(2H, d), 7.21-7.23(1H, d), 9.21(1H, s);
Mass Spectrum: m/Z 295.97 (M+1).
Step-b: Preparation of compound formula N-BoC-O-Bn-D-Tyrosine Ester [Formula (IV)]
The N-BoC D-Tyrosine Ester (III) obtained in step-a (100 grams, 0.33 moles) in dimethylformamide (500 mL) added potassium iodide (5.60 grams, 33 moles), potassium carbonate (93.6 grams, 0.67 moles) at 25-35 °C. The reaction mass was cooled to 0-5 °C and added benzyl bromide (64 grams, 0.37 moles) at 0-5 °C. Slowly raise the temperature of reaction mixture to 25-35 °C and maintained for 12 hours. Cooled the mass temperature to 10-15 °C. Charged DM water (1.0 Litre) at 10-15 °C. Charged N-Hexane (200 mL) and Stirred for 60 minutes at 20-25 °C. Filtered the Solid and washed with DM water (200 mL). To the wet Solid Charged DM water (700 mL) at 25-35 °C and stirred for an hour at room temperature. Filtered the Solid and washed with DM water (500 mL). Dried the compound at 25-35 °C to get N-Boc-O-Bn-D-Tyrosine Ester (IV) (Yield: 92 %).
1H NMR (d ppm, DMSO): 1.26-1.32 [9H, d], 2.74-2.94 (2H, m), 3.59 (3H, s), 4.08-4.12 (1H, m), 5.06 (2H, s), 6.90 (1H, d), 6.93 (1H, d), 7.13-716 (2H, d), 7.25-7.44 (6H, m);
Mass Spectrum: m/z 386.1 (M+1).

Step-c: Preparation of compound formula N-BoC-O-Bn-D-Tyrosine [Formula (V)]
The above obtained N-Boc-O-Bn-D-Tyrosine Ester (IV) obtained in step-b (100 grams, 0.25 moles) added tetrahydrofuran (500 mL) and methanol (300 mL). Added Aqueous NaOH 150 mL (1N) solution to the reaction mixture at room temperature and maintained for 3 hours. Distilled off the Solvent under vacuum below 50 °C. Cooled the mass temperature to 20-25 °C. To the reaction mixture charged aqueous HCl Solution 150 mL (1.0 N) at 20-25 °C and Ethyl acetate (1000 mL) and Stirred for 15 minutes at 25-30 °C. Seperated the organic layer and washed with 10% NaCl Solution (300 mL). Dried the Organic layer on sodium sulfate. Distilled off organic layer completely under vacuum below 50 °C. Charged n-Hexane (500 mL) to the crude at room temperature and stirred for 2 hours at 25-30 °C. Filtered the solid and washed with n-hexane (50 mL). Dried the Compound at 50 °C to N-BoC-O-Bn-D-Tyrosine (V) (Yield: 98.5 %).
1H NMR (d ppm, DMSO): 1.26-1.32 [9H, d], 2.50-2.2.79 (2H, m), 4.08-4.12 (1H, m), 5.06 (2H, s), 6.90 (1H, d), 6.93 (1H, d), 7.13-7.16 (2H, d), 7.25-7.44 (6H, m);
Mass Spectrum: m/z 386.1 (M+1).

