DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“PROCESS FOR PREPARATION OF SACUBITRIL”

Glenmark Pharmaceuticals Limited
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

The following specification particularly describes the invention and the manner in which it is to be performed.
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of sacubitril.

BACKGROUND OF THE INVENTION
Sacubitril, also known as N-(3-carboxy-1-oxopropyl)-(4S)-(p-phenylphenylmethyl)-4-amino-(2R)-methylbutanoic acid ethyl ester is represented by the structure of formula I.
I
LCZ696 is a co-crystal complex of the sodium salts of sacubitril and valsartan, in hydrated form and is represented by the structure of formula II.

II
Sacubitril, in combination with valsartan, is indicated to reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure and reduced ejection fraction.
The present invention provides a multi-step process for the preparation of sacubitril by converting it to its salt, wherein the salt of sacubitril is not isolated.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of sacubitril, a compound of formula I,
I
the process comprising:
(a) reacting ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate, a compound of formula III, or salt thereof,
III
with succinic anhydride to give sacubitril;
(b) dissolving sacubitril of step (a) in water to form an aqueous solution;
(c) subjecting the aqueous solution to a first pH adjustment in the range of 8 to 10;
(d) subjecting the aqueous solution of step (c) to first extraction step with an organic solvent to form a biphasic mixture;
(e) separating the aqueous phase from the biphasic mixture;
(f) subjecting the aqueous phase of step (e) to a second pH adjustment in the range of 4 to 6;
(g) subjecting the aqueous phase of step (f) to second extraction step with an organic solvent to form a biphasic mixture;
(h) separating the organic phase from the biphasic mixture of step (g); and
(i) isolating sacubitril, the compound of formula I, from the organic phase of step (h).

