Field of the Invention:
The present invention relates to a process for the preparation of Imodium (4-{[(1 S,3R)-1-([1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxo 5   butanoate)-(N-pentanoyl-N- {[2"-( 1 H-tetrazol-1 -id-5 -yl)[ 1,1 "-biphenyl]r4-yl]methy 1} -L-valinate) represented by the following structural formula-1:
CH3 O
^Y^\ H3C—^yN> ^ih>   ■  ° A,
,, „   J&C/. J?"!   O II
O H II    X  X -N
U 0   fi^V^N
. 3Na*
\^
Formula-1 10
Background of the Invention:
Trisodium (4- {[(1 S,3R)-1 -([ 1, l"-bi 1 phenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-
oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(l H-tetrazol-1 -id-5-yl)[ 1,1 "-biphen
yl]-4-yl]methyl}-L-valinate) is approved in USA as octadecasodium hexakis-(4-{[(lS,3R)-l-
15   ([1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino} -4-oxobutanoate)hexakis-(N-pentanoyl-N-{[2"-(lH-tetrazol-l-id-5-yl)[l,r-biphenyl]-4-yl]methyl}-L-valinate)penta decahydrate under the brand name of "Entresto".
The above said compound can also be represented as "Trisodium (4-{[(lS,3R)-l-C[l,l"-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-
20   pentanoyl-N-{[2"-(lH-tetrazol-l-id-5-yl)[l,r-biphenyl]-4-yl]methyl}-L-valinate)hemipenta hydrate", commonly known as "Trisodium Sacubitril Valsartan hemipentahydrate.".
Valsartan/sacubitril (brand name Entresto, previously known as (LCZ696) is a combination drug for use in heart failure developed by Novartis. It consists of the angiotensin receptor blocker valsartan and the neprilysin inhibitor sacubitril, in a 1:1 mixture by molecule
25   count. The combination is sometimes described as an "angiotensin receptor-neprilysin inhibitor" (ARNi). It was approved under the FDA"s priority review process on July 7,2015.

Valsartan/sacubitril is used to treat heart failure in people with reduced left ventricular ejection fraction (LVEF).[3] It is not known whether valsartan/sacubitril is useful for the treatment of heart failure people with normal LVEF.
US8877938B2 disclosed the process for the preparation of Trisodium (4-{[(lS,3R)-l-5   ([1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-CN-pentanoyl-N- {[2"-(l H-tetrazol-1 -id-5-yl)[l, 1 "-biphenyl]-4-yl]methyl}-L-valinate)hemipenta hydrate and its crystalline form.
There is a significant need in the art to develop novel polymorphic forms of the said compound of formula-1 which are stable and having advantageous physical properties such 10   as free flowability, greater stability and greater bioavailability.
Brief description of the invention:
The first aspect of the present invention is to provide a process for the preparation of
Trisodium (4-{[(lS,3R)-l-([l,l"-biphenyI]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]
15   amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2"-(l H-tetrazol-1 -id-5-yl)[l, 1 p-biphenyl]-4-yl] m ethyl} -L-valinate) compound of formula-1.
The second aspect of the present invention is to provide a process for the preparation of amorphous Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-20   oxobutyljamino} -4-oxobutanoate)-(N-pentanoyl-N- {[2"-( 1 H-tetrazol-1 -id-5-yl)[ 1,1 "-biphen yl]-4-yl] methyl}-L-valinate) compound of formula-1.
The third aspect of the present invention is to provide a process for the preparation of amorphous  Trisodium  (4-{[(lS,3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-25   oxobuty 1] amino }-4-oxobutanoate)-(N-pentanoyl-N-{ [2"-(1 H-tetrazol-1 -id-5-yl)[l, 1 "-biphen yl]-4-yl] methyI}-L-valinate) compound of formula-1.
The fourth aspect of the present invention is to provide a process for the preparation of crystalline form of Trisodium (4-{[(lSJ3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-30   methyI-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(lH-tetrazol-l-id-5-yI)[ 1,1"-biphenylJ-4-yl] methyl}-L-valinate) compound of formula-1.
The fifth aspect of the present invention is to provide novel crystalline form of
Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]

amino}-4-oxobutanoate)-(N-pentanoyl-N-{ [2"-( 1 H-tetrazol-1 -id-5-yl)[l, l"-biphenyl]-4-yl] methyl}-L-valinate) compound of formula-1, herein after designated as crystalline Form-M.
The sixth aspect of the present invention is to provide a process for the preparation of 5   crystalline Form-M of Trisodium (4-{[(lS33R)-l-([l,I"-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(l H-tetrazol-1-id-5-yl)[I,l"-biphen yl]-4-yl] methyl}-L-vaIinate) compound of formula-1.
The seventh aspect of the present invention is to provide novel crystalline form of
10   Trisodium (4-{ [(1 S,3R)-1 -([ 1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]
amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2"-(l H-tetrazol-1 -id-5-yl)[ 1,1 "-biphen   yl]-4-yl] methyl}-L-valinate) compound of formula-1, herein after designated as crystalline Form-S.
The eighth aspect of the present invention is to provide a process for the preparation 15   of crystalline Form-S of Trisodium C4-{[(lSJ3R)-l-([l,l"-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(lH-tetrazol-l-id-5-yl)[l,l"-biphen yl]-4-yl] methyl}-L-valinate) compound of formula-1.
Brief description of the Drawings: 20   Figure-1: Illustrates the PXRD pattern of crystalline Form-M of Trisodium (4-{[(lS,3R)-l-
([l>r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-
pentanoyl-N-{[2"-(lH-tetrazol-l-id-5-yl)[l,l"-biphen yl]-4-yl] methyl}-L-valinate) compound
of formula-1.
Figure-2: Illustrates the PXRD pattern of crystalline Trisodium (4-{[(lS)3R)-l-([l,l"-25   biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentano
yl-N-{ [2"-( 1 H-tetrazol-1 -id-5-yl)[l, 1 "-biphenyl]-4-yl]methyl} -L-valinate)   compound   of
formula-1 obtained according to example-6.
Figure-3: Illustrates the PXRD pattern of mono sodium salt of 4-(((2S,4R)-l-([l,I"-
biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound 30   of formula-6 obtained according to example-3.
Figure-4: Illustrates the PXRD pattern of disodium salt of (S)-2-CN-((2"-(lH-tetrazol-5-yl)-
[l3l"-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid compound of formula-7
obtained according to example-4.

