DESC:Field of the Invention
The present invention relates to the process for preparation of an anti-heart failure drug LCZ696.

Background of the invention
Valsartan/Sacubitril (brand name Entresto, previously known as LCZ696) is a combination drug consisting of two antihypertensives (blood pressure lowering drugs), valsartan and sacubitril, in a 1:1 mixture by molecule count developed by Novartis. The combination is often described as a dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) although the two effects are achieved by two different molecules. It was approved under the FDA's priority review process for use in heart failure on July 7, 2015. 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. The complex is chemically described as Octadecasodiumhexakis (4-{[(l S,3R)-l-([l, -biphenyl]- 4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl] amino}-4oxobutanoate) hexakis(N-pentanoyl-N-{[2'-(lH-tetrazol-l-id-5-yl) [l,l'-biphenyl] -4-yl]methyl}-L- valinate)-water (1/15). It’s empirical formula (hemipentahydrate) is C48H55N6O8Na3 2.5H2o. Its molecular mass is 957.99 and its schematic structural formula is

U.S. 8,877,938 B2 (the '938 patent) discloses trisodium [3-((lS,3R)-l-biphenyl-4ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate) biphenyl-4'-ylmethyl} amino) butyrate] hemipentahydrate which is crystalline form and process for its preparation. The '938 patent also discloses the pharmaceutical composition of trisodium salt of valsartan sacubitril complex. The crystalline form of trisodium salt of valsartan sacubitril complex is designated as "Form-I".

Process for the preparation of LCZ696 is disclosed in WO 2007/050546, CN105985225, CN105622535 and CN105985225.

The reported processes for the preparation of LCZ696 suffer from many disadvantages which includes difficulty in achieving desired 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 to develop simple and cost effective process for the preparation of LCZ696 with high purity and good yield.

Summary of the Invention
In one aspect, the present invention provides a process for the preparation of LCZ696 of formula I, which comprises:
a) oxidation of compound of formula II

in the presence of oxidizing agent, base, ester solvent and catalyst to obtain compound of formula III;

b) wittig reaction of compound of formula III in the presence of wittig ylide salt and ester solvent to obtain compound of formula IV;

c) hydrolysis of compound of formula IV in the presence of base, organic acid and alcohol solvent to obtain compound of formula V;

d) reduction of compound of formula V in the presence of palladium on carbon and alcohol solvent to obtain compound of formula VI;

e) deprotection followed by esterification of compound of formula VI in the presence of halogenating agent and alcohol solvent to obtain compound of formula VII;

f) reacting compound of formula VII with succinic anhydride in presence of base and halogenated solvent to obtain sacubitril of formula VIII;

g) reacting sacubitril of formula VIII with triethanolamine in presence of ether, ketone and ester solvents to obtain compound of formula XI;

h) reacting compound of formula XI with anhydrous calcium chloride in presence of water to obtain compound of formula X;

i) treating compound of formula X with valsartan in presence of sodium source, one or more solvents to obtain trisodium [3-((lS,3R)-l-biphenyl-4ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate) biphenyl-4'-ylmethyl}amino) butyrate] hemi pentahydrate of compound formula (I).

In second aspect, the present invention provides an improved process for the preparation of compound formula III, which comprises oxidation of compound of formula II

in the presence of oxidising agent to obtain compound of formula III;

In third aspect, the present invention provides an improved process for the preparation of compound formula X, which comprises converting compound of formula XI

with anhydrous calcium chloride in the presence of water to obtain compound of formula X.

In another aspect, the present invention provides process for the preparation of trisodium salt of valsartan sacubitril complex (LCZ696) of formula (I) by using inexpensive, readily available and easy to handle reagents.

In another aspect, the present invention provides process for the preparation of trisodium salt of valsartan sacubitril complex (LCZ696) of formula (I), which can be readily scaled up.

In yet another aspect, the present invention provides an improved process for the preparation of trisodium salt of valsartan sacubitril complex (LCZ696) of formula (I), which is simple, convenient, economical and environment friendly.

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect of the present invention, provides an improved process for the preparation of N-[(1S)-2-[1,1'-biphenyl]-4-yl-1-formylethyl]-1,1-dimethylethyl ester of formula (III).

Scheme – 1 illustrates the process for preparation of N-[(1S)-2-[1,1'-biphenyl]-4-yl-1-formylethyl]-, 1,1-dimethylethyl ester of formula (III).

