NOVEL COMPOUNDS AND THEIR USE IN PREPARATION OF ELAFIBRANOR AND PHARMACEUTICAL ACCEPTABLE SALTS THEROF FIELD OF THE INVENTION

The present invention relates to novel compounds of Formula I and process for the preparation thereof,

Formula I

The present invention further provides use of the compounds of Formula I or salts thereof in preparation of (T)-2-(2, 6-dimethyl -4-(3-(4-(methyl thiojphenyl )-3-oxoprop- l-en-l-yl)phenoxy)-2-methyl propanoic acid (Elafibranor) of Formula II and pharmaceutical acceptable salts thereof,

Formula II

BACKGROUND OF THE INVENTION

Elafibranor chemically known as (E)-2-(2, 6-dimethyl -4-(3-(4-(methyl thio)phenyl)-3- oxoprop-l-en-l-yl)phenoxy)-2-methylpropanoic acid and is disclosed in WO 2004/005233 Al . It is under study for the treatment of cardiometabolic diseases and to prevent the occurrence of ischemic cerebral accidents. US patent 7,385,082 discloses process of preparing elafibranor. The scheme-l mentioned below illustrates the method of the preparation of elafibranor as disclosed in US’082. Scheme-1

Although there are some processes known in the literature for preparation of elafibranor and its intermediate(s), there is a need to develop a process that is high yielding, reproducible and economical at large scale production. Therefore, the present invention provides the simple and cost effective process for the preparation of elafibranor using novel intermediates. OBJECT OF THE INVENTION

The main object of the present invention is to provide the novel compounds of Formula I as represented below:

Formula I

Another object of the present invention is to provide novel compounds of Formula I or pharmaceutically acceptable salts, solvates, hydrates and polymorphs thereof, that can be used for the preparation of Elafibranor and its pharmaceutical acceptable salts, solvates, hydrates and polymorphs thereof.

Another object of the present invention is to provide a process for the preparation of Elafibranor of Formula II with high yields and purity.

SUMMARY OF THE INVENTION

The main aspect of the present invention is to provide compounds of Formula I,

Formula I

isomers, pharmaceutical acceptable salts, polymorphs, solvates, and hydrates thereof; wherein Ri and R ₂ independently represents hydrogen, straight or branched (Ci-C ₆ ) alkyl;

R ₃ represents -CH ₂ OP ₁ , -COP ₂ ,

wherein Pi represents hydrogen, S1R ₅ ;

P ₂ represents hydrogen, halogen, OR ₅ , OCOR ₅ , S1R ₅ ;

wherein R ₅ represents hydrogen, substituted or unsubstituted alkyl , substituted or unsubstituted aryl, aralkyl, allyl group or heterocyclic ring;

R represents: or -CHO;

R ₄ represents -CHO, -X, -COP ₂ , -CO-Ar and -CH(OH)-Ar, CH ₂ OH, CN, alkyl, COX, CONR ₁ R ₂ ; wherein P ₂ is as defined above;

X is halogen;

Ar represents optionally substituted phenyl ring; and

n is the integer of 1 or 2. In another aspect, the present invention provides a process for the preparation of elafibranor of Formula II and pharmaceutically acceptable salts thereof; wherein said process comprises the steps of:

a) reacting compound of Formula XVII with compound of Formula XVIII in presence of suitable solvent to obtain allyl 2-(4-formyl-2,6-dimethylphenoxy)-2- methylpropanoate of Formula XIX;

wherein L is a leaving group;

b) converting the compound of Formula XIX to elafibranor of Formula II;

c) optionally purifying the compound of Formula II; and

d) optionally converting the compound of Formula II to its pharmaceutically acceptable salts.

In another aspect, the present invention provides the process for the preparation of elafibranor of Formula II and pharmaceutically acceptable salts thereof; wherein said process comprises the steps of:

a) coupling allyl 2-(4-formyl-2,6-dimethylphenoxy)-2-methylpropanoate compound of Formula XIX with l-(4-(methylthio)phenyl)ethan-l-one of Formula XX in presence of suitable solvent to obtain allyl (E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3- oxoprop-l-en-l-yl)phenoxy)-2-methylpropanoate of Formula XXI;

Formula XIX Formula XXI

b) converting compound of Formula XXI to Elafibranor of Formula II;

c) optionally purifying the compound of Formula II; and d) optionally converting the compound of Formula II to its pharmaceutically acceptable salts.

In another aspect, the present invention provides the preparation of elafibranor of Formula II and pharmaceutically acceptable salts thereof; wherein said process comprises the steps of:

a) reacting compound of Formula XVII with compound of Formula XVIII in presence of suitable solvent to obtain compound of Formula XIX;

Formula XVII Formula XVIII Formula XIX

wherein L is a leaving group;

b) coupling the compound of Formula XIX with compound of Formula XX in presence of suitable solvent to obtain compound of Formula XXI;

Formula XIX Formula XXI c) deprotecting the compound of Formula XXI to obtain Elafibranor of Formula II; and

d) optionally converting the compound of Formula II to its pharmaceutically acceptable salts.

