PROCESS FOR PREPARATION OF ELAFIBRANOR

PRIORITY

[0001] This application claims the benefit to Indian provisional application Nos. 201821039151, filed on 16 October, 2018 and 201821049557, filed on 28 December, 2018, the contents of which are incorporated by reference herein.

FIELD OF THE INVENTION

[0002] The present invention relates to a process for the preparation of elafibranor, optical isomers, geometric isomers, racemate, tautomers and salts thereof.

BACKGROUND OF THE INVENTION

[0003] Elafibranor is a selective PPAR modulator, with preferential action on the PARP alpha receptor family. The product is in phase III clinical trials at Genfit for the treatment of non alcoholic steatohepatitis (NASH) with fibrosis. The structure of elafibranor is depicted by formula

I,

[0004] The process for preparation of elafibranor known in the art involve additional steps of protection and deprotection of acid functional group present in elafibranor, which increases the cost of the process. There is a need in the art, therefore, for industrially applicable process which avoids additional steps.

[0005] The present invention provides a novel process for elafibranor, a compound of formula I, which is industrially feasible and does not involve additional steps of protection deprotection of acid functional group.

SUMMARY OF THE INVENTION

[0006] The present invention provides a process for the preparation of elafibranor, a compound of formula I, comprising:

a) reacting a compound of formula II or a compound of formula III with a compound of formula IV, to obtain elafibranor, a compound of formula I,

optionally, in presence of a base in a solvent; and

b) optionally, purifying elafibranor, the compound of formula I.

[0007] In one embodiment, the present invention provides a compound of formula IX,

characterized by 1H NMR having characteristic peaks at d ppm: 1.32, 2.25, 2.56, 3.94, 7.30-7.51, 7.60-7.64, 7.71-7.80, 8.08-8.11.

[0008] In another embodiment, the present invention provides a process for the preparation of a compound of formula IX,

comprising:

a) reacting elafibranor, a compound of formula I, with benzyl amine to obtain the compound of formula IX; and

b) isolating the compound of formula IX.

BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Figure 1 is a characteristic XRPD of Elafibranor (I).

[0010] Figure 2 is 1H NMR of Elafibranor benzyl amine salt (IX).

DETAILED DESCRIPTION OF THE INVENTION

[0011] In one embodiment, the present invention provides a process wherein, elafibranor, a compound of formula I is obtained as depicted in scheme I,

Scheme I.

[0012] In one embodiment, the present invention provides a process for the preparation of elafibranor, a compound of formula I,

comprising: a) reacting a compound of formula II or a compound of formula III with a compound of formula IV, to obtain elafibranor, a compound of formula I,

optionally, in presence of a base in a solvent; and

b) optionally, purifying elafibranor, the compound of formula I.

[0013] In one embodiment, the compound of formula II,

II may be reacted with the compound of formula IV,

optionally in presence of a base, to obtain elafibranor, the compound of formula I,

[0014] In one embodiment, the compound of formula II may be formed by reacting acetone with chloroform in presence of an organic or an inorganic base.

[0015] In one embodiment, the compound of formula II may be formed in situ by reacting acetone with chloroform in presence of an organic or an inorganic base.

[0016] In one embodiment, the organic or inorganic base may be selected from the group as discussed supra. [0017] In one embodiment, the base may be selected from the group consisting of an organic base such as amines; an inorganic base such as metal carbonate, metal bicarbonate, metal hydroxides and metal alkoxides.

[0018] In one embodiment, the compound of formula IP, may be reacted with the compound of formula IV,

to obtain elafibranor, the compound of formula I,

[0019] In one embodiment, the compound of formula III may be formed by reacting acetone with chloroform in presence of an organic or an inorganic base.

[0020] In one embodiment, the compound of formula III may be formed in situ by reacting acetone with chloroform in presence of organic or inorganic base.

[0021] In one embodiment, the organic base is selected from the group consisting of amines, organolithiums, tetraalkylammonium hydroxides, phosphonium hydroxides and the like.

[0022] In one embodiment, the amine is selected from the group consisting of cyclic aliphatic amine, trialkyl amines, heterocyclic amine, C1-C6 aliphatic amine, C6-C12 aryl alkyl amines, C6- C12 aryl amines and the like.

[0023] In one embodiment, the cyclic aliphatic amine is selected from the group consisting of cyclohexyl amine, dicyclohexyl amine, piperidine, piperazine and the like.