Step-d: Preparation of compound formula O-Benzyl – [(R)-tert-butyl 1-(2, 2 -dimethyl-4, 6-dioxo-1, 3-dioxan-5-yl)-3-phenylpropan-2-yl carbamate [Formula (VI)]
The N-Boc-O-Bn-D-Tyrosine (V) obtained in step-c (100 grams, 0.27 moles) dissolved in methylene dichloride (1200 mL). To the solution added Meldrums acid (58.2 grams, 0.40 moles) at -5 to -10 °C and stirred for 5 minutes and added dimethylamino pyridine (55.8 grams, 0.456 moles) and further stirred for 5 minutes at -5 to -10 °C. To the reaction mixture added dicyclohexylcarbodiimide (83.29 grams, 0.403 moles) in methylene dichloride (200 mL) Solution at -5 to -10 °C over a period of 15-20 minutes. Maintained the reaction mass up to 15-20 hours at -5 to -10 °C. Filtered the mass and washed with (100 mL) chilled methylene dichloride. Taken the filtrate and washed with 10% KHSO4 solution (3X500 mL) and finally with washed the organic layer with 10% NaCl Solution (500 mL). Dried the organic layer on Na2SO4. Distilled off organic layer completely under vacuum below 50 °C. Charged MTBE (200 mL) to the Crude at room temperature and stirred for 15 minutes. Charged n-Hexane (500 mL) and stirred for 2 hours at 25-30 °C. Filtered the solid and washed with mixture of MTBE (50 mL) and n-Hexane (200 mL). Dried the compound O-Benzyl – [(R)-tert-butyl 1-(2, 2 -dimethyl-4, 6-dioxo-1, 3-dioxan-5-yl)-3-phenylpropan-2-yl carbamate (VI) at 35-40°C (Yield: 82.7 %).
1H NMR (d ppm, DMSO): 1.20-1.30 [9H, dd], 1.48-1.73 (6H, m), 2.68-2.90 (2H, dd), 3.29-3.36 (1H, m), 5.06 (2H, s), 5.45-5.50 (1H, m), 6.91-6.94 (1H, d), 7.24-7.45 (1H, d), 7.24-7.45 (8H, m);
Mass Spectrum: m/z 498.01 (M+1).

Example 2: Process for the preparation of Sacubitril (I) or its Salts
Step-e: Preparation of compound formula (5-[2-(tertbutyloxy carbonyl) amino]-3-(4-O-benzylphenyl) propyl]-2, 2-dimethyl-1, 3-dioxane-4, 6-dione [Formula (VII)]
To the Meldrums acid derivative (VI) (100 grams, 0.201 moles) added methylene dichloride (1200 mL) and acetic acid (136 mL) at -5 to 0 °C and stirred for 15 minutes. To the reaction mixture slowly added sodium borohydrate (20.6 grams, 0.54 moles) over a period of 60 minutes at -5 to 0°C and maintained for 2 hours. Quenched the reaction mass with 10% NH4Cl solution (1000 mL) at 0-10 °C. The temperature of the reaction mass is slowly raised to 25-35 °C. Seperated the organic layer and washed with DM water (500 mL). Dried the organic layer on Na2SO4. Distilled off organic layer completely under vacuum below 50 °C. Charged MTBE (100 mL) to the crude at room temperature ans stirred for 15 minutes. Charged (200 mL) n-Hexane and stirred for 2 hours at 25-30 °C. Filtered the solid and washed with n-Hexane (100mL). Dried the (5-[2-(tertbutyloxy carbonyl) amino]-3-(4-O-benzylphenyl) propyl]-2, 2-dimethyl-1, 3-dioxane-4, 6-dione (VII) at 35-40 °C. (Yield: 98 %).
1HNMR (d ppm, DMSO): 1.23-1.50 [9H, dd], 1.59-1.74 (6H, m), 2.02-.08 (2H, dd), 2.62-2.67 (2H, m), 3.87-3.97 (1H, m), 4.12-4.15 (1H, t), 5.05 (2H, s), 6.62-6.65 (1H, d), 6.90-6.92 (2H, dd), 7.09-7.12 (2H, dd), 7.29-7.44(5H, m);
Mass Spectrum: m/z 482.17 (M-1).