In another aspect, the present invention provides crystalline compound of Formula XIX and its pharmaceutically acceptable salts

Formula XIX

In another aspect, the present invention provides crystalline compound of Formula XXI and its pharmaceutically acceptable salts

In another aspect, the present invention provides novel compounds as represented by following Formulae:

0 Formula VIII Formula IX

Formula XII Formula XIV

In another aspect, the present invention provides novel compounds selected from the group comprising of:

isopropyl (E)-2-(2,6-dimethyl-4-(3-oxoprop-l-en-l-yl)phenoxy)-2-methyl propanoate; (E)-3-(4-((l-isopropoxy-2-methyl-l-oxopropan-2-yl)oxy)-3,5-d imethylphenyl)acrylic acid;

Allyl-2-(4-formyl-2,6-dimethylphenoxy)-2-methylpropanoate;

(E)-(4-(3-(4-(( 1 -isopropoxy-2 -methyl- 1 -oxopropan-2-yl)oxy)-3 ,5 - dimethylphenyl)acryloyl)phenyl)boronic acid;

(E)-2-(4-(3-(4-boronophenyl)-3-oxoprop-l-en-l-yl)-2,6-dimeth ylphenoxy)-2- methylpropanoic acid;

allyl (E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3-oxoprop- 1 -en- 1 -yl)phenoxy)- 2-methylpropanoate;

(E)-(2-(4-(2-bromovinyl)-2,6-dimethylphenoxy)-2-methylpropox y)trimethylsilane; (E)-(4-( 1 -hydroxy-3 -(4-(( 1 -hydro xy-2-methylpropan-2-yl)oxy)-3 ,5- dimethylphenyl)allyl)phenyl)boronic acid; and

(E)-3-(4-((l-hydroxy-2-methylpropan-2-yl)oxy)-3,5-dimethylph enyl)-l-(4- (methylsulfonyl)phenyl)prop-2-en-l-ol.

DETAILED DESCRIPTION

Definitions: “Pharmaceutically acceptable salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt; organic acids such as formic acids, acetic acid, diphenyl acetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, succinic acid, benzoic acid, -chlorobenzoic acid, nicotinic acid, o- hydroxybenzoic acid, -hydroxybenzoic acid, 1 -hydroxy-naphthalene -2 -carboxylic acid, hydro xynaphthalene-2 -carboxylic acid, ethanesulfonic acid, ethane- 1,2- disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-l0- sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid; pharmaceutically acceptable bases such as metal salts including alkali metal or alkaline earth metal salts for example sodium, potassium, magnesium, calcium, barium, or zinc salts, ammonium salts; organic amines such as benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl)morpholine, l-(2- hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine, choline, diethanolamine, L-lysine, piperazine, tromethamine and the like.

The term“isomers” as used in the context of the present invention refers to all such compounds including tautomers, cis-and trans-isomers, R- and 5-enantiomers, diastereomers, D-isomers, L-isomers, and racemic mixtures of all the compounds herein described under the definitions of compound of Formula I. Further, additional asymmetric carbon atoms may be present in a substituent such as alkyl group. The compounds herein described may have asymmetric carbon atoms and may be isolated in optically active forms by synthesis from optically active starting materials, or synthesis using optically active reagents by methods known in the prior published references. The term“optionally substituted” or“(un) substituted” as used in the context of the present invention means that substitution is optional and therefore it is possible for the designated atom or moiety to be unsubstituted. As used herein, unless otherwise indicated, the term“alkyl” alone or in combination refers to a monovalent saturated aliphatic hydrocarbon radical having the indicated number of carbon atoms. The alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isopropyl, isobutyl, isopentyl, sec-butyl, tert- butyl, tert-pentyl, and the like.

As used herein, the term“halo” or“halogen” means a monovalent halogen radical or atom selected from fluoro, chloro, bromo and iodo.

“Leaving group” as used in the context of the present invention refers to compounds/groups that are replaceable and can easily depart the compound to which they are attached.

In one embodiment, the present invention provides compounds of Formula I,

Formula I

isomers, pharmaceutically acceptable salts, polymorphs, solvates or hydrates thereof; wherein Ri and R ₂ independently represents hydrogen, straight or branched (Ci-C ₆ ) alkyl;

R ₃ represents -CFhOPi, -COP ₂ ,

wherein Pi represents hydrogen, S1R5;

P ₂ represents hydrogen, halogen, OR ₅ , OCOR ₅ , S1R ₅ ;

wherein R5 represents hydrogen, substituted or unsubstituted alkyl , substituted or unsubstituted aryl, aralkyl, allyl group or heterocyclic ring; R represents:

R ₄ represents -CHO, -X, -COP ₂ , -CO-Ar and -CH(OH)-Ar, CH ₂ OH, CN, alkyl, COX, CONR _I R ₂ ; where P ₂ is as defined above;

X is halogen;

Ar represents optionally substituted phenyl ring; and

n is the integer of 1 or 2.