Scheme 1
Oxidation of N-[(1R)-2-[1,1'-Biphenyl]-4-yl-1-(hydroxyl methyl) ethyl]carbamic acid 1,1-dimethylethyl ester of formula (II) with oxidizing agent in the presence of base, solvent and catalyst to give tert-butyl [(1R)-2-biphenyl-4-yl-1-formylethyl]carbamate of formula (III). The oxidizing agents are selected from the group consisting of Tribromoisocyanuric acid (TBCA), Trifluoroacetic peracid (TFAPA) or Trichloroisocyanuric acid (TCCA) and preferably Trichloroisocyanuric acid. The base used in the reaction is sodium acetate. The solvent used in the reaction is selected from ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof and preferably using ethyl acetate. The catalyst used in the reaction is (2,2,6,6-Tetramethylpiperidin-1-yl) oxyl (TEMPO). The reaction temperature may range from -10 °C to 10 °C and preferably at a temperature in the range from -5 °C to 5 °C. The duration of the reaction may range from 2 hours to 4 hours, preferably for a period of 3 hours.

According to another aspect of the present invention, provides an improved process for the preparation of Sacubitril calcium of formula (X) from Sacubitril triethanolamine of formula (IX).

Scheme – 2 illustrates the process for preparation of a Sacubitril Calcium of formula (X).

Scheme 2
Reacting of N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester triethanolamine (XI) with Anhydrous calcium chloride in presence of water to obtain N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester calcium salt (X). The reaction temperature may range from 25 °C to 35 °C and preferably at a temperature in the range from 25 °C to 30 °C. The duration of the reaction may range from 1 to 4 hours, preferably for a period of 2 hours.

According to another aspect of the present invention, provides an improved process for the preparation of trisodium salt of valsartan sacubitril complex (LCZ696) formula (I).

Scheme – 3 illustrates the process for preparation of trisodium salt of valsartan sacubitril complex (LCZ696) formula (I).
Scheme 3
In step-a of the preparation, oxidation of N-[(1R)-2-[1,1'-Biphenyl]-4-yl-1-(hydroxyl methyl) ethyl]carbamic acid 1,1-dimethylethyl ester of formula (II) with oxidizing agent in the presence of base, solvent and catalyst to give tert-butyl [(1R)-2-biphenyl-4-yl-1-formylethyl]carbamate of formula (III). The oxidizing agents are selected from the group consisting of Tribromoisocyanuric acid (TBCA), Trifluoroacetic peracid or Trichloroisocyanuric acid (TCCA) and preferably Trichloroisocyanuric acid. The base used in the reaction is sodium acetate. The solvent used in the reaction is selected from ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof and preferably using ethyl acetate. The catalyst used in the reaction is (2,2,6,6-Tetramethylpiperidin-1-yl) oxyl (TEMPO). The reaction temperature may range from -10 °C to 10 °C and preferably at a temperature in the range from -5 °C to 5 °C. The duration of the reaction may range from 2 hours to 4 hours, preferably for a period of 3 hours.

In step-b of the preparation, wittig reaction of tert-butyl [(1R)-2-biphenyl-4-yl-1-formylethyl] carbamate of formula (III) (obtained in step-a) with wittig ylide in the presence of solvent to obtain (R,E) ethyl 5-(4-[1,1'-biphenyl]yl)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-2- methyl-2-pentenoate of formula (IV). The solvent used in the reaction is selected from ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof and preferably using ethyl acetate. The reaction temperature may range from 15 °C to 35 °C and preferably at a temperature in the range from 20 °C to 30 °C. The duration of the reaction may range from 2 hours to 4 hours, preferably for a period of 3 hours.

In step-c of the preparation, hydrolysing of (R,E) ethyl 5-(4-[1,1'-biphenyl]yl) -4-[[(1,1-dimethylethoxy)carbonyl]amino]-2-methyl-2-pentenoate of formula (IV) (obtained in step-b) in presence of base, organic acid and solvents to obtain (R,E)-5-([1,1'-biphenyl]-4-yl) -4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoic acid of formula (V). The organic acid is selected from the group consisting of acetic acid, citric acid, formic acid, methane sulfonic acid or p-toluene sulfonic acid and preferably acetic acid. The base used in the reaction is selected from the group consisting of lithium hydroxide or sodium hydroxide and preferably using sodium hydroxide. The solvents used in the reaction is selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) and preferably using methanol. The reaction temperature may range from 50 °C to 80 °C and preferably at a temperature in the range from 60 °C to 70 °C. The duration of the reaction may range from 2 hours to 4 hours, preferably for a period of 3 hours.