[0024] In one embodiment, the trialkyl amine is selected from the group consisting of triethylamine, diisoporpylethylamine (DIPEA) and the like. [0025] In one embodiment, the heterocyclic amine is selected from the group consisting of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (Dabco) pyridine, pyrimidine, 4-(dimethylamino)pyridine (DMAP) and the like.

[0026] In one embodiment, the C1-C6 aliphatic amine may be selected from the group consisting of methyl amine, propyl amine, n-butylamine and the like.

[0027] In one embodiment, C6-C12 aryl alkylamine may be selected from the group consisting of benzyl amine, phenyl ethyl amine, and the like.

[0028] In one embodiment, the C6-C12 aryl amine may be selected from the group consisting of aniline and the like.

[0029] In one embodiment, the organolithium is selected from the group consisting of methyllithium, n-butyllihtium, t-butyllithium and the like.

[0030] In one embodiment, the tetraalkylammonium hydroxide is selected from the group consisting of tetrabutylammonium hydroxide (TBAH), tetramethylammonium hydroxide and the like.

[0031] In one embodiment, the phosphonium hydroxide is selected from the group consisting of tetrabutyl phosphonium hydroxide and the like.

[0032] In one embodiment, the inorganic base is selected from the group consisting of metal carbonate, metal bicarbonate, metal hydroxide and metal alkoxides wherein the metal is selected from the group consisting of sodium, potassium, lithium, calcium, cesium or magnesium.

[0033] In one embodiment, the metal carbonate is selected from the group consisting of sodium carbonate, potassium carbonate, lithium carbonate, calcium carbonate, cesium carbonate, magnesium carbonate and the like.

[0034] In one embodiment, the metal bicarbonate is selected from the group consisting of sodium bicarbonate, potassium bicarbonate, lithium bicarbonate, calcium bicarbonate, cesium bicarbonate, magnesium bicarbonate and the like.

[0035] In one embodiment, the metal hydroxide is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, cesium hydroxide, magnesium hydroxide and the like.

[0036] In one embodiment, the metal alkoxide is selected from the group consisting of sodium methoxide, potassium t-butoxide, sodium ethoxide and the like. [0037] In one embodiment, the base may be selected from the group consisting of an organic base such as amines; an inorganic base such as metal carbonate, metal bicarbonate, metal hydroxides and metal alkoxides.

[0038] In one embodiment, the compound of formula II or the compound of formula PI may be prepared by reacting acetone with chloroform in presence of a base.

[0039] In one embodiment, the compound of formula II or the compound of III may be formed in situ by reacting acetone with chloroform in presence of a base.

[0040] In one embodiment, elafibranor the compound of formula I obtained in step‘b’ is isolated by any method known in the art. The method, may involve any of the techniques, known in the art, including filtration by gravity or by suction, centrifugation, and the like, evaporation by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying, agitated nutsche filter dryer, complete evaporation in, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum, or concentrating the solution, cooling the solution if required and filtering the obtained solid by gravity or by suction, centrifugation, and the like.

[0041] In one embodiment, the compound of formula V,

may be reacted with the compound of formula VI,

VI in presence of an organic or an inorganic base, to obtain a compound of formula IV.

[0042] In one embodiment, the compound of formula V may be reacted with the compound of formula VI at a temperature in the range of about 0°C to about l00°C.

[0043] In one embodiment, the compound of formula V may be reacted with the compound of formula VI at a temperature in the range at about 20°C to about 40°C. [0044] In one embodiment, the organic or inorganic base may be selected from the group as discussed supra.

[0045] In one embodiment, the compound of formula V,

may be reacted with the compound of formula VI,

in presence of a strong acid to obtain a compound of formula IV.

[0046] In one embodiment, the strong acid may be selected from the group consisting of hydrochloric acid, boron trifluoride, boron trioxide, p-toluene sulfonic acid and the like.

[0047] In one embodiment, the compound of formula V may be reacted with the compound of formula VI in presence of hydrochloric acid.

[0048] In one embodiment, the present invention provides (2E)-3-(4-hydroxy-3,5- dimethylphenyl)-l-[4-(methylsulfanyl)phenyl]prop-2-en-l-one, a compound of formula IV,

wherein, the level of Z isomer is less than 5% w/w.