In another embodiment, the present invention provides compound of Formula I and pharmaceutically acceptable salts, solvates, hydrates and polymorphs thereof, wherein R is CHO, Ri and R ₂ is independently methyl, R ₃ is -COP ₂ ; wherein P ₂ is OR ₅ , R ₅ is allyl group _, and is represented by compound Formula XIX;

Formula XIX In another embodiment, the present invention provides compound of Formula I and pharmaceutically acceptable salts, solvates, hydrates and polymorphs thereof, wherein Ri and R ₂ is independently methyl, R ¾ is -COP ₂ ; wherein P ₂ is OR5, R5 is allyl group and R represents: wherein R ₄ is -CO-Ar; wherein Ar group is substituted with -S-CH _3, and is represented by compound Formula XXI;

Formula XXI In another embodiment, the present invention provides use of novel compounds of Formula I or pharmaceutically acceptable salts, solvates, hydrates and polymorphs thereof, in preparation of elafibranor. In another aspect, the present invention provides crystalline compound of Formula XIX and its pharmaceutically acceptable salts

Formula XIX

In another aspect, the present invention provides crystalline compound of Formula XXI and its pharmaceutically acceptable salts

Formula XXI

In another embodiment, the present invention provides a process of preparation of elafibranor and pharmaceutically acceptable salts thereof; wherein said process comprises the steps of:

a) reacting compound of Formula XVII with compound of Formula XVIII in presence of suitable solvent to obtain allyl 2-(4-formyl-2,6-dimethylphenoxy)-2- methylpropanoate of Formula XIX;

Formula XVII Formula XVIII Formula XIX

wherein L is a leaving group; b) converting the compound of Formula XIX to elafibranor of Formula II;

c) optionally purifying the compound of Formula II; and

d) optionally converting compound of Formula II to its pharmaceutically acceptable salts.

In another embodiment, the present invention provides a process of preparation of elafibranor and pharmaceutically acceptable salts thereof; wherein said process comprises the steps of:

a) coupling allyl 2-(4-formyl-2,6-dimethylphenoxy)-2-methylpropanoate compound of Formula XIX with l-(4-(methylthio)phenyl)ethan-l-one of Formula XX in presence of suitable solvent to obtain allyl (E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3- oxoprop-l-en-l-yl)phenoxy)-2-methylpropanoate of Formula XXI;

Formula XIX Formula XXI

b) converting the compound of Formula XXI to elafibranor of Formula II;

c) optionally purifying the compound of Formula II; and

d) optionally converting the compound of Formula II to its pharmaceutically acceptable salts.

In one another embodiment, the present invention provides a process for the preparation of elafibranor and pharmaceutically acceptable salts thereof; wherein said process comprises the steps of:

a) reacting compound of Formula XVII with compound of Formula XVIII in presence of suitable solvent to obtain compound of Formula XIX;

Formula XVII Formula XVIII Formula XIX wherein L is a leaving group;

b) coupling the compound of Formula XIX with compound of Formula XX in presence of suitable solvent to obtain compound of Formula XXI;

Formula XIX Formula XXI c) deprotecting the compound of Formula XXI to obtain Elafibranor of Formula II; and d) optionally converting the compound of Formula II to its pharmaceutically acceptable salts.

In another embodiment, the solvent used for preparation of elafibranor, and/or pharmaceutically acceptable salts, isomers, solvates, hydrates thereof, is selected from the group comprising of toluene, xylene, chlorobenzene, cyclohexane, hexane, heptane, acetonitrile, propionitrile, dimethyl acetamide (DMA), dimethylformamide (DMF), N- methyl pyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), tetrahydrofuran (THF), dioxane, methyltetrahydrofuran, diethyl ether, acetone, methyl ethyl ketone (MEK), methyl tert-butyl ketone, methanol, ethanol, butanol, isopropyl alcohol, tert-butanol, methyl isobutyl ketone (MP3K), methylene chloride, carbon tetrachloride, ethyl acetate, propyl acetate, butyl acetate, t-butl acetate, acetoacetates, water and mixture thereof.

In another embodiment, coupling of compound of Formula XVII with compound of Formula XVIII is optionally carried out in presence of base wherein said base is selected from the group comprising of sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), cesium hydroxide (Cs(OH)2), cesium acetate (CsOAc), sodium acetate (NaOAc) and potassium acetate (KOAc), sodium bicarbonate (NaHCCh), potassium carbonate (K2CO3), sodium carbonate (Na2C0 ₃ ), and potassium bicarbonate (KHCO3). The most preferred base is potassium carbonate.

In another embodiment, coupling of compound of Formula XIX with compound of Formula XX may be carried out in presence of catalyst wherein said catalyst is selected from the group comprising hydrochloric acid (HC1), hydrogen iodide (HI), hydrogen bromide (HBr), hydrogen fluoride (HF), sulfuric acid (H ₂ SO ₄ ), phosphoric acid (H ₃ PO ₄ ) and the like; alkali/alkaline earth metal hydroxides selected from NaOH, LiOH, KOH, Ca(OH) ₂ ; carbonates selected from K ₂ CO ₃ , CS ₂ CO ₃ , Na ₂ C0 _3; metal alkoxides; organic amines selected from triethyl amine, pyridine, NaN¾, NaH, LDA; and mixture thereof. The most preferred catalyst is HC1.

In another embodiment, the reagent used for deprotecting the allyl group of compound of Formula XXI is selected from the group comprising of Azobisisobutyronitrile (AIBN), and Me3SiONa, Pd/Triethylamine/formic acid. The most preferred reagent is Azobisisobutyronitrile.

In one another embodiment, the leaving group is selected from hydroxyl, OR ₅ , halogen and the like, wherein R ₅ is selected from mesylate, tosylate, triflate, (un) branched, (un) saturated alkyl group or any carbon containing moiety, sulfur containing moiety and silyl containing moiety.