In step-d of the preparation, reduction of (R,E)-5- ([1,1'-biphenyl] -4-yl)-4- ((tert-butoxycarbonyl)amino)-2-methylpent-2-enoic acid of formula (V) (obtained in step-c) with reducing agent in presence of solvent to obtain (2R,4S)-5-(biphenyl-4-yl) -4-((tert-butoxycarbonyl)amino)-2-methylpentanoic acid of formula (VI). The solvents used in the reaction is selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) and preferably using methanol. The reaction temperature may range from 15 °C to 25 °C and preferably at a temperature in the range from 15 °C to 20 °C. The duration of the reaction may range from 4 hours to 7 hours, preferably for a period of 5 hours.

In step-e of the preparation, deprotection and esterification of (2R,4S)-5-(biphenyl-4-yl)-4-((tert-butoxy carbonyl) amino)-2-methylpentanoic acid of formula (VI) (obtained in step-d) with halogenating agent in presence of solvent to obtain (2R,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride of formula (VII). The halogenating agent is selected from the group consisting of phosphorous oxychloride, phosphorous pentachloride or thionyl chloride and preferably using thionyl chloride. The solvents used in the reaction is selected from alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) and preferably using ethanol. The reaction temperature may range from 40 °C to 60 °C and preferably at a temperature in the range from 50 °C to 55 °C. The duration of the reaction may range from 1 hour to 5 hours, preferably for a period of 3 hours.

In step-f of the preparation, reacting of (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride pentanoate (VII) (obtained in step-e) with succinic anhydride in presence of base and solvents to obtain 4-{[(2S,4R)-1-(4-Biphenyl- 4-yl)-5-ethoxy-4-methyl-5-oxo-pentan-2-yl] amino}-4-oxobutanoic acid (VIII). The base may be an inorganic base or organic base. Examples of suitable inorganic bases include alkaline metal hydroxides, alkaline metal bicarbonates, alkaline metal carbonates, or alkaline alkoxides. Examples of suitable organic bases include pyridine, triethylamine or N,N-diisopropylethylamine. Examples of suitable halogenated solvent include dichloromethane, trichloroethylene, carbon tetrachloride, or methyl chloroform. 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 2 to 4 hours, preferably for a period of 3 hours.

In step-g of the preparation, reacting of N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester (VIII) (obtained in step-e) with triethanolamine in presence of base and solvents to obtain N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester triethanolamine (XI). The solvent used in the reaction is selected from mixture of ether and ester solvents. The ether solvent selected from the group consisting of tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether or methyl isobutyl ether. The ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate or pentyl acetate. 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 10 to 14 hours, preferably for a period of 12 hours.

In step-h of the preparation, reacting of N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester triethanolamine (XI) with calcium chloride in presence of water to give N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester calcium salt (X). The reaction temperature may range from 40 °C to 60 °C and preferably at a temperature in the range from 50 °C to 55 °C. The duration of the reaction may range from 1 hour to 4 hours, preferably for a period of 2 hours.

In step-i of the preparation, reacting a sacubitril calcium and a valsartan or sacubitril and valsartan in the presence of sodium ion source in one or more of solvents to give trisodium salt of valsartan sacubitril complex. The sodium ion source is selected from sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide or sodium 2-ethylhexanoate and preferably using sodium hydroxide. The solvents used in the reaction is selected from ethyl acetate, methyl tert-butyl ether (MTBE), isopropyl acetate, water or acetone 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 1 to 4 hours, preferably for a period of 3 hours.

The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.