Figure-5: Illustrates the PXRD pattern of crystalline Form-S of Trisodium (4-{[(lS,3R)-l-
([ 1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3 -methyl -4-oxo butyl] amino} -4-oxo butanoate)- (N-
pentanoyI-N-{[2"-(lH-tetrazol-l-id-5-yl)[l,l"-biphen yl]-4-yl] methyl}-L-valinate) compound
of formula-1. 5
Detailed description of the Invention:
The "suitable solvent" used in the present invention can be selected from but not
limited to "hydrocarbon solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, pet
ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl
0 ether, diisopropyl ether, methyl tert-butyl ether, dimethoxyethane, diethoxyethane, dibutoxyethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, tert-butyl acetate and the like; "polar-aprotic solvents" such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro
5 solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcohol solvents" such as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, tert-butanol, n-pentanol, ethane-1,2-diol, propane-1,2-diol, alkyl ethers of ethylene
!0 glycol or propylene glycol selected from but not limited to ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monopropyl ether, ethylene glycol monoisopropyl ether, ethylene glycol monobutyl ether, ethylene glycol monophenyl ether, ethylene glycol monobenzyl ether, diethylene. glycol monomethyl ether, diethylene glycol monoethyl ether, diethylene glycol mono-n-butyl ether and the like; "polar solvents" such as
15   water; formic acid, acetic acid or mixtures thereof.
The term "suitable base" used in the present invention refers to "inorganic bases" selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, cesium bicarbonate and the like;
10 "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium

methoxide, potassium ethoxide, lithium methoxide, lithium ethoxide, sodium tert.butoxide,
potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as
sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such
as sodium amide, potassium amide, lithium amide and the like; alkali metal and alkali earth
5   metal salts of acetic acid such as sodium acetate, potassium acetate, magnesium acetate,
calcium acetate and the like; ammonia; "organic bases" like dimethylamine, diethylamine,
diisopropyl mine, diisopropylethylamine, diisobutylamine, triethylamine, triisoprnpyl amine,
tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), imidazole, N-
methylimidazole, I,8-diazabicyclo[5.4.0] undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-
10   ene(DBN), N-methylmorpholine (NMM), l,4-diazabicyclo[2.2.2]octane (DABCO), 2,6-
lutidine and the like; "organolithium bases" such as methyl lithium, n-butyl lithium, lithium
diisopropylamide  (LDA)  and  the  like;  "organosilicon  bases"  such  as  lithium
hexamethyldisilazide (LiHMDS),  sodium  hexamethyldisilazide  (NaHMDS),  potassium
hexamethyldisilazide (KHMDS) and the like or their mixtures.
15
The first aspect of the present invention provides process for the preparation of
Trisodium (4- {[(I S,3R)-1 -([ 1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]
amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(IH-tetrazol-l-id-5-yl)[l,l"-biphenyl)-4-
yl]methyl}-L-valinate) compound of formula-1, comprising of:
20 a) Reacting   the   (2R,4S)-5-([I,l"-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-
methylpentanoic acid compound of formula-2 with thionyl chloride in ethanol solvent
to  provide  (2R,4S)-ethyl  5-([l,r-biphenyl]-4-yl)-4-amino-2-methyl  pentanoate
hydrochloride compound of formula-3,
b) optionally, purifying the compound of formula-3 from a suitable solvent,
25 c) reacting the compound of formula-3 with succinic anhydride in presence of a suitable
base in a suitable solvent to provide 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yl)-5-ethoxy-4-
methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-4,
d) treating the compound of formula-4 in-situ with tromethamine in a suitable solvent to
provide tromethamine salt of 4-(((2S,4R)-l-([l,r-biphenyl]-4-yl)-5-ethoxy-4-methyl-
30 5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-5,