In a preferred embodiment, the present invention provides a process of preparation of Elafibranor of Formula II and pharmaceutically acceptable salts thereof, wherein said process comprising of reaction steps as mentioned in the scheme below: Scheme-2:

In another embodiment, the present invention provides a process for the preparation of elafibranor of Formula II, its pharmaceutically acceptable salts, isomers, solvates, hydrates or mixture thereof, by employing compound of Formula I, or salts thereof as intermediates.

In furthermore embodiment, there is provided a substantially pure Elafibranor or pharmaceutically acceptable salts thereof, wherein said Elafibranor or pharmaceutically acceptable salts are substantially free of impurities of Formula Q, R, S, T and U wherein each individual impurity is less than about 0.3%w/w and total impurities less than 1% w/w, more specifically less than 0.5% w/w;

Formula U In another embodiment, the present invention provides substantially pure compound of Formula I and specifically compound of Formula XIX and XXI having purity of about 99.0% and above, preferably 99.5% and above and most preferably, 99.9% and above.

In another embodiment, the present invention provides a process for the preparation of elafibranor of Formula II or its pharmaceutically acceptable salt thereof, by following a process as mentioned in the scheme 3 below: Scheme-3:

In another embodiment, the oxidizing agent used for the oxidation of compound of Formula V is selected from the group comprising of CrCh/fFSCF (Jones reagent), Tollen’s reagent, potassium permanganate (KMn0 ₄ ), mthenium trichloride -hydrogen peroxide (RUCI3-H2O2), potassium chromate (K ₂ 0G ₂ 07), (2, 2, 6, 6-

Tetramethylpiperidin-l-yl)oxyl or (2,2,6,6-tetramethylpiperidin-l-yl)oxidanyl (TEMPO), sodium hypochlorite (NaOCl), sodium chlorite (NaQ0 ₂ ) _, and trichloroisocyanuric acid (TCCA). The most preferred oxidizing agent is Jones reagent.

In another embodiment, the catalyst used for coupling of compound of Formula VI with compound of Formula VII is selected from the group comprising of oxalyl chloride, thionyl chloride, sulphuryl chloride, phosphorus pentachloride (PCl ₅ ), phosphorus oxychloride (POCI ₃ ), and acetyl chloride (CH ₃ COCI).

In another embodiment, the Lewis acid used for coupling of compound of Formula VI with compound of Formula VII is selected from the group comprising of AIX3, FeX3, BX ₃ , BX ₃ .OEt ₂ , ZnX ₂ , InX ₃ , SbX ₅ , TiX ₄ , BiX ₃ , SnX ₄ , GaX _3, ScX _3, HfX _4; wherein, X is halogen, OTf (triflate group); or Bronsted acids such as hydrogen fluoride (HF), sulfuric acid (H ₂ S0 ₄ ), phosphoric acid (FbP0 ₄ ) or acidic oxides such as silica-alumina type or cation-exchange resins. The most preferred Lewis acid is A1CL _.

In another embodiment, the reagent used for the thiomethylation of compound of Formula IX is selected from the group comprising of 1 ,2 -dime thyldisulfide and S- methyl hydrogen thiosulfate. The most preferred reagent for thiomethylation is 1,2- dimethyldisulfide.

In another embodiment, the catalyst used for the thiomethylation of compound of Formula IX is selected from the group comprising of di-tertiary-butyl peroxide (DTBP), Eosin Y disodium. The most preferred catalyst is di-tertiary-butyl peroxide. In one another embodiment, the present invention provides a process of preparation of elafibranor of Formula II or its pharmaceutically acceptable salt by employing novel compounds of Formula XII and XIV, wherein said process comprising the reaction steps as mentioned in the scheme below: Scheme-4:

In another embodiment, the reagent used for the generation of Grignard reagent for the coupling of compound of Formula XII with the compound of Formula XIII is selected from magnesium metal or isopropyl magnesium chloride. The most preferred Grignard reagent is magnesium metal.

In another embodiment, the oxidizing agent used for the oxidation of compound of Formula XIV is selected from the group comprising of Cr0 ₃ /FbS0 ₄ (Jones reagent) Tollen’s reagent, KMn0 ₄ , mthenium trichloride -hydrogen peroxide (RUCI3-H2O2), K2&2q ₇ , (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl or (2,2,6,6-tetramethylpiperidin-l- yl)oxidanyl (TEMPO), Sodium hypochlorite (NaOCl), sodium chlorite (NaCl0 ₂ ) _, and Trichloroisocyanuric acid (TCCA).The most preferred oxidizing agent is Jones reagent.

In another embodiment, the reducing agent used for the reduction of compound of Formula XV is selected from the group comprising of triethyl silane, lithium aluminum hydride (L1AIH4) and Samarium (II) iodide (SmF). The most preferred reducing agent is triethyl silane.

In another embodiment, the catalyst used for the reduction of compound of Formula XV is selected from the group comprising of tris-(pentafluorophenyl)borane, titanium tetrachloride (TiCU), and titanium oxide (T1O2). The most preferred reducing agent is tris-(pentafluorophenyl)borane.

In one another embodiment, the present invention provides a process of preparation of Elafibranor of Formula II or its pharmaceutically acceptable salts, by employing novel compounds of Formula XII and Formula XVI, wherein said process comprising the reaction steps as mentioned in the scheme below:

Scheme-5:

In another embodiment, the reagent used for the generation of Grignard reagent for the coupling of compound of Formula XII with the compound of Formula VII is selected from magnesium metal or isopropyl magnesium chloride. The most preferred Grignared reagent is magnesium metal.