[0049] In one embodiment, the present invention provides (2E)-3-(4-hydroxy-3,5- dimethylphenyl)-l-[4-(methylsulfanyl)phenyl]prop-2-en-l-one, a compound of formula IV, wherein, the level of Z isomer is less than 2% w/w.

[0050] In one embodiment, the present invention provides (2E)-3-(4-hydroxy-3,5- dimethylphenyl)-l-[4-(methylsulfanyl)phenyl]prop-2-en-l-one, a compound of formula IV, wherein, the level of Z isomer is less than 1% w/w. [0051] In one embodiment, the present invention provides (2E)-3-(4-hydroxy-3,5- dimethylphenyl)-l-[4-(methylsulfanyl)phenyl]prop-2-en-l-one, a compound of formula IV, wherein, the level of Z isomer is less than 0.5% w/w.

[0052] In one embodiment, the present invention provides (2E)-3-(4-hydroxy-3,5- dimethylphenyl)-l-[4-(methylsulfanyl)phenyl]prop-2-en-l-one, a compound of formula IV, wherein, the level of Z isomer is less than 0.1% w/w.

[0053] In one embodiment, the present invention provides (2E)-3-(4-hydroxy-3,5- dimethylphenyl)-l-[4-(methylsulfanyl)phenyl]prop-2-en-l-one, a compound of formula IV, wherein, the Z isomer is substantially absent.

[0054] In one embodiment, the present invention provides, (2E)-3-(4-hydroxy-3,5- dimethylphenyl)-l-[4-(methylsulfanyl)phenyl]prop-2-en-l-one, a compound of formula IV,

characterized by 1H NMR having characteristic peaks at d ppm: 2.30 (6H), 2.55 (3H), 7.31 (4H), 7.4 (1H), 7.75 (1H), 7.97 (2H).

[0055] In one embodiment, elafibranor, a compound of formula I, is purified, by the process comprising:

i) reacting elafibranor, a compound of formula I,

with benzyl amine to form a compound of formula IX,

and

ii) treating the compound of formula IX with an acid to form elafibranor, the compound of formula

I,

[0056] In one embodiment, the acid used in step‘ii’ may be selected from hydrochloric acid, nitric acid, acetic acid sulfuric acid and the like.

[0057] In one embodiment, the acid used in step‘ii’ may be hydrochloric acid.

[0058] In one embodiment, the present invention provides elafibranor, the compound of formula I with purity of at least 99.0%, as determined by HPLC.

[0059] In one embodiment, the present invention provides elafibranor, the compound of formula

I with purity of at least 99.5%, as determined by HPLC.

[0060] In one embodiment, the present invention provides elafibranor, the compound of formula I with purity of at least 99.9%, as determined by HPLC.

[0061] In one embodiment, the present invention provides base addition salt of elafibranor, the compound of formula I,

[0062] In one embodiment, the present invention provides a process for elafibranor, the compound of formula I,

comprising: a) reacting elafibranor, the compound of formula I with a base to form base addition salt of elafibranor; and

b) treating base addition salt of elafibranor with an acid to form elafibranor, the compound of formula I,

[0063] In one embodiment, the base may be selected from organic or inorganic base.

[0064] In one embodiment, the organic base may be selected from the group as discussed supra.

[0065] In one embodiment, the organic base may be selected from the group consisting of benzyl amine, phenyl ethyl amine, dicyclohexyl amine, cyclohexyl amine, piperidine, piperazine, aniline, diisopropylethyl amine (DIPEA) and the like.

[0066] In one embodiment, the inorganic base may be selected from the group as discussed supra.

[0067] In one embodiment, the present invention provides a process for elafibranor, the compound of formula I,

comprising:

a) reacting elafibranor, the compound of formula I, with sodium hydroxide to form sodium salt of elafibranor, a compound of formula VIII,

and

b) reacting sodium salt of elafibranor with an acid to form elafibranor the compound of formula I. [0068] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I,

comprising:

a) reacting elafibranor, the compound of formula I, with benzyl amine to form benzyl amine salt of elafibranor, a compound of formula IX,

and

b) reacting benzyl amine salt of elafibranor, the compound of formula IX with an acid to form elafibranor the compound of formula I.

[0069] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I,

wherein, elafibranor, the compound of formula I is isolated by dissolving inorganic salt of elafibranor in water, treating with acid, extracting in organic solvent followed by removal of the solvent.