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a characteristic XRPD of sacubitril-valsartan trisodium hemipentahydrate (LCZ696) as obtained in example 3.
Figure 2 is a DSC thermogram of sacubitril-valsartan trisodium hemipentahydrate (LCZ696) as obtained in example 3.
Figure 3 is a TGA thermogram of sacubitril-valsartan trisodium hemipentahydrate (LCZ696) as obtained in example 3.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of sacubitril, a compound of formula I,
I
the process comprising:
(a) reacting ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate, a compound of formula III, or salt thereof,
III
with succinic anhydride to give sacubitril;
(b) dissolving sacubitril of step (a) in water to form an aqueous solution;
(c) subjecting the aqueous solution to a first pH adjustment in the range of 8 to 10;
(d) subjecting the aqueous solution of step (c) to first extraction step with an organic solvent to form a biphasic mixture;
(e) separating the aqueous phase from the biphasic mixture;
(f) subjecting the aqueous phase of step (e) to a second pH adjustment in the range of 4 to 6;
(g) subjecting the aqueous phase of step (f) to second extraction step with an organic solvent to form a biphasic mixture;
(h) separating the organic phase from the biphasic mixture of step (g); and
(i) isolating sacubitril, the compound of formula I, from the organic phase of step (h).
In (a) of the process for the preparation of sacubitril, ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate, the compound of formula III, or salt thereof, is reacted with succinic anhydride to give sacubitril.
The reaction may be carried out in the presence of a suitable base. The suitable base includes but is not limited to triethylamine, diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, or mixtures thereof.
In one embodiment, the compound of formula III is reacted with succinic anhydride in the presence of triethylamine.
In (b) of the process for the preparation of sacubitril, the sacubitril obtained in step (a) is dissolved in water to form an aqueous solution.
The temperature may be in the range of about -0°C to about 30°C.
In (c) of the process for the preparation of sacubitril, the aqueous solution obtained in step (b) is subjected to a first pH adjustment in the range of 8 to 10.
In one embodiment, the first pH adjustment is carried out by the addition of a base.
In one embodiment, the base is selected from the group consisting of alkali metal carbonate such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonate; alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate; alkaline earth metal bicarbonate; and mixtures thereof.
In one embodiment, the alkali metal carbonate includes but is not limited to sodium carbonate, potassium carbonate.
In one embodiment, the alkali metal bicarbonate includes but is not limited to sodium bicarbonate, potassium bicarbonate.
In one embodiment, the pH of the aqueous phase is adjusted in the range of 8 to 10 by the addition of alkali metal carbonate.
In one embodiment, the pH of the aqueous phase is adjusted to about 9 to about 10 using sodium carbonate.
The temperature may be in the range of about -0°C to about 30°C.
In (d) of the process for the preparation of sacubitril, the aqueous solution of step (c) is subjected to first extraction step with an organic solvent to form a biphasic mixture.
In one embodiment, the organic solvent used in the first extraction step is selected from the group of esters, ethers, halogenated hydrocarbons, aromatic hydrocarbons, and mixtures thereof.
In one embodiment, the esters include but are not limited to methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate; the ethers include but are not limited to dimethyl ether, diethyl ether, diisopropyl ether; the halogenated hydrocarbons include but are not limited to dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride; the aromatic hydrocarbons include but are not limited to benzene, toluene.
In one embodiment, the aqueous solution of step (c) is subjected to first extraction step with ethyl acetate to form a biphasic mixture.
In (e) of the process for the preparation of sacubitril, the aqueous phase is separated from the biphasic mixture obtained in step (d).
In (f) of the process for the preparation of sacubitril, the aqueous phase of step (e) is subjected to a second pH adjustment in the range of 4 to 6.
In one embodiment, in (f) of the above process, the acid is selected from the group consisting of inorganic acid, organic acid, and mixtures thereof.
In one embodiment, the inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; the organic acid includes but is not limited to acetic acid, citric acid, trifluoroacetic acid, oxalic acid, sulfonic acid.
In one embodiment, the pH of the aqueous phase is adjusted in the range of 4 to 6 by the addition of inorganic acid.
In one embodiment, the pH of the aqueous phase is adjusted to about 4 to about 5 using hydrochloric acid.
In (g) of the process for the preparation of sacubitril, the aqueous phase of step (f) is subjected to second extraction step with an organic solvent to form a biphasic mixture.
In one embodiment, in (g) of the above process, the organic solvent used in the second extraction step is selected from the group of esters, ethers, halogenated hydrocarbons, aromatic hydrocarbons, and mixtures thereof.
In one embodiment, the esters include but are not limited to methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate; the ethers include but are not limited to dimethyl ether, diethyl ether, diisopropyl ether; the halogenated hydrocarbons include but are not limited to dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride; the aromatic hydrocarbons include but are not limited to benzene, toluene.
In one embodiment, the aqueous solution of step (f) is subjected to second extraction step with ethyl acetate to form a biphasic mixture.
In (h) of the process for the preparation of sacubitril, the organic phase is separated from the biphasic mixture of step (g).
In one embodiment, the organic phase is optionally treated with alumina.
In (i) of the process for the preparation of sacubitril, sacubitril is isolated from the organic phase of step (h).
In one embodiment, sacubitril is isolated by removing the solvent from the organic phase of step (h). Removal of solvent may be accomplished by substantially complete evaporation of the solvent or concentrating the organic phase. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg.
The organic phase of step (h) may be washed with water and dried before removal of solvent.
In one embodiment, the present invention provides sacubitril obtained by a process as described herein, wherein the level of impurity A, impurity B or impurity C is less than 0.15% w/w relative to the amount of sacubitril
A
R1=H, R2=H (Impurity A1)
R1=H, R2=tBu (Impurity A2)
B C.
In one embodiment, the present invention provides sacubitril, wherein the level of impurity A1 or impurity B is less than 0.15% w/w relative to the amount of sacubitril obtained in step (i),
A1 B.
The present invention provides sacubitril obtained by the above process, as analyzed by chemical purity using high performance liquid chromatography (HPLC) with the conditions described below:
Reagents and Solvents:
o-phosphoric acid (AR Grade)
Acetonitrile (Gradient Grade)
Methanol (HPLC Grade)
Water (Milli Q or equivalent)
Chromatographic Conditions:
Apparatus: A High Performance Liquid Chromatograph equipped with quaternary gradient pumps, variable wavelength UV detector attached with data recorder and integrator software.
Column: Inertsil ODS 3V, C18, 250 X 4.6mm, 5?
Column temperature: 35°C
Sample Cooler temperature: 25°C
Mobile Phase:
Mobile phase A = Buffer
Buffer: 0.1% o-phosphoric acid in water.
Mobile phase B = Acetonitrile: Methanol (90: 10, v/v)
Time (min.) % Mobile Phase A % Mobile Phase B
0.01 70 30
30 55 45
45 30 70
65 30 70
67 70 30
75 70 30
Diluent: Water: Acetonitrile (1: 1, v/v)
Flow Rate: 1.0mL/minute
Detection: UV 210nm
Injection Volume: 10µL
The retention time of sacubitril is about 40.75 minutes under these conditions.
Relative retention time for impurity A1 is about 0.66 and impurity B is about 0.95 with respect to sacubitril.
In one embodiment, the sacubitril obtained in step (i) is further converted to LCZ696, a compound of formula II,