Step-f: Preparation of compound formula (5-[2-(tertbutyloxy carbonyl)amino]-3-(4-O-benzylphenyl)propanoyl]-2,2,5-trimethyl-1,3-dioxane-4,6-dione [Formula (VIII)]
To the Meldrums acid derivative-2 (VII) of step-e (100 grams, 0.201 moles) in DMF (700 mL) added K2CO3 (34.2grams, 0.25moles) at 25-35 °C and stirred for 15 minutes. The reaction mixture was cooled to 0-5 °C and slowly added methyl Iodide (38.15 grams, 0.27 moles) over a period of 30 minutes and maintained for 3 hours. Filtered the salts and washed with DMF (100 mL). The Filtrate was taken and poured into DM water (2.0 Litre) and stirred for 15 minutes. The crude was extracted with MTBE (500 mL). The aqueous layer was back extracted with MTBE (400 mL). Combined all the organic layers and washed with 10% NaCl solution (500 mL) and dried on Na2SO4. Distilled off organic layer completely under vacuum below 50 °C. To the crude charged n-Hexane (500 mL) and stirred for 60 minutes at room temperature. Filtered the solid and washed with n-Hexane (100 mL). Dried the Compound (5-[2-(tertbutyloxy carbonyl) amino]-3-(4-O-benzylphenyl) propanoyl]-2, 2, 5-trimethyl-1, 3-dioxane-4, 6-dione (VIII) at 35-40 °C (Yield: 72.8 %).
1H NMR (d ppm, DMSO): 1.30 [9H, s], 1.56-1.60 (3H, t), 1.69-1.74 (6H, d) 2.12-2.37 (2H, m), 2.50-2.64 (2H, m), 3.65-3.84 (1H, m), 5.03 (2H, s), 6.01-6.05 (1H, d), 6.86-6.89 (2H, dd), 7.05-7.08 (2H, dd), 7.26-7.43 (5H, m);
Mass Spectrum: m/z 498.07 (M-1).

Step-g: Preparation of compound formula Tert.butyloxy amino-5-(4-O-benzyl phenyl)-3-methyl-2-oxopyrrolidine carboxylate [Formula (IX)]
Charged methylated Meldrum’s acid Derivative (VIII) of step-f (100 grams) to the toluene (1.5 Litre) at 25-35 °C and stirred for 15 minutes. The temperature of the reaction slowly raised to reflux and maintained for 24-48 hours at Reflux. Distilled off reaction mass completely under vacuum below 55 °C. Purify the Compound on 60-120 Silica column by using Ethyl acetate and Hexane to get Tert.butyloxy amino-5-(4-O-benzyl phenyl)-3-methyl-2-oxopyrrolidine carboxylate (IX) (Yield: 62 %).
1H NMR (d ppm, DMSO): 0.96-1.00 [3H, t], 1.48-1.55 (9H, m), 1.58-1.59 (1H, dd), 1.89-1.96 (1H, m), 2.44-2.51 (1H, m), 2.58-2.94 (2H, m), 4.07-4.11 (1H, m), 5.07 (2H, s), 6.95-6.98 (2H, d), 7.08-7.14 (2H, dd); 7.30-7.46 (5H, m);
Mass Spectrum: m/z 296 (M+1).

Step-h: Preparation of compound formula (2R)-4-[(tert.butyloxy carbonyl) amino]-5-(4-O-benzylphenyl)-2-Methyl pentanoic acid [Formula (X)]
Charged cyclized racemic compound (IX) of step-g (100 grams, 0.25 moles) with tetrahydrofuran (1000 mL) 25-35 °C and stirred for 15 minutes. Charged Methanol (500 mL) to the reaction mass. To the reaction mass charged LiOH (50 grams, 2.08 moles) and maintained for 5 hours. The pH of the reaction mass was adjusted to 4-5 with Acetic acid. Distilled off reaction mass completely under vacuum below 40 °C. To the reaction mass charged DM water (500 mL) and Ethyl acetate (500 mL) at 25-35 °C and stirred for 15 minutes and separated the layers. The organic layer was washed with DM water (300 mL) and 10% NaCl Solution (300 mL). Taken the organic layer and Dried over sodium sulphate. Distilled off organic layer completely under vacuum below 50 °C. Charged n-Hexane (500 mL) and stirred for 60 minutes at room temperature. Filtered the Solid and washed with n-Hexane (50 mL) and dried 35-45°C to get crude 88 grams (yield 85 %). The crude was taken and charged Ethanol (500 mL) at room temperature and stirred for 15 minutes. The reaction mixtures was charged with S(-)- PEA (1.0 Equivalent) at 20-25 °C and stirred for 2 hours. Filtered the solid and washed with Ethanol (100 mL) and dried. The solid was taken and charged MDC (1500 mL), purified water (500 mL) and adjusted pH to 5-6 with 2N aqueous HCl (250 mL) and stirred for 1 hr and separated the layers. The organic layer was distilled off and completely under vacuum below 50 °C to get (2R)-4-[(tert.butyloxy carbonyl) amino]-5-(4-O-benzylphenyl)-2-Methyl pentanoic acid (X) (Yield: 75 %).
1H NMR (d ppm, DMSO): 0.95-1.04 [3H, t], 1.10-1.12 (3H, m), 1.14-1.24 (9H, m), 1.65-1.71 (1H, m), 2.43-2.59 (4H, m), 3.54-3.99 (1H, m), 4.02-4.07 (2H, m), 5.05 (2H, s), 6.64-6.67 (2H, d), 6.89-6.92 (2H, dd), 7.04-7.08 (2H, dd), 7.29-7.44 (5H, m);
Mass Spectrum: m/z 342(M+1).