EXPERIMENTAL PROCEDURE
Example 1: Preparation of (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoic acid [Formula (V)]

Step-a: Preparation of tert-butyl [(1R)-2-biphenyl-4-yl-1-formylethyl] carbamate [Formula (III)]
N-[(1R)-2-[1,1'-Biphenyl]-4-yl-1-(hydroxymethyl)ethyl]carbamic acid 1,1-dimethylethyl ester (II) (100 grams) was dissolved in ethyl acetate (1.3 Litres) in round bottom flask at 25 to 30 °C. Sodium acetate(50 grams) is added to the above solution and the reaction mass is cooled to -10 to -5 °C. Charged TEMPO(1.0 grams) at -10 to -5 °C. Trichloro isocyanuric acid (TCCA) (25.5 grams) was added to the reaction mixture in lot wise over a period of 30 to 60 minutes and maintained for 3 hours at -10 to 0 °C. After completion of the reaction, filtered the mass and washed with Ethyl acetate (100 mL). Separated the organic layer and washed with 10% Sodium thiosulfate Solution (500 mL) and 10% NaCl Solution (250 mL) to obtain tert-butyl [(1R)-2-biphenyl-4-yl-1-formylethyl] carbamate.

Step-b: Preparation of (R,E) ethyl 5-(4-[1,1'-biphenyl]yl)-4-[[(1,1-dimethylethoxy)carbonyl]amino]-2-methyl-2-pentenoate [Formula (IV)]
To the organic layer obtained in step-a, wittig salt (Ethyl 2-(triphenylphosphoranylidene) propionate) (132.82 grams) was added at room temperature and maintained for 2 to 3 hours. After completion of reaction distilled off the reaction mass completely under vacuum below 50 °C. Co-distilled with methanol (100 mL) to obtain solid (R, E) ethyl 5-(4-[1,1'-biphenyl] yl)-4-[[(1,1-dimethylethoxy) carbonyl] amino]-2-methyl-2-pentenoate.

Step-c: Preparation of (R, E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl) amino)-2-methylpent-2-enoic acid [Formula (V)]
To the crude obtained in step-b is dissolved in methanol (1.2 Lt) at 25-35 °C. To the obtained solution in Step-b, add purified water (500 mL) and NaOH (28.1 grams). The temperature of the reaction mixture was slowly raised to 60-70 °C and maintained for 2 hours. After completion of reaction added purified water (400 mL) and acetic acid (130 mL) and maintained for 15 minutes at 60-70 °C. The temperature of the reaction mixture slowly cooled to 25-35°C and maintained for 2 hours. Filtered the solid and washed with methanol: water (1:1) (100 mL) to obtain (R, E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpent-2-enoic acid.

Purification:
To the crude obtained in step-c, charged Methanol (500 mL) and acetic acid (10 mL) at 25-35 °C. The temperature of the mixture was raised to 60-65 °C and maintained for 15 minutes. To the mixture slowly added purified water (500 mL) . The temperature of the mass slowly cooled to 25-35 °C over a period of 1-2 hours and maintained for 2 hours. Filtered the Solid and washed with 1:1 mixture (Methanol 50 mL: Purified water 50 mL). Dried the Compound in HAO at 50-60°C until MC reaches below 0.5%.
Yield: 77%
1H NMR (d ppm, DMSO-d6): 12.33 (b, 1H), 7.56-7.65 (dd , 4 H), 7.42-7.47 (t, 2 H), 7.26-7.36 (m, 3H), 7.17-7.20 (d, 1 H), 6.51-6.54 (d, 1H), 4.41-4.49 (t, 1 H), 2.88-2.90 (m, 3 H), 2.83-2.86 (m, 2H), 1.60 (s, 3H), 1.32 (d, 9H).

Example 2: Preparation of (2R, 4S)-5-(biphenyl-4-yl)-4-((tert-butoxycarbonyl) amino)-2-methylpentanoic acid [Formula (VI)]
A reaction flask was charged with (R,E)-5-([1,1'-biphenyl]-4-yl)-4-((tert-butoxycarbonyl) amino)-2-methylpent-2-enoic acid (V) (100 grams) (obtained in Example -1), in methanol (2.5 liters) and added 10 % palladium on charcoal (10 grams) followed by hydrogenation at 3-5 Kg/Cm2 for 5 hours at 15-25°C. After completion of the reaction, the catalyst was removed by filtration and the filtrate was distilled off completely under vacuum below 60°C to get solid. Dissolve the solid compound in 200 ml of Ethylacetate at 50°C and cooled to 25-35 °C and Isolated with n-Heptane (600 mL) at room temperature (RT). Raised temperature to 50 °C and slowly cooled to 25-35°C maintained for 2 hours. Filtered the solid and washed with n-Heptane (100 mL). Dried the solid at 50-60 °C. Yield: 58%
1H NMR (d ppm, DMSO-d6): 12.00 (s, 1H), 7.62-7.64 (d, 2H), 7.55-7.57 (d, 2H), 7.42-7.47 (t, 2H), 7.31-7.36 (t, 1H), 7.23-7.27 (t, 2H), 6.72-6.74 (d, 1H), 3.64-3.69 (m, 1H), 2.62-2.69 (dd,, 2H), 2.39- 2.51(m, 1H), 1.70-1.79 (m, 9H), 1.36-1.37 (d, 1H), 1.32(d, 3H).