[0070] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I, wherein, elafibranor, the compound of formula I is isolated by dissolving sodium salt of elafibranor in water, treating with acid, extracting in organic solvent followed by removal of the solvent. [0071] In one embodiment, the organic solvent may be selected from the group consisting of esters, aromatic hydrocarbon, ketones, aliphatic ether and the like.

[0072] In one embodiment, the ester solvent may be selected from the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate and the like.

[0073] In one embodiment, the ketone solvent is selected from the group consisting of acetone and the like.

[0074] In one embodiment, the aliphatic ether solvent is selected from the group consisting of diethyl ether, tetrahydrofuran, and the like.

[0075] In one embodiment, the aromatic hydrocarbon solvent is selected from the group consisting of toluene, xylene and the like.

[0076] In one embodiment, the acid may be selected from the group consisting of hydrochloric acid, acetic acid, sulfuric acid, nitric acid and the like.

[0077] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I,

wherein, elafibranor, the compound of formula I is isolated by reacting crude elafibranor, the compound of formula I, with organic amine, treating the organic amine salt of elafibranor with inorganic base, then acid; extracting in organic solvent followed by removal of the solvent.

[0078] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I,

wherein, elafibranor, the compound of formula I is isolated by reacting crude elafibranor, the compound of formula I, with benzyl amine, treating the benzyl amine salt of elafibranor, a compound of formula IX, with sodium hydroxide, then with acid; extracting in organic solvent followed by removal of the solvent.

[0079] In one embodiment, crude elafibranor may be obtained by reacting compound of formula IV with the compound of formula II or the compound of formula III.

[0080] In one embodiment, the present invention provides a benzyl amine salt of elafibranor, a compound of formula IX

[0081] In one embodiment, the present invention provides a benzyl amine salt of elafibranor, a compound of formula IX

characterized by 1H NMR having characteristic peaks at d ppm: 1.32 (s, 6H), 2.25 (s, 6H), 2.56

(s, 3H), 3.94 (s, 2H), 7.30-7.51 (m, 9H), 7.60-7.64 (d, 1H), 7.71-7.80 (d, 1H), 8.08-8.11 (d, 2H).

[0082] In one embodiment, the present invention provides a crystalline benzyl amine salt of elafibranor, a compound of formula IX,

[0083] The present invention provides a process for the preparation of a compound of formula IX,

comprising the steps of:

a) reacting elafibranor, a compound of formula I,

with benzyl amine to obtain the compound of formula IX; and

b) isolating the compound of formula IX.

[0084] In one embodiment, reaction of elafibranor, a compound of formula I, with benzyl amine may be carried out in a solvent.

[0085] In one embodiment, the solvent may be selected from the group as discussed supra.

[0086] In one embodiment, the solvent used in step‘a’ may be selected from the group as discussed supra.

[0087] In one embodiment, the reaction of elafibranor, a compound of formula I, with benzyl amine may be carried out at reflux temperature.

[0088] In one embodiment, the present invention provides a process for elafibranor, the compound of formula I,

wherein, elafibranor, the compound of formula I is obtained in geometrically pure form.

[0089] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I, wherein, elafibranor, the compound of formula I is obtained in E isomeric form wherein, the level of Z isomer is less than 5% w/w.

[0090] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I wherein, the level of Z isomer in the obtained elafibranor, a compound of formula I, is less than 2% w/w of elafibranor, the compound of formula I.

[0091] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I wherein, the level of Z isomer in the obtained elafibranor, a compound of formula I, is less than 1% w/w of elafibranor, the compound of formula I.

[0092] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I wherein, the level of Z isomer in the obtained elafibranor, a compound of formula I, is less than 0.5% w/w of elafibranor, the compound of formula I.

[0093] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I wherein, the level of Z isomer in the obtained elafibranor, a compound of formula I, is less than 0.1% w/w of elafibranor, the compound of formula I.

[0094] In one embodiment, the present invention provides elafibranor, a compound of formula I,

wherein, the level of Z isomer is less than 5% w/w.

[0095] In one embodiment, the present invention provides elafibranor, a compound of formula I, wherein, the level of Z isomer is less than 2% w/w.

[0096] In one embodiment, the present invention provides elafibranor, a compound of formula I, wherein, the level of Z isomer is less than 1% w/w.