In another embodiment, the oxidizing agent used for the oxidation of compound of Formula XVI is selected from the group comprising of Cr0;¾/H2S0 ₄ (Jones reagent), Tollen’s reagent, KMn0 ₄ , mthenium trichloride -hydrogen peroxide (RUCI3-H2O2), K ₂ Cr ₂ 0 ₇ , (2,2,6,6-Tetramethylpiperidin-l-yl)oxyl or (2,2,6,6-tetramethylpiperidin-l- yl)oxidanyl (TEMPO), Sodium hypochlorite (NaOCl), sodium chlorite (NaCl0 ₂ ) _, and trichloroisocyanuric acid(TCCA).The most preferred oxidizing agent is Jones’s reagent. In another embodiment, the reagent used for the thiomethylation of compound of Formula IX is selected from the group comprising of l,2-dimethyldisulfane, S-methyl hydrogen thiosulfate. The most preferred reagent for thiomethylation is 1,2- dimethyldisulfide.

In another embodiment, the catalyst used for the thiomethylation of compound of Formula IX is selected from the group comprising of di-tertiary-butyl peroxide (DTBP), Eosin Y disodium. The most preferred catalyst is di-tertiary-butyl peroxide.

In general embodiment, the solvent used for preparation of elafibranor of Formula II is selected from the group comprising of toluene, hexane, heptane, acetonitrile, dimethyl acetamide (DMA), dimethylformamide (DMF), N-methyl pyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), tetrahydrofuran (THF), dioxane, methyltetrahydrofuran, acetone, methyl ethyl ketone (MEK), methanol, ethanol, methyl isobutyl ketone (MIBK), and mixture thereof.

In general embodiment, the base used for preparing elafibranor of Formula II is selected from the group comprising of sodium hydroxide (NaOH), potassium hydroxide (KOH), lithium hydroxide (LiOH), cesium hydroxide (Cs(OH)2), cesium acetate (CsOAc), sodium acetate (NaOAc) and potassium acetate (KOAc), sodium bicarbonate (NaHCCh), potassium carbonate (K2CO3), sodium carbonate (Na ₂ C0 ₃ ), and potassium bicarbonate (KHCO3).

In a preferred embodiment, the present invention provides a substantially pure amorphous form of elafibranor or its pharmaceutically acceptable salts, wherein said amorphous form is substantially free of any crystalline form.

In further embodiment, the present invention provides elafibranor or pharmaceutically acceptable salts thereof, characterized by particle size wherein, d^ is between 0.1 pm to 200pm. In a preferred embodiment, the elafibranor or pharmaceutical acceptable salts thereof, is characterized by particle size wherein, d^ is between 1.0 pm to l50pm. In a preferred embodiment, the elafibranor or pharmaceutical acceptable salts thereof, is characterized by particle size wherein, d^ is between 1.0 pm to lOOpm.

In a preferred embodiment, the elafibranor or pharmaceutical acceptable salts thereof, is characterized by particle size wherein, d^ is less than about 200pm.

In one another embodiment, the elafibranor or pharmaceutical acceptable salts thereof, prepared as per the process of the present invention is characterized with purity above 99%, preferably above 99.5%, and more preferably above 99.9%. In further embodiment, the present invention provides a substantially pure crystalline form of elafibranor or pharmaceutical acceptable salts thereof.

In a preferred embodiment, the present invention provides a substantially pure crystalline form of elafibranor or its pharmaceutical acceptable salts, wherein said crystalline form is substantially free of amorphous form.

In another preferred embodiment, the present invention provides a solid dispersion of elafibranoror its pharmaceutical acceptable salt together with a pharmaceutically acceptable carrier, processes for preparation thereof, and pharmaceutical compositions prepared therefrom.

In one another embodiment, the present invention further provides a composition comprising elafibranor or its pharmaceutical acceptable salt optionally with one pharmaceutical acceptable excipients. The embodiments of the present invention are exemplified herein below:

EXAMPLES

Example 1: Synthesis of isopropyl (E)-2-(2,6-dimethyl-4-(3-oxoprop-l-en-l- yl)phenoxy)-2-methylpropanoateof Formula V

(2£’)-3-(4-Hydroxy-3,5-dimethylphenyl)acrylaldehyde of Formula III (100 g, 567 mM, 1.0 eq.) was dissolved in 50 mL of acetone and potassium carbonate (235 g, 1.7 M, 3.0 eq.) was added. Stirred for 15 minutes and added isopropyl 2-bromo-2- methylpropanoate (355.4 g, 1.7 M, 3.0 eq.) of Formula IV. The reaction mixture was heated for 12 hrs under reflux. Reaction mixture was filtered and solid cake was washed by acetone. Filtrate was concentrated under vacuum and crude was purified by column chromatography to get the compound of Formula V.

Yield: 125 g, 72.3%,

Purity: 96% on HPLC.

Example 2: Synthesis of (E)-3-(4-((l-isopropoxy-2-methyl-l-oxopropan-2-yl)oxy)- 3,5-dimethylphenyl)acrylic acid of Formula VI

To a solution of compound of Formula V (125 g, 0.41M, 1.0 eq.) in acetone (625 ml), Jones reagent (410 ml, 1.02 M, 2.5 eq.) was added dropwise at 0 °C. The reaction mixture was stirred for 6 hrs at ambient temperature. Precipitates formed were filtered off and the excess reagent was quenched by adding isopropyl alcohol at 0 °C. The solution was then concentrated under vacuum and extracted by ethyl acetate (1.0 Lx 3). The organics were combined and distilled off. Crude material obtained was purified by column chromatography to get the compound of Formula VI.