II
the process comprising:
(a) preparing a mixture of sacubitril and valsartan in an organic solvent;
(b) adding aqueous sodium hydroxide solution to the mixture of step (a); and
(c) isolating LCZ696, the compound of formula II, from the mixture of step (b).
In (a) of the above process, sacubitril and valsartan are mixed in an organic solvent.
The organic solvent includes, but is not limited to ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride and the like; nitriles such as acetonitrile, butyronitrile, isobutyronitrile, propionitrile and the like; esters such as methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate and the like; ethers such as dimethyl ether, diethyl ether, diisopropyl ether, tert-butyl methyl ether, tetrahydrofuran, dioxane and the like; amide solvents such as dimethylformamide, acetamide and the like; or mixtures thereof.
In (b) of the above process, aqueous sodium hydroxide solution is added to the mixture of step (a).
The reaction may be carried out at a temperature in the range of about -5°C to about 30°C.
The stirring time may range from about 1 hour to about 12 hours, or longer.
In (c) of the above process, LCZ696, the compound of formula II, is isolated from the mixture of step (b) by a process comprising:
(p) removing the solvent from the mixture of step (b); or
(q) treating the mixture of step (b) with an anti-solvent; or
(r) partially or completely evaporating the mixture of step (b) and adding an organic solvent selected from esters, halogenated hydrocarbons, ethers, alcohols, ketones, hydrocarbons, or mixtures thereof to the obtained reaction mass followed by removal of the solvent; or
(s) filtering the mixture of step (b).
The organic solvent includes but is not limited to esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; halogenated hydrocarbons such as dichloromethane, chloroform, ethylene dichloride, and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 1-octanol and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; or mixtures thereof.
Removal of solvent may be accomplished by filtering the obtained solid, substantially complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg.
In one embodiment, the present invention provides a process for the preparation of sacubitril, a compound of formula I,
I
the process comprising:
(a) reacting ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate, a compound of formula III, or salt thereof,
III
with succinic anhydride to give sacubitril;
(b) dissolving sacubitril of step (a) in water to form an aqueous solution;
(c) subjecting the aqueous solution to a first pH adjustment in the range of 8 to 10 by the addition of a base;
(d) subjecting the aqueous solution of step (c) to first extraction step with an organic solvent to form a biphasic mixture;
(e) separating the aqueous phase from the biphasic mixture;
(f) subjecting the aqueous phase of step (e) to a second pH adjustment in the range of 4 to 6 by the addition of an acid;
(g) subjecting the aqueous phase of step (f) to second extraction step with an organic solvent to form a biphasic mixture;
(h) separating the organic phase from the biphasic mixture of step (g); and
(i) isolating sacubitril, the compound of formula I, from the organic phase of step (h).
In one embodiment, in (c) of the above process, the base is selected from the group consisting of alkali metal carbonate such as sodium carbonate, potassium carbonate, caesium carbonate; alkaline earth metal carbonate; alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate; alkaline earth metal bicarbonate; and mixtures thereof.
In one embodiment, the alkali metal carbonate includes but is not limited to sodium carbonate, potassium carbonate.
In one embodiment, the alkali metal bicarbonate includes but is not limited to sodium bicarbonate, potassium bicarbonate.
In one embodiment, the pH of the aqueous phase is adjusted in the range of 8 to 10 by the addition of alkali metal carbonate.
In one embodiment, the base selected is sodium carbonate.
In one embodiment, in (d) of the above process, the organic solvent used in the first extraction step is selected from the group of esters, ethers, halogenated hydrocarbons, aromatic hydrocarbons, and mixtures thereof.
In one embodiment, the esters include but are not limited to methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate; the ethers include but are not limited to dimethyl ether, diethyl ether, diisopropyl ether; the halogenated hydrocarbons include but are not limited to dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride; the aromatic hydrocarbons include but are not limited to benzene, toluene.
In one embodiment, the organic solvent used in the first extraction step is ethyl acetate.