[0097] In one embodiment, the present invention provides elafibranor, a compound of formula I, wherein, the level of Z isomer is less than 0.5% w/w. [0098] In one embodiment, the present invention provides elafibranor, a compound of formula I, wherein, the level of Z isomer is less than 0.1% w/w.

[0099] In one embodiment, the present invention provides elafibranor, a compound of formula I, wherein, the Z isomer is substantially absent.

[0100] In one embodiment, the present invention provides a process for elafibranor, the compound of formula I, wherein, elafibranor, the compound of formula I is obtained in racemic form.

[0101] In one embodiment, the present invention provides crystalline elafibranor, the compound of formula I,

characterized by X-ray powder diffraction (XRPD) spectrum having characteristic peak reflections at about 10.7, 15.04, 17.11, 17.27 and 23.66± 0.2° 2Q.

[0102] In one embodiment, the present invention provides elafibranor, a compound of formula I,

characterized by 1H NMR having characteristic peaks at d ppm: 1.55, 2.29, 2.55, 7.31 (J= 8.55Hz), 7.44, 7.73 (J= l 5.5Hz), 7.97 (J= 8.55Hz), 12.97.

[0103] In one embodiment, the present invention provides elafibranor, a compound of formula I,

wherein, the level of one or more impurities represented by A, B, C, and D,

is less than 0.15% w/w, as determined by HPLC.

[0104] In one embodiment, the present invention provides elafibranor, a compound of formula I with purity of at least 99.0% wherein, the level of one or impurities represented by A, B, C, and D, is less than 0.15% w/w, as determined by HPLC.

[0105] In one embodiment, the present invention provides elafibranor, optical isomers, geometric isomers, racemate, tautomers, salt or solvate thereof, the compound of formula I, obtained by the processes herein described, having a D10, D50 and D90 particle size of less than about 250 microns, preferably less than about 150 microns, preferably less than about 100 microns, more preferably less than about 50 microns, still more preferably less than about 30 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 elafibranor or salt, solvate thereof into any of the foregoing desired particle size range.

[0106] In one embodiment, the present invention provides a process wherein elafibranor, a compound of formula I is obtained as depicted in scheme II,

Acetone, base &

Scheme II.

[0107] In one embodiment, a compound of formula VII,

is obtained by reacting the compound of formula II,

II

or the compound of formula III, with the compound of formula V, optionally in presence of a base.

[0108] In one embodiment, the compound of formula II or the compound of formula PI may be formed in situ by reacting acetone with chloroform in presence of an organic or an inorganic base. In one embodiment, the compound of formula VI, may be reacted with the compound of formula VII,

to obtain elafibranor, the compound of formula I,

[0109] In one embodiment, the compound of formula VI may reacted with the compound of formula VII to obtain elafibranor, the compound of formula I, in presence of a strong acid.

[0110] In one embodiment, the acid may be selected from the group as discussed supra.

[0111] In one embodiment, the formula VI may reacted with the compound of formula VII to obtain elafibranor, the compound of formula I, in presence of an organic or an inorganic base.

[0112] In one embodiment the organic or inorganic base may be selected from the group as discussed supra. [0113] In one embodiment, the present invention provides a process for elafibranor, the compound of formula I,

comprising the steps of:

a) reacting a compound of formula II or a compound of formula IP, with a compound of formula

V,

and

b) reacting a compound of formula VI with a compound of formula VII,

to obtain elafibranor, the compound of formula I,

[0114] In one embodiment, elafibranor the compound of formula I obtained in step b is isolated by any method known in the art as discussed supra.

[0115] In one embodiment, the present invention provides a process for elafibranor, a compound of formula I, wherein, elafibranor, a compound of formula I, is purified by any method known in the art. The method, may involve any of the techniques, known in the art, including recrystallization, column chromatography, extraction, filtration, slurrying in solvent, precipitation from a solvent, and the like.

[0116] In one embodiment, the present invention provides a compound of formula VII,

[0117] X-ray powder diffraction profiles were obtained using an X-ray diffractometer (Philips X’Pert Pro, PANalytical). The measurements were carried out with a Pre FIX module programmable divergence slit and anti-scatter Slit (Offset 0.00°) ; target, Cu; filter, Ni; detector, X’Celerator; Scanning Mode; Active length (2Q) = 2.122°; generator 45KV; tube current 40mAmp. The samples were scanned in the full 2Q range of 2-50° with a“time-per-step” optimized to 50 sec.