Yield: 110 g, 83.6%

Purity: 94.5% on HPLC.

Example 3: Synthesis of (E)-(4-(3-(4-((l-isopropoxy-2-methyl-l-oxopropan-2- yl)oxy)-3,5-dimethylphenyl)acryloyl)phenyl)boronic acid of Formula VIII: To compound of Formula VI (110 g, 0.34 M, 1.0 eq.) and AlCb (54.4 g, 0.41 M, 1.2 eq.) was 1.0 L of DCM and cooled to 0-5 °C. To reaction mixture added oxalyl chloride (52.1 g, 0.41 M, 1.2 eq.) drop wise. Allowed reaction mass to attain ambient temperature and stirred for 2 hrs. Added phenylboronic acid (45.1 g, 0.37 M, 1.1 eq.) and stirred for 12 hrs at ambient temperature. Upon reaction completion, reaction mass was distilled off and degassed. Added 500 ml of water and extracted with 300 ml ethyl acetate three times. Organics were combined and distilled off. Cmde material was purified by column chromatography to get the compound of Formula VIII.

Yield: 102 g, 70%

Purity: 96.3% on HPLC

Example 4: Synthesis of (E)-2-(4-(3-(4-boronophenyl)-3-oxoprop-l-en-l-yl)-2,6- dimethylphenoxy)-2-methylpropanoic acid of Formula IX

Compound of Formula VIII (102 g, 0.24 M, 1.0 eq.) was dissolved in isopropyl alcohol (500 ml) and added 5% (aq.) sodium hydroxide solution (48 g, 1.2 M, 5 eq.) drop wise. The reaction mixture was heated to 40-45 °C and stirred for 12 hrs. Reaction mass was distilled off and degassed well. Added 500 ml of water and washed by 250 ml dichloromethane three times. Aqueous layer was charged in the reaction flask and its pH was adjusted to 4.0-4.5 by adding 1N HC1. Extracted the aqueous layer by 500 ml ethyl acetate three times. Organics were combined and distilled off. Crude material was dissolved in 100 ml acetone and added drop wise to pre-stirred 1.5 litre hexane. Compound IX crystalizes out of solution.

Yield: 84.5 g, 92%

Purity: 98 % on HPLC

Example 5: Synthesis of Elafibranor

Compound of Formula IX (84.5 g, 0.22 M, 1.0 eq.), 1 ,2-dimethyldisulfide (41.4 g, 0.44 M, 2.0 eq.), di-tertiarybutyl peroxide (DTBP) (96.5 g, 0.66 M, 3.0 eq.), and MeCN (300 ml) were taken in a 5.0 L RBF. The reaction mixture was stirred at 90 °C for 12 h in air. After cooling to room temperature, the product was diluted with fFO (1.5 L) and extracted with EtOAc (4 x 1.0 L). The extracts were combined and washed by brine (3 x 1.0 L) and dried over Na ₂ S0 ₄ . The mixture was filtered, and filtrate was evaporated. Cmde material was dissolved in tetrahydrofuran (425 ml) and added hexane dropwise (675 ml). The mixture was cooled to 15-20 °C. Elafibranor crystallizes out and stirred for 2 hrs. Material was filtered, suck dried and finally vacuum oven dried at 45-50 °C for 12 hrs to get the compound of Formula II.

Yield: 51 g, 60%

Purity: 99.92% on HPLC

Example 6: Synthesis of (E)-(2-(4-(2-bromovinyl)-2,6-dimethylphenoxy)-2- methylpropoxy) trimethylsilane of Formula XII

4-[(£’)-2-Bromovinyl]-2,6-dimethylphenol of Formula X (100 g, 0.44 M, 1.0 eq.) was taken in a 1.0 L, 4-neck RBF and added acetone (500 ml). Added potassium carbonate (304 g, 2.2 M, 5 eq.) Stirred for 15 minutes and added (2-bromo-2-methylpropoxy) trimethylsilane (495.4 g, 2.2 M, 5.0 eq.) of Formula XI. The reaction mixture was heated for 12 hrs at reflux. Consumption of starting material was checked on TEC. After the completion the reaction mixture was filtered and solid cake was washed by acetone. Filtrate was concentrated under vacuum and cmde was purified by column chromatography to get the compound of Formula XII.

Yield: 117.7 g, 72%

Purity: 95.7% on HPFC

Example 7: Synthesis of (E)-3-(4-((l-hydroxy-2-methylpropan-2-yl)oxy)-3,5- dimethylphenyl)-l-(4-(methylsulfonyl)phenyl)prop-2-en-l-olof Formula XIV

In a 4-neck, 2.0 F RBF was taken THF (500 ml) and magnesium (19.4 g, 0.81 M, 3.0 eq.). Added a pinch of iodine and stirred for 15 minutes. The reaction mass was heated to reflux. The reaction mass was stirred for 30 min at reflux. A solution of compound of Formula XII (100 g, 0.27 M, 1.0 eq.) in THF (300 ml) was prepared and added drop wise into the reaction mass. Grignard reagent formation starts after 15 minutes accompanied by vigorous reflux. The reaction mass was stirred for 2 hrs at reflux. The reaction mass was cooled to 0-5 °C. Prepared a solution of 4-

(methylsulfonyl)benzaldehyde (149.2 g, 0.81 M, 3.0 eq.) of Formula XIII in THF (200 ml) and added to reaction mass drop wise. Allowed the reaction mass to attain ambient temperature and stirred for 2 hrs. Once reaction complies on HPLC, the reaction was quenched by adding a saturated solution (aq.) of ammonium chloride (250 ml). Organics were evaporated under vacuum and aqueous layer was extracted by ethyl acetate (300 ml x 2). Organics were combined and distilled off. Crude material was purified by column chromatography to get the compound of Formula XIV.