Example 3: Preparation of (2R,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride [Formula (VII)]
Charged (2R,4S)-4-Amino-5-(biphenyl-4-yl)-2-methyl pentanoic acid (VI) (obtained in Example -2) (100 grams) to ethanol (400 mL) at 25-35 °C and stirred for 10 minutes. Cooled the reaction mass temperature to 15-20 °C and thionyl chloride (49.64 grams) was added stirred for 15 minutes. The reaction mass temperature was raised to 50-60 °C and maintained for 3 hours. After completion of the reaction, distilled off the reaction mass completely under vacuum below 50 °C. The reaction mass was Co-distilled with toluene (400 mL) below 60 °C up to 1.0 volume below 60 °C. To the crude added Ethanol at 40-50 °C. Cooled the reaction mass to 25-35 °C and added methyl tert-butyl ether (MTBE) (1000 mL) at room temperature room temperature. Raised the mass temperature to 4-50°C and stirred for 30 minutes. Slowly cooled to room temperature and maintained for 2 hours Filtered the solid and washed with MTBE (100 mL). Dried the solid at 60°C and slurry the compound with mixture of Ethylacetate (500 mL) and cyclohexane (500 mL) filtered the solid and washed with 100 ml mixture of Ethylacetate and cyclohexane (1:1). Dried the solid at 60 °C to obtain (2R,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride. Yield: 93%
1H NMR (d ppm, DMSO-d6): 8.27 (bs, 3H), 7.63-7.68 (dd, 4H), 7.44-7.49 (t, 2H), 7.33-7.37 (t, 1H), 3.95 -4.02 (q, 2H), 3.34-3.38 (s, 1H), 3.04-3.11 (dd, 1H), 2.72-2.85 (m, 2H) , 1.81-1.91 (m, 1H),1.56-1.65 (m, 1H), 1.05-1.11 (d,6H).

Example 4: Preparation of N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester triethanolamine salt [Formula (IX)]

Step a: Preparation of N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester [Formula (VIII)]
(2R,4S)-4-Amino-5-(biphenyl-4-yl)-2-methylpentanoic acid ethyl ester hydrochloride (VII) (110 grams) (obtained in Example 3) was dissolved in dichloromethane (1100 mL) and succinic anhydride (44.34 grams). The mass was cooled to 15-20 °C. To the above solution triethylamine (44.79 grams) was added and the reaction mass was stirred at 25-35 °C for 3 hours. After completion of reaction Charged purified water (330 mL) and cooled the mass temperature to 15-20 °C. Adjusted the reaction mass pH to 1.0 - 2.0 with 2N aqueous HCl Solution (110 mL) and stirred for 30 minutes at 25-30 °C. The reaction mass was settled for 10 minutes and separated the layers. Charged purified water (550 mL) and Stirred for 5 minutes and settled for 10 minutes and separated the layers. To the organic layer charged 10% NaCl Solution (550 mL) and stirred for 5 minutes settled for 10 minutes and separated the layers. Distilled off the organic layer completely under vacuum below 40 °C to obtain N-(3-carboxy-1-oxopropyl)- (4S)- (pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester.