e) treating the compound of formula-5 with a suitable acid in a suitable solvent followed
by treating the obtained compound with a suitable sodium source in a suitable solvent
to provide mono sodium salt of 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yl)-5-ethoxy-4-
methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6,
5 f)  optionally purifying the obtained compound using a suitable solvent or mixture of
solvents to provide pure compound of formula-6,
g) treating   the   (S)-2-(N-((2"-(lH-tetra20l-5-yl)-[lJl"-biphenyl]-4-yl)methyl)pentan
amido)-3-methylbutanoic acid compound of formula-8 with a suitable sodium source
in a suitable solvent to provide disodium salt of (S)-2-(N-((2"-ClH-tetrazol-5-yl)-[l,r-
10 biphenyl]-4-yl)methyl)pentanamido)-3 -methylbutanoic acid compound of formula-7,
h) reacting the compound of formula-6 obtained in step-(e) or step-(f) with the
compound of formula-7 obtained in step-(g) in a suitable solvent to provide trisodium
(4-{ [(1 S,3R)-1 -([ 1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino} -
4-oxobutanoate)-(N-pentanoyl-N- {[2"-( 1 H-tetrazol-1 -id-5-yl)[ 1,1 *-biphenyl]-4-yl]
15 methyl} -L-valinate) compound of formul a-1,
Wherein, in step-(c) the suitable base is selected from organic base or inorganic base. In step-(e) & (g) the suitable sodium source is selected from hydrates, hydroxides, carbonates
or bicarbonates of sodium. In step-e) the suitable acid is selected from acetic acid, formic acid, dil. HC1 and the like; 20   In step-(b) to (h) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, hydrocarbon solvents, nitrile solvents, ether solvents, chloro solvents, polar aprotic solvents, polar solvents like water or mixture thereof.
The preferred embodiment of the present invention provides a process for the 25   preparation of Trisodium (4-{[(lS,3R)-l-C[l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(l H-tetrazol-l-id-5-yl)[l, 1"-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1, comprising of:
a) Reacting   the   (2R,4S)-5-([l,r-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-
methylpentanoic acid compound of formula-2 with thionyl chloride in ethanol to
30 provide (2R,4S)-emyl5-([l,r-biphenyl]-4-yl)-4-amino-2-methylpentanoate
hydrochloride compound of formuIa-3,
7

b) purifying the compound of formula-3 from methyl tertiary butyl ether to provide pure compound of formula-3,
c) reacting the compound of formula-3 with succinic anhydride in presence of triethylamine in dichloromethane to provide 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yI)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-4,
d) treating the compound of formula-4 in-situ with tromethamine in ethylacetate to provide tromethamine salt of 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-5,
I e) treating the compound of formula-5 with dil. HC1 in methyl tertiary butyl ether
followed by treating the obtained compound with aqueous sodium hydroxide in acetonitrile to provide mono sodium salt of 4-(((2S,4R)-l-([l,r-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6,
f) purifying the obtained compound using methyl tertiary butyl ether to provide pure compound of formula-6,
g) treating the (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,l"-biphenyl]-4-yl)methyl)pentan amido)-3-methylbutanoic acid compound of formula-8 with aqueous sodium hydroxide in acetone to provide disodium salt of (S)-2-(N-((2"-(lH-tetrazol-5-yl)-
I [l,l"-biphenyl]-4-yl)methyl)pentanamido)-3-methyl  butanoic  acid  compound  of
formula-7, h) reacting the compound of formula-6 obtained in step-(e) or step-(f) with the
compound of formula-7 obtained in step-(g) in methanol to provide Trisodium (4-
{[(lS,3R)-l-([l,l"-biphenyI]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-
i oxobutanoate)-(N-pentanoyl-N-{ [2"-(l H-tetrazol-1 -id-5-yl)[l, 1 "-biphenyl]-4-
yl]methyl}-L-valinate) compound of formula-1.
The second aspect of the present invention provides a process for the preparation of amorphous  Trisodium  (4-{[(l S,3R)-1 -([1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3 -methyl-4-)   oxobutyl] amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2"-( 1 H-tetrazol-1 -id-5 -yl) [1,1"-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-l, comprising of:
o

a) Reacting the tromethamine salt of 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yI)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-5 with a suitable acid in a suitable solvent to provide 4-(((2S,4R)-I-([I,r-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yI)amino)-4-oxobutanoic acid compound of formula-4,
b) reacting the obtained compound with (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid compound of fbrmiila-8 in presence of a suitable sodium source in a suitable solvent to provide Trisodium (4-{[(lS,3R)-l-([ 1, l"-biphenyl]-4-y lmethy l)-4-ethoxy-3-methyl-4-oxobuty 1] amino}-4-oxo butanoate)-(N-pentanoyl-N- {[2"-( 1 H-tetrazol-1 -id-5-yl)[l, 1 "-biphenyl]-4-yl]methyl} -L-valinate) compound of formula-1,
c) adding suitable solvent to the obtained compound,
d) stirring the reaction mixture,
e) filtering the reaction mixture and distilling off the solvent from the filtrate to get amorphous compound of formula-1.
Wherein, in step-(b) the suitable sodium source is selected from hydrates, hydroxides, carbonates or bicarbonates of sodium.
In step-a) the suitable acid is selected from acetic acid, formic acid, dil. HC1 and the like; In step-(a) to (c) the suitable solvent is same as defined in first aspect of the present
invention.
The preferred embodiment of the present invention provides a process for the preparation of amorphous Trisodium (4-{[(lS,3R)-l-([l,l"-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyI]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(lH-tetrazol-l-id-5-yl)[l,r-biphenyl]-4-yl]methyl}-L-valinate) compound of formula-1, comprising of:
a) Reacting the tromethamine salt of 4-(((2S,4R)-l-([l,r-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-5 with dil. HCI in methyl tertiary butyl ether and water to provide 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-4,