Step-i: Preparation of compound formula Ethyl (2R)-4-amino-5-(4-O-benzyloxy phenyl)-2-Methyl pentanoate [Formula (XI)]
Charged (2R)-4-[(tert.butyloxy carbonyl) amino]-5-(4-O-benzylphenyl)-2-Methyl pentanoic acid (X) compound (100 grams, 0.25 moles) to ethanol (1000 mL) at 25-35 °C and stirred for 15 minutes. Cooled the reaction mass temperature to 0-5 °C thionyl chloride (50 grams) was added at 0-10 °C and stirred for 15 minutes. The reaction mass temperature was raised to reflux and maintained for 3 hours at reflux. After completion of the reaction, distilled off the reaction mass completely under vacuum below 50 °C. The reaction mass was Codistilled with Hexane (50 mL) and Stirred for 60 minutes at room temperature. Filtered the Solid and washed with Hexane (50ml). Dried the Solid Ethyl (2R)-4-amino-5-(4-O-benzyloxy phenyl)-2-Methyl pentanoate (XI) at 35-45 °C. (Yield: 85 %).
1H NMR (d ppm, DMSO): 0.93-1.01 [3H, t], 1.10-1.12 (3H, m), 1.17-1.18 (1H, m), 2.47-2.52 (4H, m), 3.41-3.48 (1H, m), 4.00-4.04 (2H, m), 5.06 (2H, s), 6.91-6.96 (2H, dd), 7.32-7.38 (2H, dd), 7.40-7.46 (5H, m);
Mass Spectrum: m/z 342(M+1).

Step-j: Preparation of compound formula Ethyl-(2R)-4-(2,2-DimethylPropanamide)-5-(4-O-phenyloxybenzyl)-2-methylpentanoate [Formula (XII)]
Charged Ethyl (2R)-4-amino-5-(4-O-benzyloxy phenyl)-2-Methyl pentanoate (XI) (100 grams, 0.25 moles) in Ethanol (1000 mL) at 25-35 °C and stirred for 15 minutes. The temperature of the reaction mass was cooled to 0-5 °C. To the reaction mass Pivolyl chloride (50 grams) was added at 0-10 °C and stirred for 15 minutes. The temperature of the reaction mass was raised to 25-35°C and maintained for 24 hours at room temperature. After completion of the reaction was charged DM water (500 mL) and separated the organic layer and washed with 10% NaHCO3 Solution, finally washed with 10% brine Solution (500 mL). Dried the Organic layer and distilled off completely under vacuum below 50 °C. Purified the Compound on Column to get Ethyl-(2R)-4-(2,2-DimethylPropanamide)-5-(4-O-phenyloxybenzyl)-2-methylpentanoate (XII) (Yield: 85 %).
1H NMR (d ppm, DMSO): 0.95-1.04 [3H, t], 1.01-1.10 (12H, m), 1.39-1.99 (2H, m), 2.49-2.64 (2H, m), 3.96-3.99 (1H, m), 4.02-4.06 (2H, m), 5.05 (2H, s), 6.87-6.88 (2H, d), 6.89-6.90 (2H, dd),7.03-7.11 (2H, dd), 7.31-7.44 (5H, m);
Mass Spectrum: m/z 426.18(M+1).