In one embodiment, in (f) of the above process, the acid is selected from the group consisting of inorganic acid, organic acid, and mixtures thereof.
In one embodiment, the inorganic acid includes but is not limited to hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid; the organic acid includes but is not limited to acetic acid, citric acid, trifluoroacetic acid, oxalic acid, sulfonic acid.
In one embodiment, the pH of the aqueous phase is adjusted in the range of 4 to 6 by the addition of inorganic acid.
In one embodiment, the acid selected is hydrochloric acid.
In one embodiment, in (g) of the above process, the organic solvent used in the second extraction step is selected from the group of esters, ethers, halogenated hydrocarbons, aromatic hydrocarbons, and mixtures thereof.
In one embodiment, the esters include but are not limited to methyl acetate, ethyl acetate, n-propyl acetate, tert-butyl acetate; the ethers include but are not limited to dimethyl ether, diethyl ether, diisopropyl ether; the halogenated hydrocarbons include but are not limited to dichloromethane, chloroform, carbon tetrachloride, ethylene dichloride; the aromatic hydrocarbons include but are not limited to benzene, toluene.
In one embodiment, the organic solvent used in the second extraction step is ethyl acetate.
In one embodiment, the present invention provides a one-pot process for the preparation of sacubitril, a compound of formula I,
I
the process comprising:
(a) reacting ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate, a compound of formula III, or salt thereof,
III
with succinic anhydride to give sacubitril;
(b) dissolving sacubitril of step (a) in water to form an aqueous solution;
(c) subjecting the aqueous solution to a first pH adjustment in the range of 8 to 10;
(d) subjecting the aqueous solution of step (c) to first extraction step with an organic solvent to form a biphasic mixture;
(e) separating the aqueous phase from the biphasic mixture;
(f) subjecting the aqueous phase of step (e) to a second pH adjustment in the range of 4 to 6;
(g) subjecting the aqueous phase of step (f) to second extraction step with an organic solvent to form a biphasic mixture;
(h) separating the organic phase from the biphasic mixture of step (g); and
(i) isolating sacubitril, the compound of formula I, from the organic phase of step (h).
The term “one-pot” means the steps referred to are in-situ and the intermediates are not isolated. The term “not isolated” means the intermediates referred to are not separated as a solid.
In one embodiment, the term “one-pot” means the process of the invention is carried out without isolation of sacubitril in the form of a salt, as a solid compound.
The steps (a), (b), (c), (d), (e), (g), (g), (h) and (i) are as discussed supra.
In one embodiment, the present invention provides a process for the preparation of sacubitril, the compound of formula I, wherein the intermediate solid salt of sacubitril is not isolated.
In one embodiment, the present invention provides a process for the preparation of LCZ696, the compound of formula II, wherein the intermediate solid salt of sacubitril is not isolated.
In one embodiment, the present invention provides sacubitril, as obtained by the process described herein, with a purity of =99.5%, wherein the intermediate solid salt of sacubitril is not isolated.
In one embodiment, the present invention provides sacubitril, as obtained by the process described herein, with a purity of =99.5% and the level of impurity A1 or impurity B less than 0.15% w/w relative to the amount of sacubitril, wherein the intermediate solid salt of sacubitril is not isolated.
The present invention provides sacubitril with a purity of =99.5% and the level of impurity A1 or impurity B less than 0.15% w/w relative to the amount of sacubitril, wherein the process involves purification by first pH adjustment followed by first extraction step, second pH adjustment, followed by second extraction step, without isolation of sacubitril in the form of a salt, as a solid compound.
In one embodiment, the present invention provides sacubitril, as obtained by the process described herein, with a chiral purity of =99.5%, wherein the intermediate solid salt of sacubitril is not isolated.
In one embodiment, the present invention provides pharmaceutical compositions comprising LCZ696 obtained by the processes herein described, having a D50 and D90 particle size of less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns. The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state LCZ696 into any of the foregoing desired particle size range.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