b) reacting the obtained compound with (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,r-biphenylJ-
4-yI)methyl)pentanamido)-3-methylbutanoic acid compound of formula-8 in presence
of aqueous sodium hydroxide in acetonitrile to provide Trisodium (4-{[(lS,3R)-l-
([1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3 -methyl-4-oxobutyl]amino} -4-oxobutanoate)-
5 (N-pentanoyl-N-{[2"-(lH-tetra2ol-l-id-5-yl)[l3r-biphenyI]-4-yl]methyl}-L-valinate)
compound of formula-1,
c) adding aqueous methanol to the obtained compound,
d) stirring the reaction mixture,
e) filtering the reaction mixture and distilling off the solvent from the filtrate to get
10        amorphous compound of formula-1.
The third aspect of the present invention provides a process for the preparation of
amorphous  Trisodium  (4-{[(l S,3R)-l-([l,r-biphenyI]-4-ylmethyl)-4-ethoxy-3-methyl-4-
oxobutyl] amino} -4-oxobutanoate)-(N-pentanoyl-N-{ [2"-( lH-tetrazol-1 -id-5-yl)[ 1,1 "-biphen
15   yI]-4-yl] methyl}-L-valinate) compound of formula-1, comprising of:
a) Reacting the mono sodium salt of 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yl)-5-ethoxy-4-
methyl-5-oxopentan-2-yl)arnino)-4-oxobutanoic acid compound of formula-6 with
disodium   salt   of  (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,l"-biphenyl]-4-yl)methyl)
pentanamido)-3-methylbutanoic acid compound of formula-7 in a suitable solvent,
20 b) stirring the reaction mixture,
c) filtering the reaction mixture and distilling off the solvent from the filtrate to get
amorphous compound of formula-1.
Wherein, the suitable solvent used in step-(a) is same as defined in first aspect of the
I present invention.
;   25
| The preferred embodiment of the present invention provides a process for the
! preparation of amorphous Trisodium (4-{[(lS,3R)-l-([l,l"-biphenyl]-4-ylmethyl)-4-ethoxy-
> 3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(lH-tetrazol-l-id-5-
j yl)[l,l "-biphen yl]-4-yl] methyl}-L-valinate) compound of formula-1 comprising of:
I 30      a) Reacting the mono sodium salt of 4-(((2S,4R)-I-([l,l"-biphenyl]-4-yl)-5-ethoxy-4-
4 methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6 with

disodium   salt   of  (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl) pentanamido)-3-methylbutanoic acid compound of formula-7 in aqueous methanol,
b) stirring the reaction mixture for 30 minutes,
c) filtering the reaction mixture and distilling off the solvent from the filtrate to get 5 amorphous compound of formula-1.
The fourth aspect of the present invention provides a process for the preparation of crystalline  form  of  Trisodium  (4-{[(lS,3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(l H-tetrazol-1-id-5-)   yl)[l,l"-biphen yl]-4-yl] methyl}-L-valinate) compound of formula-1, comprising of:
a) Reacting the mono sodium salt of 4-(((2S,4R)-l-([l,r-biphenyl]-4-yl)-5-ethoxy-4-
methyI-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6 with
disodium   salt   of   (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,l"-biphenyl]-4-yl)methyl)
pentanamido)-3-methylbutanoic acid compound of formula-7 in a suitable solvent,
5 b) stirring the reaction mixture,
c) filtering the solid and drying to get crystalline compound of formula-1.
Wherein, the suitable solvent used in step-(a) is same as defined in first aspect of the present invention.
) The preferred embodiment of the present invention provides a process for the
preparation of crystalline compound of formula-1 comprising of:
a) Reacting the mono sodium salt of 4-(((2S,4R)-l-([l,r-biphenyl]-4-yl)-5-ethoxy-4-
methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6 with
disodium   salt   of   (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,l"-biphenyl]-4-yl)methyl)
5 pentanamido)-3-methylbutanoic acid compound of formuIa-7 in methyl tertiary butyl
ether,
b) stirring the reaction mixture for 30 minutes,
c) filtering the solid and drying to get crystalline compound of formula-1,
) The fifth aspect of the present invention provides a novel crystalline form of
Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]

amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2"-( 1 H-tetrazol-1 -id-5 -yl) [1,1 "-biphen   yl] -4-yl] methyl}-L-valinate) compound of formula-1, herein after designated as crystalline Form-M.
Further, the crystalline Form-M of compound of formula-1 characterized by its
PXRD pattern having characteristic peaks at 3.1, 3.3, 4.2, 4.5, 5.0, 6.1, 8.9, 9.9, 10.5, 10.9,
5   12.5, 13.2,14.9, 15.5, 16.3, 17.0,17.7, 18.6, 19.5, 19.9, 20.8, 21.6, 22.7, 26.3 and 27.2 ± 0.2°
of 2-theta values. The said crystalline form-M is further characterized by its PXRD pattern as
illustrated in figure-1.
The sixth aspect of the present invention provides a process for the preparation of 3   crystalline Form-M of Trisodium (4-{[(lS,3R)-l-([l,l"-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2"-(l H-tetrazol-1 -id-5-yl)[l,l"-biphen yl]-4-yl] methyl}-L-valinate) compound of formula-1, comprising of:
a) Reacting the mono sodium salt of 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yl)-5-ethoxy-4-
methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6 with
5 disodium   salt   of   (S)-2-CN-((2"-(lH-tetrazol-5-yl)-[l,l"-biphenyl]-4-yl)methyl)
pentanamido)-3-methylbutanoic acid compound of formula-7 in a suitable solvent,
b) stirring the reaction mixture,
c) filtering the solid and drying to get crystalline Form-M of compound of formula-1. Wherein, the suitable solvent used in step-(a) is same as defined in first aspect of the
0   present invention.
The seventh aspect of the present invention provides a novel crystalline form of
Trisodium (4- {[(1 S,3R)-1 -([ 1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3 -methyl-4-oxobutyl]
amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(lH-tetrazol-l-id-5-yl)[l,l "-biphen yl]-4-yl] 5   methyl} -L-valinate) compound of formula-1, herein after designated as crystalline Form-S.
Further, the crystalline Form-S of compound of formula-1 characterized by its PXRD
pattern having characteristic peaks at 3.1, 4.6, 6.2, 7.2, 9.2, 10.5, 11.80, 12.5, 12.8, 15.8,
16.5, 17.5, 18.4, 18.8, 19.9, 20.8, 21.3, 21.9, 22.3 and 25.0 ± 0.2° of 2-theta values. The said
crystalline form-S is further characterized by its PXRD pattern as illustrated in figure-5.
0
The eighth aspect of the present invention provides a process for the preparation of
crystalline Form-S of Trisodium (4-{[(lS,3R)-l-([l,l"-biphenyl]-4-ylmethyl)-4-ethoxy-3-

methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(lH-tetra2ol-l-id-5-yl)[l,l"-biphen yl]-4-yl] methyl }-L-valinate) compound of formula-1, comprising of:
a) Reacting the mono sodium salt of 4-(((2S,4R)-l-([l,r-biphenyl]-4-yl)-5-ethoxy-4-
methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6 with
5 disodium   salt   of   (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,r-biphenyl]-4-yl)methyl)
pentanamido)-3-methylbutanoic acid compound of formula-7 in a suitable solvent under nitrogen atmosphere,
b) stirring the reaction mixture,
c) filtering the solid and drying to get crystalline Form-S of compound of formula-1.
10 Wherein, the suitable solvent used in step-(a) is same as defined in first aspect of the
present invention.
The preferred embodiment of the present invention is to provide a process for the preparation of crystalline Form-S of Trisodium (4-{[(lS,3R)-l-([l,l"-biphenyl]-4-ylmethyl)-15   4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(lH-tetrazol-l-id-5-yl)[l,l"-biphen yl]-4-yl] methyl}-L-valinate) compound of formula-1 comprising of:
a) Reacting the mono sodium salt of 4-(((2S,4R)-l-([l,r-biphenyl]-4-yI)-5-ethoxy-4-
methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6 with
disodium   salt   of  (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[lsl"-biphenyl]-4-yl)methyl)
20 pentanamido)-3-methylbutanoic acid compound of formula-7 in n-Heptane at 0 to
5°C under nitrogen atmosphere,
b) stirring the reaction mixture for 2 hours at 0 to 5°C,
c) filtering the solid and drying to get crystalline Form-S of compound of formula-1.
25 In another embodiment of the present invention provides a process for the preparation
of crystalline Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl] amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2"-(l H-tetrazol-1 -id-5-yl)[ 1,1 "-biphen yl]-4-yl]methyl}-L-valinate) hemipentahydrate comprising of:
a) Reacting the mono sodium salt of 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yl)-5-ethoxy-4-
30 methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6 with
disodium   salt   of   (S^-CN-^HlH-tetrazol-S-yO-tlJ"-biphenyll^-yOmethyl) pentanamido)-3-methylbutanoic acid compound of formula-7 in aqueous methanol,

b) stirring the reaction mixture for 90 minutes,
c) isolating the solid from acetonitrile to get the crystalline Trisodium (4-{[(lS,3R)-l-([1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-( 1 H-tetrazol-1 -id-5-yi)[ 1,1 "-biphen yl]-4-yl]methyl}-L-valinate)
5 hemipentahydrate.
The crystalline Form-M, Form-S and crystalline compound of formula-1 obtained
from the present invention can also be used for the preparation of amorphous form of
compound of formula-1.
10 Further, the crystalline Form-M, Form-S & amorphous form of compound of
formula-1 obtained from the present invention is useful in the preparation of pharmaceutical composition.
Trisodium (4-{ [(1 S,3R)-1 -([1,1 "-biphenyl]-4-ylmethyl)-4-ethoxy-3-methyl-4-
15 oxobutyl]amino} -4-oxobutanoate)-(N-pentanoyl-N- {[2"-( 1 H-tetrazol-1 -id-5-yl)[ 1,1 "-biphen yl]-4-yl] methyl}-L-valinate) compound of formula-1 produced by the present invention can be further micronized or milled in a conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited 20 to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
The invention also encompasses pharmaceutical compositions comprising compound
of formula-1  or salts thereof of the present invention.  As used herein, the term 25   "pharmaceutical compositions" or "pharmaceutical formulations" include tablets, pills,
powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection
preparations.
P-XRD Method of Analysis:
30 PXRD analysis of compound of formula-1 was carried out by using BRUKER/D8
ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous
scan speed of 0.03°/min.
The process of the present invention is schematically represented as below:

CL CL
^**^f^N SOCI,. Elhanol    ,   ^"""ir^
1^   jL Methyl tertiaiybutyl elher N^**v.
BwHN-^-^Y0" CIH,H2N"A-^Y0X/"
Formula-2  ° Formula-3 O
Succinic anhydride
Triethylamine
^TS. HC1 ^•""s^ Dichloromethane
fl MTBE   J] r f> * -i
I   1 Aceionitrile |   1 Tromethamine |f   |
V^v Acetone ^-^^ ,  "   Ethylacetate "k*^
. \TB+ I    1 n-Heptane/Acetone f    1 f    I
O   Formula-* O  Formula-5 L I Forraula-I
l ^^if ^  -JN»*   ^^if ^ Na0H
■a O  ^-L O  ^L Acetoniuile
I    J  \ Acetone I tt  X
fS^ttfS^l/ n-Heptane (S***s~s^~*"ti"
Formula-7 Formula-8  /
|l   J o
. Formulu-1
The best mode of carrying out the present invention is illustrated by the below
mentioned examples. These examples are provided as illustration only and hence should not
be construed as limitation to the scope of the invention.
5
Examples:
Example-1:  Preparation  of  (2R,4S)-ethyl  5-([l,l"-biphenyII-4-yl)-4-amino-2-methyl pentanoate hydrochloride (Formula-3)
! Thionyl chloride (49.4 ml) was added to a precooled solution containing ethanol (600
]   10   ml) and (2R,4S)-5-([l,r-biphenyl]-4-yl)-4-((tert-butoxycarbonyl)amino)-2-methylpentanoic
acid-compound of formula-2 (200 gms) at 0-5°C. Heated the reaction mixture to 55-60°C and

stirred for 6 hours at the same temperature. Distilled off the solvent completely under reduced pressure and co-distilled with methyl tertiary butyl ether. Cooled the reaction mixture to 25-30°C. Methyl tertiary butyl ether (1400 ml) was added to the obtained compound. Heated the reaction mixture to 50-55°C and stirred for 30 minutes at the same 5 temperature. Cooled the reaction mixture to 25-30°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with methyl tertiary butyl ether and dried to get the title compound. Yield: 172.3 gms; M.R: 150-158°C; Purity by HPLC: 99.46%. Example-2: Preparation of tromethamine salt of 4-(((2S,4R)-l-([l,l,-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid (Formula-5)
10 Succinic anhydride (43.14 gms) was added to a mixture of dichloromethane (300 ml)
and (2R,4S)-ethyl 5-([l,r-biphenyl]-4-yl)-4-amino-2-methylpentanoate hydrochloride compound of formula-3 (100 gms) at 25-30°C. Triethyl amine (60.5 ml) was slowly added to the reaction mixture at 25-30°C and stirred for 3 hours at the same temperature. Water was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature.
15 Separated the organic and aqueous layers and extracted the aqueous layer with dichloromethane. Combined both the organic layers and washed, with water. Distilled off the solvent completely from the organic layer and co-distilled with ethyl acetate under reduced pressure. Ethyl acetate (600 ml) was added to the obtained compound at 25-30°C. Tromethamine (38.2 gms) was added to the reaction mixture at 25-30°C. Heated the reaction
20   mixture to 60-65°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 5 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 137.8 gms; M.R: 114-118°C; Purity by HPLC: 99.96°C. Example-3: Preparation of mono sodium salt of 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yl)-5-
25   ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid (Formula-6)
A mixture of methyl tertiary butyl ether (250 ml), tromethamine salt of 4-(((2S,4R)-l-
([l,r-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid
compound of formula-5 (50gms) and water (150 ml) were stirred for 10 minutes at 25-30°C. Acidified the reaction mixture using aqueous hydrochloric acid solution at 25-30°C and
30   stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were

separated and aqueous layer was extracted with methyl tertiary butyl ether. Combined both the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure. Acetonitrile (125 ml) and acetone (125 ml) were added to the reaction mixture at 25-30°C. Pre-cooled aqueous sodium hydroxide solution was
j slowly added to the reaction mixture at 15-20°C. Raised the reaction mixture temperature to 25-30°C and stirred for 60 minutes at 25-30°C. Distilled off the solvent completely from the reaction mixture and co-distilled with n-Heptane. Acetone (100 ml) and n-Heptane (400 ml) were added to the obtained solid at 25-30°C and stirred for 60 minutes at the same temperature. Filtered the solid, washed with n-Heptane and dried to get the title compound.
)   Yield: 17.3 gms. The PXRD pattern of the obtained compound is illustrated in figure-3.
Example-4: Preparation of disodium salt of (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,l"-biphenyI]-4-yl)methyI)pentanamido)-3-methylbutanoic acid (Formula-7)
A mixture of valsartan (20 gms), methanol (20 ml) and acetonitrile (80 ml) were stirred for 15 minutes at 25-30°C. Cooled the reaction mixture to 10-15°C. Aqueous sodium
5   hydroxide solution [3.7 gm in 4.0 ml of water) was slowly added to the reaction mixture at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 1 "/i hour at the same temperature. Distilled off the solvent under reduced pressure and co-distilled with n-Heptane. To the obtained solid, n-Heptane (80 ml) and acetone (20 ml) was added at 25-30°C and stirred for 1 hour at the same temperature.
3   Filtered the solid, washed with n-Heptane and dried to get the title compound. Yield: 20.2 gms; RS Purity by HPLC: 99.84 %; Chiral Purity by HPLC: 99.69%. The PXRD pattern of the obtained compound is illustrated in figure-4.
Example-5:  Preparation of amorphous Trisodium (4-{[(lS,3R)-l-([l,l"-biphenyl]-4-5   ylmethyl)-4-ethoxy-3-methyl-4-oxobutyI]amino}-4-oxobutanoate)-(N-pentanoyI-N-{[2"-(lH-tetrazol-l-id-5-yI)[l,l"-biphen yl]-4-yl] methyI}-L-valinate) (Formula-1)
A mixture of methanol (10 ml), water (1 ml), mono sodium salt of 4-(((2S,4R)-l-
([l,r-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid
compound of formula-6 (2 gms) and disodium salt of (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,l"-
0   biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid compound of formula-7 (2.21
gms) were stirred for 30 minutes at 25-30°C. Filtered the reaction mixture through hyflow