Step b: Preparation of N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester triethanolamine salt [Formula (IX)]
To the crude obtained in above step-a, charge Ethyl acetate and distilled off completely under vacuum below 50 °C. Charge MTBE (1650 mL) and Ethyl acetate (550 mL) at 25-35 °C. To the reaction mass, slowly add triethanolamine (47.2 grams in 110 mL acetone). Maintained for 12 hours at 25-35 °C. Filtered the solid and washed with MTBE (110 mL). Taken wet solid and charged acetone (110 mL) at room temprature. Charged cyclohexane (1110 mL) at 25-35 °C. Maintained for 2 hours at 25-35 °C. Filtered the solid and washed with cyclohexane (110 mL). Dried the Solid under vacuum below 45 °C until LOD comes to below 1.00% (w/w).
Yield: 87.0%
1H-NMR (d ppm, DMSO-d6): 7.75-7.78 (d, 1H), 7.63-7.65 (d, 2H) , 7.56-7.59 (d, 2H) ,7.45-7.47 (dd, 2H), 7.31-7.36 (t, 1H), 7.24-7.27 (d, 2H), 5.37 (bs, 3H), 3.92-4.02 (m, 3H), 3.40-3.44 (t, 7H), 2.71- 2.75 (t, 2H), 2.50-2.69 (m, 7H), 2.44-2.47 (d, 2H), 2.36-2.38 (d, 2H ), 2.28-2.32 (t, 3H), 1.76-1.81 (m, 1H), 1.42-1.75 (m, 1H), 1.37-1.40 (t, 3H), 1.34-1.35 (d, 3H).

Example 5: Preparation of N-(3-carboxy-1-oxopropyl)-(4S)-(pphenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester calcium salt [Formula (X)]
A reaction flask was charged with a mixture of Sacubitril-Triethanolamine salt (90 grams, obtained in Example 4) and water (1080 mL) at 25-35 °C and stirred for 30 minutes at 25-35°C.Keep this solution aside. Taken another round bottom flask charged purified water (540 mL) into round bottom flask at 25-35 °C. charged calcium chloride (14.25 grams) at room temperature. Stirred for 15 min to get clear solution. Added the Sacubitril-Triethanolamine solution to the Second round bottom flask at room temperature. Maintained for 1-2 hours at room temperature. Filtered the solid and washed with purified water (2X180 mL). Dry the solid under vacuum below 50 °C until Moisture comes to below 8.0%(w/w). Milled the compound to get fine powder Again dry the compound until Moisture of the compound reaches to below 1.5%(w/w) to get N-(3-carboxy-1-oxopropyl)- (4S)- (phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester calcium salt. Yield: 75%
1H-NMR (d ppm, DMSO-d6): 7.96-7.99 (d, 1H), 7.61-7.63 (dd, 2H), 7.54-7.56 (dd, 2H), 7.40-7.45 (t, 2H), 7.30-7.34 (t, 1H), 7.22-7.25 (dd, 2H), 3.91-4.0 (m, 3H), 2.49-2.76 (m, 2H), 2.21-2.25 (m, 4H), 1.71-1.78 (m, 1H), 1.35-1.44 (m, 1H), 1.09-1.11 (d, 3H), 1.07 (m, 3H).

Example 6: Preparation of trisodium salt of valsartan sacubitril complex (LCZ696)
A reaction flask was charged with a mixture Sacubitril calcium (10.0 grams, obtained in Example 5) and Ethyl acetate (150 mL) and stirred for 10 minutes at 25-35 °C. An aqueous solution of 2N HCl (50 mL) was added. The layers were separated extracted the aqueous layer with Ethylacetae (50 mL) and washed with purified water (60 mL). The organic layer was taken and distilled off the reaction mass completely under vacuum below 40 °C. To the reaction mass acetone (200 mL) was added at 25-35 °C. To the reaction mixture valsartan (10.0 grams) was added. Dissolved NaOH (2.7 grams) in Purified Water (6.0 mL). The solution was added to reaction mass at 25-35 °C and stirred for 2 hours. The temperature of the mass slowly raised to 45 °C. Isopropyl acetate (100 mL) added slowly over a period of 15-30 minutes at 45 °C. Distilled off the reaction mass up to 15 volumes under vacuum below 50 °C. Co-distilled the reaction mass with isopropyl acetate (150 mL x 2) under vacuum below 50 °C. Charged isopropyl acetate (200 mL) and distilled up to 15 volumes under vacuum below 50 °C. Slowly cooled the reaction mass to 25-30 °C and stirred for 3 hours. Filtered the Solid and washed with Isopropyl acetate (25 mL x 2). Dried the solid under vacuum below 35 °C for 10 hours.
Yield: 82%.
1H-NMR (d ppm, DMSO-d6): 8.20-8.22 (d,1H), 7.63-7.66 (d, 2H), 7.50-7.58 (t, 4H), 7.42-7.47 (t, 2H), 7.24-7.39 (m, 8H), 7.11-7.13 (d , 1H), 7.00-7.07 (m, 3H), 6.93-6.96 (d, 2H), 4.54-4.63 (t, 2H), 4.4-4.48 (q, 2H), 3.95-4.02 (q , 2H), 3.91-3.93 (m, 1H), 3.67-3.70 (d, 1H), 2.60-2.75 (m, 2H), 2.50-2.56 (d, 1H), 2.37-2.46 (m , 2H), 1.96-2.23 (m, 7H), 1.70-1.79 (m, 1H), 1.50-1.59 (m, 2H), 1.24-1.43 (m, 4H), 1.03-1.18 (m, 8H), 0.86-0.92 (m, 8H), 0.70-0.74 (t, 3H), 0.63-0.65 (d,3H).
,CLAIMS:1. A process for the preparation of LCZ696 of formula (I),