EXAMPLES

EXAMPLE 1: Preparation of ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride
To a stirred solution of (2R,4S)-5-(biphenyl-4-yl)-4-[(tert-butoxycarbonyl)amino]-2-methylpentanoic acid (100g) in ethanol at about 0°C to about 5°C, was added thionyl chloride (93.07g). The reaction mixture was warmed to about 20°C to about 30°C and was stirred for about 6h to about 7h. The reaction mixture was concentrated under reduced pressure and ethanol was added to it. The temperature of the reaction mixture was raised to about 45°C to about 55°C to get a clear solution. The reaction mixture was cooled to about 20°C to about 30°C and n-heptane was added to it under stirring. The reaction mixture was cooled to about 0°C to about 10°C, stirred, filtered and washed with heptane to give an off-white solid.
Yield: 70g
HPLC purity: 99.42%

EXAMPLE 2: Preparation of sacubitril
To a stirred solution of ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride (50g) in methylene dichloride (500mL) at about 0°C to about 5°C was added triethylamine (43.63g) and succinic anhydride (17.25g). The reaction mixture was warmed to about 20°C to about 30 °C and was stirred for about 60min to about 90min. The reaction mixture was concentrated under vacuum to give a residue. The residue was dissolved in water and the solution was cooled to about 10°C to about 15°C. The pH of the solution was adjusted to about 9 to about 10 using sodium carbonate solution. The aqueous solution was extracted with ethyl acetate. The aqueous layer was cooled to about 0°C to about 5°C and the pH was adjusted to about 4 to about 5 using 1N hydrochloric acid solution. Ethyl acetate was added to it and the two layers were separated. The organic layer was washed with water, dried and concentrated under vacuum to give sacubitril as oil.
Yield: 45g
HPLC Purity: 99.66%
Impurity A1: 0.11%
Impurity B: Not detected