bed and washed with methanol. Distilled off the solvent completely from the obtained filtrate
under reduced pressure to get the title compound. Yield: 3.3 gms.
Example-6:  Preparation  of crystalline Trisodium  (4-{[(lS,3R)-l-([l,l"-biphenyl]-4-
ylmethyI)-4-ethoxy-3-methyl-4-oxobutylJamino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-
5   (lH-tetrazol-l-id-5-yl)[l,l"-biphen yI]-4-yl] niethyl}-L-valinate) (Formula-1)
A mixture of methyl tertiary butyl ether (50 ml), mono sodium salt of 4-(((2S,4R)-l-
([l,l,-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid
compound of formuIa-6 (10 gms) and disodium salt of (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,r-
biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid compound of formula-7 (11
10   gms) were stirred for 45 minutes at 25-30°C. Filtered the reaction mixture and washed with
methyl tertiary butyl ether and drying to get the title compound. Yield: 17.5 gms.
The PXRD pattern of the obtained compound is illustrated in figure-2.
Example-7: Preparation of crystalline Form-M of Trisodium (4-{[(lS,3R)-l-([l,l"-
biphenyI]-4-ylmethyl)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-
15   pentanoyl-N-IP"-tlH-tetrazoI-l-id-S-yOIl.l"-biphenyll^-yllmethylJ-L-valinate)
(Formula-1)
A mixture of n-Heptane (50 ml), mono sodium salt of 4-(((2S,4R)-l-([l,l"-biphenyl]-
4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic   acid   compound   of
formula-6 (10 gms) and disodium salt of (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,l"-biphenyl]-4-
20   yl)methyl)pentanamido)-3-methylbutanoic acid compound of formula-7 (11 gms) were
stirred for 45 minutes at 25-30°C. Filtered the reaction mixture and washed with n-Heptane
and drying to get the title compound. Yield: 18.0 gms.
The PXRD pattern of the obtained compound is illustrated in figure-1.
Example-8: Preparation of amorphous Trisodium (4-{[(lS,3R)-l-([l,r-biphenyl]-4-
25   ylmethyl)-4-ethoxy-3-methyl-4-oxobutyI]amino}-4-oxobutanoate)-(N-pentanoyI-N-{[2"-
(lH-tetrazol-l-id-5-yl)[l,l"-biphen yl]-4-yl] methyl}-L-valinate) (Formula-1)
A mixture of methyl tertiary butyl ether (500 ml), tromethamine salt of 4-(((2S,4R)-l-
([l,r-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid
compound of formula-5 (100 gms) and water (300 ml) were stirred for 10 minutes at 25-
30   30°C. Hydrochloric acid solution (30 ml) was slowly added to the reaction mixture at 25-
30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers

were separated and aqueous layer was extracted with methyl tertiary butyl ether. Combined the organic layers and washed with water. Distilled off the solvent completely from the organic layer under reduced pressure.
Methanol (100 ml) was added to the obtained residue at 15-20°C. (S)-2-(N-((2"-(lH-5 tetrazol-5-yl)-[l,l"-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid compound of formula-8 (81.8 gms) and acetonitrile (500 ml) were added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Pre-cooled aqueous sodium hydroxide solution [21.0 gms of sodium hydroxide dissolved in 250ml of water] was slowly added to the reaction mixture at 15-20°C. Raised the reaction mixture temperature to 25-
10 30°C and stirred for 4 hours at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent from the obtained filtrate and co-distilled with acetonitrile under reduced pressure. Acetonitrile (500 ml) was added to the obtained compound at 25-30°C and stirred for 60 minutes at the same temperature. Filtered the solid and washed with acetonitrile under nitrogen atmosphere.
15 Methanol (500 ml) and water (50 ml) were added to the obtained wet compound at
25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely from the obtained filtrate under reduced pressure to get the title compound. Yield: 140 gms. Example-9:  Preparation  of crystalline Form-S of Trisodium  (4-{[(lS,3R)-l-([l,l"-
20   biphenyl]-4-ylmethyI)-4-ethoxy-3-methyl-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N^^"-tlH-tetrazol-l-id-S-yOl^l"-biphenyll^-ylimethylJ-L-valinate) (Formula-1)
A mixture of n-Heptane (150 ml), mono sodium salt of 4-(((2S,4R)-l-([l,l"-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound
25 of formula-6 (25 gms) and disodium salt of (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,l"-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid compound of formula-7 (27.65 gms) were stirred for 2 hours at 0-5°C under nitrogen atmosphere. Filtered the solid and washed with n-Heptane under nitrogen atmosphere. Drying the solid under reduced pressure to get the title compound.Yield: 54.4 gms. Particle size distribution (D90) < 50 um.
30   The PXRD pattern of the obtained compound is illustrated in figure-5.