Step-k: Preparation of compound formula (Ethyl-(2R)-4-(2,2-DimethylPropanamido)-5-(4-hydroxyphenyl)-2-methylpentanoate [Formula (XIII)]
Charged Ethyl-(2R)-4-(2,2-DimethylPropanamido)-5-(4-O-phenyloxybenzyl)-2-methylpentanoate (XII) (100 grams, 0.25 moles) in methanol (1000 mL) 25-35 °C and stirred for 15 minutes and charged Pd/C (5%W/W) and raised the reaction mass temperature to 30-40 °C and applied pressure 1-5 Kg H2 gm/Cm2 and maintained for four hours. After completion of the reaction filtered palladium on celite and washed bed with methanol (100 mL). Distilled off organic layer completely under vacuum below 50 °C and proceeded further without isolation (Ethyl-(2R)-4-(2,2-DimethylPropanamido)-5-(4-hydroxyphenyl)-2-methylpentanoate.
1H NMR (d ppm, DMSO): 0.95-1.04 [3H, t], 1.01-1.10 (12H, m), 1.39-1.99 (2H, m), 2.49-2.64 (2H, m), 3.96-3.99 (1H, m), 4.02-4.06 (2H, m), 5.05 (2H, s), 6.89-6.90 (2H, dd), 7.03-7.11 (2H, dd), 7.31-7.44 (5H, m), 9.11 (1H);
Mass Spectrum: m/z 336.08(M+1).

Step-l: Preparation of compound formula Ethyl-(2R)-4-(2,2-DimethylPropanamide)-2-Methyl-5-[4-{Tri flouro methyl sulfonyl)oxy}phenyl] pentanoate [Formula (XIV)]
Charged (Ethyl-(2R)-4-(2,2-DimethylPropanamido)-5-(4-hydroxyphenyl)-2-methylpentanoate (XIII) (100 grams, 0.25 moles) in methylene dichloride (1000 mL) at 25-35 °C and stirred for 15 minutes. To the reaction mass charged Pyridine (30 mL) and stirred for 15 minutes at room temperature. Cooled the reaction mass to 0-5 °C and added Triflic anhydride (55 grams) over a period of 30 minutes and maintained for 2 hours. After completion of reaction quenched the mass with DM water (500 mL). Seperated the layers and washed with 5% Dil.HCl solution (500 mL) and finally with 10% NaCl solution (500 mL). Dried the organic layer on sodium sulphate and distilled off completely under vacuum below 40 °C. Purified the Compound on Column by using Ethyl acetate and Hexane to get Ethyl-(2R)-4-(2,2-DimethylPropanamide)-2-Methyl-5-[4-{Tri flouro methyl sulfonyl)oxy}phenyl] pentanoate (XIV).
1H NMR (d ppm, DMSO): 0.93-0.99 [3H, t], 1.10-1.1.19 (9H, m), 1.28 (1H), 1.46-1.55 (2H, m), 2.67-2.84 (2H, m), 3.96-3.99 (1H, m), 4.02-4.06 (2H, m), 7.11-7.14 (1H, dd), 7.29-7.40 (4H, m);
Mass Spectrum: m/z 468.12(M+1).