which comprises:
a) oxidation of compound of formula II

in the presence of oxidizing agent, base, ester solvent and catalyst to obtain compound of formula III;

b) witting reaction of compound of formula III in the presence of witting salt and ester solvent to obtain compound of formula IV;

c) hydrolysis of compound of formula IV in the presence of base, organic acid and alcohol solvent to obtain compound of formula V;

d) reduction of compound of formula V in the presence of palladium on carbon and alcohol solvent to obtain compound of formula VI;

e) deprotection followed by esterification of compound of formula VI in the presence of halogenating agent and alcohol solvent to obtain compound of formula VII;

f) reacting compound of formula VII with succinic anhydride in presence of base and halogenated solvent to obtain Sacubitril of formula VIII;

g) reacting Sacubitril of formula VIII with triethanolamine in presence of base and ether or ester solvents to obtain compound of formula XI;

h) reacting compound of formula XI with calcium chloride in presence of water to obtain compound of formula X;

i) reacting sacubitril calcium of compound of formula X with valsartan in presence of sodium source and ester solvent to obtain trisodium [3-((lS,3R)-l-biphenyl-4ylmethyl-3-ethoxycarbonyl-l-butylcarbamoyl) propionate-(S)-3'-methyl-2'-(pentanoyl{2"-(tetrazol-5-ylate) biphenyl-4'-ylmethyl} amino) butyrate] hemipentahydrate of compound formula (I).

2. An improved process for the preparation of carbamic acid, N-[(1S)-2-[1,1'-biphenyl]-4-yl-1-formylethyl]-, 1,1-dimethylethyl ester of formula (III), which comprises: oxidation of carbamic acid, N-[(1S)-2-[1,1'-biphenyl]-4-yl-1-(hydroxymethyl)ethyl]-, 1,1-dimethyl ethyl ester formula II

in the presence of oxidizing agent, base, ester solvent and catalyst to give compound of formula III.

3. An improved process for the preparation of Sacubitril calcium formula (X), which comprises
reacting Sacubitril triethanolamine compound of formula XI

with calcium chloride in presence of water to obtain Sacubitril calcium of formula X;

4. The process as claimed in claims 1 and 2, wherein the oxidizing agent in step-a is selected from the group consisting of Tribromoisocyanuric acid, Trifluoroacetic peracid or Trichloroisocyanuric acid.

5. The process as claimed in claims 1 and 2, wherein the catalyst is 2,2,6,6-Tetramethylpiperidinyloxy.

6. The process as claimed in claims 1 and 2, wherein the organic acid used in step-c is selected from the group consisting of acetic acid, citric acid, formic acid, methane sulfonic acid or p-toluene sulfonic acid.

7. The process as claimed in claim 1, wherein the halogenation reagent used in step-e is selected from the group consisting of phosphorous oxychloride, phosphorous pentachloride or thionyl chloride.

8. The process as claimed in claim 1, wherein sodium source used in step-i is selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, sodium methoxide or sodium 2-ethylhexanoate.

9. The process as claimed in claims 1, 2 and 3; wherein the solvents is selected from the group consisting of ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s); alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s); ether solvent selected from the group comprising of tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s); halogenated aliphatic hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s).

10. The process as claimed in claims 1, 2 and 3, wherein the base is selected from the group consisting of pyridine, triethylamine, N,N-diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or lithium hydroxide.

Dated this 25th day of June 2019,