Examplc-10: Preparation of mono sodium salt of 4-(((2S,4R)-l-([l,r-biphenyl]-4-yl)-5-ethoxy-4-mcthyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid (Formula-6)
A mixture of methyl tertiary butyl ether (500 ml), tromethamine salt of 4-(((2S,4R)-l-
([1,1 "-biphenyl]-4-yl)-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid
5 compound of formula-5 (100 gms) and water (300 ml) were stirred for 10 minutes at 25-30°C. Acidified the reaction mixture using aqueous hydrochloric acid solution at 25-30°C and stirred for 15 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with methyl tertiary butyl ether. Combined both the organic layers and washed with water. Distilled off the solvent completely from the
)   organic layer under reduced pressure to get compound of formula-4 as a residue.
Acetonitrile (100 ml) was added to the obtained residue at I5-20°C. Pre-cooled aqueous sodium hydroxide solution was slowly added to the reaction mixture at 15-20°C. Raised the reaction mixture temperature to 25-30°C and stirred for 90 minutes at 25-30°C. Filtered the reaction mixture and washed with acetonitrile. Distilled off the solvent
>   completely from the filtrate and co-distilled with methyl tertiary butyl ether. Methyl tertiary butyl ether (800 ml) was added to the obtained solid at 25-30°C and stirred for 90 minutes at the same temperature. Filtered the solid, washed with methyl tertiary butyl ether and dried to get the title compound. Yield: 70.0 gms. Melting Range: 140 to 150°C
)   The PXRD pattern of the obtained compound is illustrated in figure-3.
Example-11:  Preparation of disodium salt of (S)-2-(N-((2"-(lH-tetrazol-5-yl)-[l,r-biphenylJ-4-yI)methyl)pentanamido)-3-methylbutanoic acid (FormuIa-7)
A mixture of valsartan (100 gms) and acetone (300 ml) were stirred for 15 minutes at 25-30°C. Cooled the reaction mixture to 10-15°C. Aqueous sodium hydroxide solution [17.4
5 gm in 18 ml of water) was slowly added to the reaction mixture at 10-I5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the reaction mixture and washed with acetone. Acetone (1000 ml) and seeding material of compound of formula-7 were added to the filtrate at 25-30°C. Cooled the reaction mixture to 15-20°C and stirred for 15 hours at the same temperature. Filtered the
)   solid, washed with acetone and dried to get the title compound.

Yield: 98.0 gms; Melting Range: 240 to 250°C. The PXRD pattern of the obtained compound is illustrated in figure-4. Example-12: Preparation of crystalline Trisodium (4-{[(lS,3R)-l-([l»l"-biphenyl|-4-ylmethyI)-4-ethoxy-3-methyI-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{|2"-5   (lH-tetrazoI-l-id-5-yI)[l,l"-bipheny]]-4-yl] methyl}-L-valinate)hemipentahydrate
A mixture of acetonitrile (200 ml), mono sodium salt of 4-(((2S,4R)-l-([l,r-biphenyl]-4-y])-5-ethoxy-4-methyl-5-oxopentan-2-yl)amino)-4-oxobutanoic acid compound of formula-6 (50 gms) and disodium salt of (S)-2-(N-((2"-(lH-tetra2ol-5-yl)-[l,r-biphenyl]-4-yl)methyl)pentanamido)-3-methylbutanoic acid compound of formula-7 (55.3 gms) were
10 stirred for 10 minutes at 25-30°C. Methanol (50 ml) and water (25 ml) were added to the reaction mixture and stirred for 1 14 hours at 25-30°C Filtered the reaction mixture and washed with methanol. Distilled-off the solvent completely from the obtained filtrate under reduced pressure and co-distilled with acetonitrile. Acetonitrile (250 ml) was added to the obtained solid and stirred the reaction mixture for 1 hour at 25-30°C. Filtered the solid and
15 washed with acetonitrile and drying to get the title compound. Yield: 106.0 gms. Melting range: 134-138°C. Water content: 4.0% to 6.0 % w/w.
The PXRD pattern of the obtained compound is similar to the crystalline Trisodium Sacubitril Valsartan hemipentahydrate disclosed in US8877938B2. Example-13: Preparation of amorphous Trisodium (4-{[(lS,3R)-l-([l,l"-biphenyl]-4-
20   ylmethyl)-4-ethoxy-3-methyI-4-oxobutyl]amino}-4-oxobutanoate)-(N-pentanoyl-N-{[2"-(lH-tetrazoI-l-id-5-yl)[l,l"-biphenyl]-4-yl]methyl}-L-valinate)(Formula-l)
Methanol (500 ml) and water (50 ml) were added to the compound of formula-1 (100 gms) at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Distilled off the solvent completely
25   from the obtained filtrate under reduced pressure to get the title compound. Yield: 95.0 gms.
The present inventors have repeated the process disclosed in Example-1 of US8877938 and characterized the obtained glossy solid as amorphous form.