Step-m: Preparation of compound formula (2R, 4S)-5-Biphenyl-4-amino-2-methylpentanoate. Hydrochloride [Formula (XV)]
Charged Ethyl-(2R)-4-(2,2-DimethylPropanamide)-2-Methyl-5-[4-{Tri flouro methyl sulfonyl)oxy}phenyl] pentanoate (XIV) in Toluene 25-35 °C and stirred for 15 minutes. Charged potassium carbonate and phenyl Boronicacid at 25-30 °C and and Stirred for 15 minutes. The reaction mass was charged with tetrakis triphenyl phosphine ligand at room temperature. The temperature of the reaction mass was raised to 90-95 °C and maintained for 15 hours. After completion of the reaction filtered the reaction mass on celite and washed the organic layer with ethyl acetate and charged water and stirred for 15 minutes. The organic layer washed with 10% NaCl solution. Dried the organic layer on sodium sulphate. Distilled off organic layer completely under vacuum below 50 °C. Purified the Compound on Column by eluting with Ethyl acetate and Hexane. Deprotection with trifloroacetic acid in methylene dichloride. Finally isolated as Salt of hydrochloride to get Ethyl (2R)-4 Amino -5-biphenyl-4-yl-2-methyl pentanoate.Hydrochloride (XV).
1H-NMR (d ppm, DMSO) : 8.27 (3H, bs), 7.63 – 7.68 (4H, dd), 7.44 – 7.49 (2H, t), 7.33-7.37 (1H, t), 3.95 – 4.02 (2H, q), 3.34 - 3.38 (1H, s), 3.04 – 3.11 (1H, dd), 2.72 – 2.85 (2H, m) , 1.81 – 1.91 (1H, m), 1.56- 1.65 (1H, t), 1.05 -1.11 (6H, d);
Mass Spectrum: m/z 312 (M+1).

Step-n: Preparation of compound formula 3-{[(2S,4R)-1-{[1,1'-biphenyl]-4-yl}-5-ethoxy-4-methyl-5-oxopentan-2-yl]carbamoyl} propanoic acid [Formula (I)]
Ethyl (2R)-4-Amino-5-biphenyl-4-yl-2-methyl pentanoate hydrochloride was dissolved in dichloromethane (12 mL) and the mass was cooled to 0-5 °C. A catalytic amount of 4-dimethylaminopyridine and succinic anhydride (0.2 grams) were then added. Triethylamine (0.26 grams) was added and the reaction mass was stirred at 25-35 °C for 3 hours, after which the organic layer was washed with a 1N HCl solution and 10% brine solution. The organic layer was concentrated completely under vacuum to get N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (I).
1H-NMR (d ppm, CDCl3): 12.2 (1H, bs), 7.74 - 7.77 (1H, d), 7.63 - 7.66 (2H, d), 7.56 -7.59 (2H, d), 7.42 - 7.47 (2H, t), 7.31 - 7.36 (1H, t), 7.23 - 7.26 (2H, d), 3.89 - 4.02 (3H, m), 2.62 - 2.75 (2H, m), 2.50 - 2.73 (1H, m), 2.24 - 2.30 (2H, m), 2.27 - 2.30 (2H, m), 1.71-1.81 (1H, m), 1.33 -1.43 (1H, m), 1.09 - 1.14 (3H, t), 1.03 - 1.06 (3H, d);
Mass Spectrum: m/z 412 (M+1).
,CLAIMS:1. A process for the preparation of Sacubitril comprising the steps of:
a) amine protection of compound of formula II in presence of base and solvent

to give compound of formula III;

b) benzylating of compound of formula III with benzyl bromide in presence of base and solvent to give compound of formula IV;

c) hydrolyzing of compound of formula IV in presence of base and solvent to give compound of formula V;

d) converting of compound of formula V in presence of N, N'-Dicyclohexylcarbodiimide (DCC) and DMAP to give compound of formula VI;

e) reducing of compound of formula VI with reducing agent in presence of solvent to give compound of formula VII;

f) methylating of compound of formula VII with methylating agent in presence of inorganic base and solvent to give compound of formula VIII;

g) converting of compound of formula VIII in presence of hydrocarbon solvents to compound of formula IX;

h) converting of compound of formula IX to compound of formula X in presence of S (-)- Phenylethylamine and inorganic base and solvent;