Yield: 65.3 g, 60%

Purity: 96.2% on HPLC

Example 8: Synthesis of (£')-2-(2,6-dimethyl-4-(3-(4-(methylsulfonyl)phenyl)-3- oxoprop-l-en-l-yl)phenoxy)-2-methylpropanoic acid of Formula XV

To a solution of compound of Formula XIV (65 g, 0.16 M, 1.0 eq.) in acetone (325 ml), Jones reagent (160 ml, 0.4 M, 2.5 eq.) was added drop wise at 0 °C. The reaction mixture was stirred for 6 hrs at ambient temperature. Precipitate formed was filtered off and the excess reagent was quenched by adding isopropyl alcohol at 0 °C. The solution was then concentrated under vacuum and extracted by ethyl acetate (500 ml x 3). The organics were combined and distilled off. Crude material obtained was purified by column chromatography to get the compound of Formula XV.

Yield: 46.8 g, 70%

Purity: 97%on HPLC

Example 9: Synthesis of Elafibranor

In a 4-neck, oven-dried 500 mL RBF was charged with tris-(pentsfluorophenyl)borane (2.32 g, 0.01 M, 10 mol%), Triethyl silane(l 16 g, 1.0 M, 10 equiv), and compound of Formula XV (41.6 g, 0.1 M, 1.0 eq.). The solution in RBF was air evacuated and heated to 100 °C for 8 h. The reaction mass was cooled to ambient temperature and passed through a small plug of silica gel using Et ₂ 0 (250 ml). The ethereal solution was dried (Na ₂ S0 ₄ ) and filtered, and the solvent was removed under reduced pressure. The mixture was then subjected to high vacuum at 70 °C until the unreacted hydrosilane was removed from the system. Cmde material was dissolved in tetrahydrofirran (200 ml) and added hexane dropwise (325 ml). The mixture was cooled to 15-20 °C. Elafibranor crystallizes out and stirred for 2 hrs. Material was filtered, suck dried and finally vacuum oven dried at 45-50 °C for 12 hrs to get compound of Formula II. Yield: 26.9 g, 70%

Purity: 99.85% on HPLC

Example 10: Synthesis of (E)-(4-(l-hydroxy-3-(4-((l-hydroxy-2-methylpropan-2- yl)oxy)-3,5-dimethylphenyl)allyl)phenyl)boronic acid of Formula XVI

In a 4-neck, 2.0 L RBF was taken THF (500 ml) and magnesium (19.4 g, 0.81 M, 3.0 eq.). Added a pinch of iodine and stirred for 15 minutes. The reaction mass was heated till THF reflux. The reaction mass was stirred for 30 min at reflux. A solution of XII (100 g, 0.27 M, 1.0 eq.) in THF (300 ml) was prepared and added drop wise into the reaction mass. Grignard reagent formation starts after 15 minutes accompanied by vigorous reflux. The reaction mass was stirred for 2 hrs at reflux. The reaction mass was cooled to 0-5 °C. Prepared a solution of 4-Formylphenylboronic acid (121.4 g, 0.81 M, 3.0 eq.) of Formula VII in THF (200 ml) and added to reaction mass drop wise. Allowed the reaction mass to attain ambient temperature and stirred for 2 hrs. Once reaction complies on HPFC, the reaction was quenched by adding a saturated solution (aq.) of ammonium chloride (250 ml). Added sodium chloride (100 g) and stirred for 30 minutes. The layers were separated and aqueous layer was further extracted by ethyl acetate (300 ml x 2). Organics were combined and distilled off. Crude material was purified by column chromatography to get the titled compound of Formula XVI. Yield: 59.8 g, 60%

Purity: 96.2% on HPFC

Example 11: Synthesis of (E)-2-(4-(3-(4-boronophenyl)-3-oxoprop-l-en-l-yl)-2,6- dimethylphenoxy)-2-methylpropanoic acid of Formula IX To a solution of compound of Formula XVI (56 g, 0.15 M, 1.0 eq.) in acetone (325 ml), Jones reagent (150 ml, 0.375 M, 2.5 eq.) was added dropwise at 0 °C. The reaction mixture was stirred for 6 hrs at ambient temperature. Precipitate formed was filtered off and the excess reagent was quenched by adding isopropyl alcohol at 0°C. The solution was then concentrated under vacuum and extracted by ethyl acetate (500 ml x 3). The organics were combined and distilled off. Crude material obtained was purified by column chromatography to get the compound of Formula IX.