EXAMPLE 3: Preparation of sacubitril-valsartan trisodium hemipentahydrate (LCZ696)
To a stirred solution of sacubitril (50g) in acetone was added valsartan (52.91g) at about 20°C to about 30°C. The reaction mixture was cooled to about 10°C to about 15°C and sodium hydroxide solution (14.55g dissolved in 42.5mL water) was added dropwise maintaining the temperature at about 10°C to about 15°C. The reaction mixture was warmed to about 20°C to about 30°C and was stirred for about 2h. The reaction mixture was concentrated under vacuum and isopropyl acetate was added to it. The solvent was distilled under vacuum at about 20°C to about 30°C. This operation of addition of isopropyl acetate and distillation is repeated once to give a solid. Isopropyl acetate was added to the solid and the mixture was stirred for about 2h. The solid was filtered under nitrogen atmosphere, washed with isopropyl acetate and dried at about 30°C under vacuum to give sacubitril-valsartan trisodium hemipentahydrate.
Yield: 100g
HPLC purity: 99.83%
Water content by KF: 4.97%
Elemental Analysis:
Carbon Hydrogen Nitrogen
60.09% 6.28% 8.84%
XRPD:
Pos. [°2Th.] d-spacing [Å] Rel. Int.[%] Pos. [°2Th.] d-spacing [Å] Rel. Int.[%]
4.16 21.23 100.00 18.10 4.90 12.37
4.44 19.88 3.79 18.79 4.72 4.12
4.91 17.98 23.99 19.39 4.57 7.68
5.09 17.35 24.36 19.68 4.50 8.41
5.32 16.58 22.34 20.10 4.41 5.61
5.63 15.68 9.34 20.69 4.29 3.83
6.47 13.65 1.50 21.22 4.18 6.77
8.31 10.62 2.83 21.63 4.10 4.11
8.90 9.93 2.91 22.67 3.92 9.11
9.80 9.01 4.42 22.99 3.86 7.55
10.66 8.29 1.32 23.41 3.79 4.65
11.54 7.66 0.86 25.18 3.53 3.17
12.51 7.07 63.70 25.50 3.49 3.25
13.66 6.47 4.70 26.29 3.38 1.25
14.32 6.18 3.98 27.13 3.28 6.50
14.86 5.95 14.63 27.63 3.22 3.18
15.30 5.78 7.42 31.11 2.87 2.16
16.01 5.53 3.39 32.61 2.74 1.37
16.91 5.24 18.10 37.97 2.36 0.55
17.58 5.04 9.53

EXAMPLE 4: Preparation of sacubitril
To a stirred solution of ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride (20g) in methylene dichloride (200mL) at about 0°C to about 5°C was added triethylamine (17.5g) and succinic anhydride (6.9g). The reaction mixture was warmed to about 20°C to about 30 °C and was stirred for about 60min to about 90min. The reaction mixture was concentrated under vacuum to give a residue. The residue was dissolved in water and the solution was cooled to about 10°C to about 15°C. The pH of the solution was adjusted to about 9 to about 10 using sodium carbonate solution. The aqueous solution was extracted with ethyl acetate. The aqueous layer was cooled to about 0°C to about 5°C and the pH was adjusted to about 4 to about 5 using 1N hydrochloric acid solution. Ethyl acetate was added to it and the two layers were separated. The organic layer was washed with water and neutral Alumina was added to it. The mixture was stirred for about 1h and filtered to remove neutral Alumina. The filtrate was concentrated under vacuum to give sacubitril as oil.
Yield: 18g.
HPLC purity: 99.54%
Impurity A1: Not detected
Impurity B: 0.06%

EXAMPLE 5: Purification of sacubitril
Sacubitril (20g) with HPLC purity of 99.28% and 0.23% of impurity A1 was dissolved in ethyl acetate (200mL). Neutral Alumina (20g) was added to the reaction mixture which was stirred for about 1h. The reaction mixture was filtered to remove neutral Alumina. The filtrate was concentrated under vacuum to give sacubitril as oil.
Yield: 18g
HPLC purity: 99.54%
Impurity A1: 0.01%

EXAMPLE 6: Preparation of sacubitril solid
Sacubitril oil (10g) was dissolved in ethyl acetate (5mL). The solution was heated to about 40°C to about 50°C and hexane (100mL) was added to it. The reaction mixture was then cooled to about 20°C to about 30 °C, stirred for about 2h, filtered and dried to give solid crystalline sacubitril.
Yield: 8g

COMPARATIVE EXAMPLE 1: Preparation of sacubitril
To a stirred solution of ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride (20g) in methylene dichloride (200mL) at about 0°C to about 5°C was added triethylamine (12mL) and succinic anhydride (8.6g). The reaction mixture was warmed to about 20°C to about 30 °C and stirred for about 60min. The pH of the reaction mixture was adjusted to about 1 to about 3 using 1N hydrochloric acid solution. The two layers were separated and the organic layer was washed with water, dried and concentrated under vacuum to give sacubitril as oil.
Yield: 23g
HPLC purity: 96.24%
Impurity A1: 2.57%
Impurity B: 0.42%