i) deprotection followed by esterification of compound of formula X in presence of halogenated reagent solvent to give compound of formula XI;

j) amine protecting of compound of formula XI with protecting groups in presence of base and solvent to give compound of formula XII;

k) deprotecting of compound of formula XII to give compound of formula XIII in presence of palladium on carbon and alcohol solvent;

l) reacting of compound of formula XIII with triflic anhydride in presence of solvent to give compound of formula XIV;

m) suzuki coupling of compound of formula XIV to give compound of formula XV carried out in the presence of phenylboronic acid, metal catalyst and a solvent;

n) reacting compound of formula XV with succinic anhydride in presence of base and solvent to give Sacubitril of formula (I).
2. The process according to claim 1, wherein the reducing agent in step-e is selected from the group consisting of lithium aluminum hydride, sodium hydride, DIBAL-H or sodium bis(2-methyoxyethoxy)aluminumhydride.
3. The process according to claim 1, wherein the solvents is selected from the group consisting of halogenated solvents include dichloromethane, trichloroethylene, carbon tetrachloride, methyl chloroform, or mixtures; hydrocarbon solvents include toluene, xylene, or mixtures; ethereal solvents include tetrahydrofuran, diethyl ether, 1,4-dioxane, methyl tert-butyl ether, or mixtures; alcohol solvent include methanol, ethanol, propanol, isopropanol or mixtures.
4. The process according to claim 1, wherein the methylating agent in step-f is selected from the group consisting of methyl iodide, methyl bromide, diazomethane, dimethyl carbonate, dimethyl dicarbonate or dimethyl sulphate.
5. The process according to claim 1, wherein the base is an inorganic base or an organic base; organic base is selected from the group consisting of pyridine, triethylamine, and N,N-diisopropylethylamine; inorganic base selected from the group consisting of alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, and alkaline alkoxides; alkaline metal hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or lithium hydroxide.
6. The process according to claim 1, wherein the halogenation reagent is selected from the group consisting of phosphorous oxychloride, phosphorous pentachloride, and thionyl chloride; wherein the amine protection group is selected from the group consisting of a carboxybenzyl (Cbz), a tert-butyloxycarbonyl (BOC), pivolyl, Acetyl, triflouroacetyl..
7. The process according to claim 14, wherein the metal catalyst selected from the group consisting of tetrakis (triphenylphosphine) palladium (0), bis (triphenylphosphine) palladium (II) dichloride, bis (dibenzylideneacetone) palladium (0), tris (dibenzylideneacetone) palladium (0), palladium(II) acetate, copper, cuprous bromide, cuprous iodide or (±)-2,2’-bis(diphenylphosphino)-1,1’-binaphtalene (rac-BINAP).
8. A process for the preparation of Sacubitril Intermediate of formula VI comprising the steps of:
a) amine protection of compound of formula II in presence of base and solvent

to give compound of formula III;

b) benzylating of compound of formula III with benzyl bromide in presence of base and solvent to give compound of formula IV;

c) hydrolyzing of compound of formula IV in presence of base and solvent to give compound of formula V;

d) converting of compound of formula V in presence of N, N'-Dicyclohexylcarbodiimide (DCC) and DMAP to give compound of formula VI;
9. A process for the preparation of Sacubitril form intermediate of formula VI comprising the steps of:
a) reducing of compound of formula VI

to give compound of formula VII;

b) methylating of compound of formula VII to give compound of formula VIII;

c) converting of compound of formula VIII to compound of formula IX;

d) converting of compound of formula IX to compound of formula X;

e) deprotection followed by esterification of compound of formula X to give compound of formula XI;

f) converting of compound of formula XI to give compound of formula XII;

g) deprotecting of compound of formula XII to give compound of formula XIII;

h) converting of compound of formula XIII to give compound of formula XIV;

i) suzuki coupling of compound of formula XIV to give compound of formula XV;

j) converting of compound of formula XV to give Sacubitril of formula (I).
10. Intermediates of compound formulae VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV which are useful in the preparation of Sacubitril of formula (I).