Yield: 40.5 g, 70%

Purity: 97% on HPLC

Examplel2: Synthesis of Elafibranor

Compound of Formula IX (38.2 g, 0.1 M, 1.0 eq.), 1 ,2-dimethyldisulfide (18.8 g, 0.2 M, 2.0 eq.), di-tertiarybutyl peroxide (DTBP) (43.8 g, 0.3 M, 3.0 eq.), and acetonitrile (200 ml) were taken in a 5.0 L RBF. The reaction mixture was stirred at 90 °C for 12 h. After cooling to room temperature, the product was diluted with FhO (1.5L) and extracted with ethyl acetate (4 x 1.0 L). The extracts were combined and washed by brine (3 x 1.0 L) and dried over Na ₂ S0 ₄ . The mixture was filtered, and filtrate was evaporated. Crude material was dissolved in tetrahydrofuran (425 ml) and added hexane dropwise (675 ml). The mixture was cooled to 15-20 °C. Elafibranor crystallizes out and stirred for 2 hrs. Material was filtered, suck dried and finally vacuum oven dried at 45-50 °C for 12 hrs to get the compound of Formula II.

Yield: 23 g, 60%

Purity: 99.92% on HPLC

Example 13: Synthesis of vinyl 2-(4-formyl-2, 6-dime thylphenoxy)-2- methylpropanoate of Formula XIX

To 4-hydro xy-3,5-dimethylbenzaldehyde (75.1 g, 0.5 M, 1.0 eq.) of Formula XVII in a 2.0 L RBF was added acetonitrile (400 ml) and stirred for 15 minutes. Added potassium carbonate (345.5 g, 2.5 M, 5.0 eq.) followed by allyl-2-bromo-2- methylpropanoate (517.5 g, 2.5 M, 5.0 eq.) of Formula XVIII. The reaction mass was heated to 80 °C and stirred. After 24 hrs, added more of allyl-2-bromo-2- methylpropanoate (207 g, 1.0 M, 2 eq.) and stirred for 12 hrs. Added another 5 eq. of allyl-2-bromo-2-methylpropanoate (207 g, 1.0 M, 2.0 eq.) and stirred for another 12 hrs. Reaction mass was filtered and solids were washed by acetonitrile (50 ml x 2). Filtrate was collected and distilled off. The concentrated residue was degassed well for 1 hour at 5 mbar to get compound of Formula XIX.

Yield: 103.6 g, 75%

Purity: 97% on HPLC

Example 14: Synthesis of allyl (E)-2-(2,6-dimethyl-4-(3-(4-(methylthio)phenyl)-3- oxoprop-l-en-l-yl)phenoxy)-2-methylpropanoate of Formula XXI

In a 1.0 L, 4-neck RBF was charged compound of Formula XIX (99.4 g, 0.36 M, 1.0 eq.) and 4-(methylthio)acetophenone of Formula XX (59.8 g, 0.36 M, 1.0 eq.). isopropanol.HCl (1.0 L, 10% w/w) and stirred for 24 hrs at room temperature. The reaction was quenched by adding 2.0 L DM water and stirred for 30 min. Added diisopropyl ether (1.0 L) and stirred for 15 min. Layers were separated and aqueous layer was again extracted by diisopropyl ether (1.0 L x 2). Combined organic layers were collected and distilled off. Degassed material was taken in methanol (100 mL), stirred at RT for overnight. Filtered the mass and washed with methanol (25 ml). The wet material was dried under vacuum at 40-45°C to yield Formula XXI.

Yield: 122.2 g

Purity: 98% on HPLC

Example 15: Synthesis of Elafibranor

To a compound of Formula XXI (84.9 g, 0.2 M, 1.0 eq.) in dimethyl formamide (5.0 mL) was added NaOH (0.236 g, 0.006 M, 5.0 eq) and DM Water (2.0 mL) and stirred for 22 hrs at Rroom temperature. After reaction completion, as monitored by TLC, was added DM Water (10 mL) and Ethyl Acetate (10 mL) and stirred for 30 min. pH was adjusted to 5 with cone HC1 and layer separated. The ethyl acetate layer was degassed. Yield Elafibranor of Formula II. Yield: (67.92g, 89%)

Example 16: Crystalline form of Elafibranor of Formula II

In a 250 ml, 4-neck round bottomed flask was taken crude Elafibranor (10 g). To crude Elafibranor, was added 40 ml of tetrahydrofuran (THF). Added more THF to reaction mixture, till clear solution. Reaction mixture was stirred for 1 hour. Added 12V hexane (120 ml) drop wise at 20-25 °C and stirred for 2 hrs. Cooled material to 15-20 °C and stirred for 4 hrs. Material was filtered and cake was slurry washed by a 1 :3 mixture of THF: hexane (2x2 V). Cake was suck dried and crystals were dried under vacuum at 45-50 °C for 12 hrs to get 8.94g of crystalline form of Elafibranor of Formula II.

Example 17: Amorphous form of Elafibranor of Formula II

In a 250 ml, 4-neck round bottomed flask was taken crude elafibranor (10 g). To crude elafibranor, was added 30 ml of dichloromethane (DCM). Heated the reaction mixture to 35-40 °C and stirred for 1 hour. The reaction mass was cooled quickly to 0°C at 10 °C/min). Stirred for 1 hr. Material was filtered and cake was slurry washed by a diisopropyl ether (2V). Cake was suck dried under vacuum at 45-50 °C for 12 hrs to get 7.92 g of amorphous form of Elafibranor of Formula II.