COMPARATIVE EXAMPLE 2: Preparation of sacubitril
To a stirred solution of ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate hydrochloride (20g) in methylene dichloride (200mL) at about 0°C to about 5°C was added triethylamine (17.5g) and succinic anhydride (6.9g). The reaction mixture was warmed to about 20°C to about 30 °C and was stirred for about 60min to about 90min. The reaction mixture was concentrated under vacuum to give a residue. The residue was dissolved in water and the solution was cooled to about 10°C to about 15°C. The pH of the solution was adjusted to about 11 to about 13 using sodium hydroxide solution. The aqueous solution was extracted with ethyl acetate. The aqueous layer was cooled to about 0°C to about 5°C and the pH was adjusted to about 4 to about 5 using 1N hydrochloric acid solution. Ethyl acetate was added to it and the two layers were separated. The organic layer was washed with water, dried and concentrated under vacuum to give sacubitril as oil.
Yield: 18g
HPLC purity: 94.24%
Impurity A1: 5.07%

,CLAIMS:WE CLAIM

1. A process for the preparation of sacubitril, a compound of formula I,
I
the process comprising:
(a) reacting ethyl (2R,4S)-4-amino-5-(biphenyl-4-yl)-2-methylpentanoate, a compound of formula III, or salt thereof,
III
with succinic anhydride to give sacubitril;
(b) dissolving sacubitril of step (a) in water to form an aqueous solution;
(c) subjecting the aqueous solution to a first pH adjustment in the range of 8 to 10;
(d) subjecting the aqueous solution of step (c) to first extraction step with an organic solvent to form a biphasic mixture;
(e) separating the aqueous phase from the biphasic mixture;
(f) subjecting the aqueous phase of step (e) to a second pH adjustment in the range of 4 to 6;
(g) subjecting the aqueous phase of step (f) to second extraction step with an organic solvent to form a biphasic mixture;
(h) separating the organic phase from the biphasic mixture of step (g); and
(i) isolating sacubitril, the compound of formula I, from the organic phase of step (h).

2. The process as claimed in claim 1, wherein the step (a) is carried out in the presence of a base.

3. The process as claimed in claim 2, wherein the base is selected from the group consisting of triethylamine, diisopropylethylamine, pyridine, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, and mixtures thereof.

4. The process as claimed in claim 1, wherein in step (c), the first pH adjustment is carried out by the addition of a base selected from the group consisting of alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, alkaline earth metal bicarbonate, and mixtures thereof.

5. The process as claimed in claim 1, wherein the organic solvent of step (d) is selected from the group consisting of esters, ethers, halogenated hydrocarbons, aromatic hydrocarbons, and mixtures thereof.

6. The process as claimed in claim 1, wherein in step (f), the second pH adjustment is carried out by the addition of an acid selected from the group consisting of inorganic acid, organic acid, and mixtures thereof.

7. The process as claimed in claim 1, wherein the organic solvent of step (g) is selected from the group consisting of esters, ethers, halogenated hydrocarbons, aromatic hydrocarbons, and mixtures thereof.

8. The process as claimed in claim 1, wherein the level of impurity A1 or impurity B is less than 0.15% w/w relative to the amount of sacubitril obtained in step (i),
A1 B.

9. The process as claimed in claim 1, further comprising converting sucubitril, the compound of formula I to LCZ696, a compound of formula II,

II
the process comprising:
(a) preparing a mixture of sacubitril and valsartan in an organic solvent;
(b) adding aqueous sodium hydroxide solution to the mixture of step (a); and
(c) isolating LCZ696, the compound of formula II, from the mixture of step (b).

Dated this 16th day of March, 2018

(Signed)____________________
DR. MADHAVI KARNIK
SENIOR GENERAL MANAGER-IPM
GLENMARK PHARMACEUTICALS LIMITED