[0118] High performance liquid chromatography (HPLC) was performed for detecting purity and the percentage of Z-isomer present in the elafibranor.

[0119] 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 feature and advantages.

Examples

[0120] Example 1: Preparation of (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-l-[4-

(methylsulfanyl)phenyl]prop-2-en-l-one (IV)

A solution of 4'-(methylthio)acetophenone (lO.Og, 0.06mol) and 4-hydroxy-3,5- dimethylbenzaldehyde (9.0 g, 0.06mol) in saturated hydrogen chloride isopropanol (lOOml) was stirred at about 0°C to about 5°C for about 6h; then raised the temperature to about 20°C to about 30°C and stirred for about l8h. After completion of the reaction, water was added to the reaction mass and stirred for about 2h to about 3h. The precipitated solid was filtered and recrystallized from isopropanol to afford (2E)-3-(4-hydroxy-3,5-dimethylphenyl)-l-[4- (methylsulfanyl)phenyl]prop-2-en-l-one as a yellow solid (compound IV; l6.0g) m/z = 299 (M+l) ¾ NMR CDCh d ppm: 2.30 (6H), 2.55 (3H), 7.31 (4H), 7.4 (1H), 7.75 (1H), 7.97 (2H).

[0121] Example 2: 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3-oxopr op-l-en-l- yl}phenoxy)-2-methylpropanoic acid (Elafibranor, I)

Pulverized sodium hydroxide (13.2g, 0.33mol) was added to a suspension of compound IV (lO.Og, 0.033mol) in acetone (lOOml). The reaction mixture was stirred at about 0°C to about 5°C for about 30min; chloroform (4.4g, 0.036mol) was added drop wise over the course of about 30min and stirred overnight at about 20°C to about 25°C. After completion of reaction, acetone was removed under vacuum. The residue was dissolved in water (lOOml), acidified with hydrochloric acid (HC1) and extracted with ethyl acetate. The organic layer was separated and concentrated under vacuum to obtain the crude product which was purified by column chromatography to furnish 2-(2,6- dimethyl-4- {( 1 E)-3 - [4-(methylsulfanyl)phenyl] -3 -oxoprop- 1 -en- 1 -yl} phenoxy)-2- methylpropanoic acid elafibranor (I) as a pale yellow solid of (7.0 g, 55% yield; purity>99%) ' H NMR CDCh d ppm: 1.55 (s, 6H), 2.29 (s, 6H), 2.55 (s, 3H), 7.31 (d, J= 8.55Hz, 2H), 7.44 (s, 2H), 7.73 (d, J= 15.5Hz, 1H), 7.97 (d, J= 8.55Hz, 2H), 12.97 (s, 1H) MS (ES-MS): 383.3 (M-l)

[0122] Example 3: Preparation of 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3- oxoprop-l-en-l-yl}phenoxy)-2-methylpropanoic acid (Elafibranor, I)

l,l,l-trichloro-2-methylpropan-2-ol (8.8g, 0.05mol) was added to a suspension of compound IV (lO.Og, 0.033mol) in acetone (lOOml). The reaction mixture was stirred at about 0°C to about 5°C for about 30min and pulverized sodium hydroxide (6.6g, O. l65mol) was added in lots over the course of about 3h. The reaction mixture was stirred overnight at about 20°C to about 25°C. After completion of the reaction, acetone was removed under vacuum to afford a residue which was dissolved in water; acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was separated and concentrated under vacuum to yield the crude product which was purified by column chromatography to furnish 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3- oxoprop-l-en-l-yl}phenoxy)-2-methylpropanoic acid (elafibranor, I) as a pale yellow solid (7.0 g, 55% yield; punty>99%) 1H NMR CDCh d ppm: 1.55 (s, 6H), 2.29 (s, 6H), 2.55 (s, 3H), 7.31 (d, J = 8.55Hz, 2H), 7.44 (s, 2H), 7.73 (d); , J = 15.5Hz, 1H), 7.97 (d, J = 8.55Hz, 2H), 12.97 (s, 1H).

[0123] Example 4: Preparation of 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3- oxoprop-l-en-l-yl}phenoxy)-2-methylpropanoic acid (Elafibranor, I)

l,l,l-trichloro-2-methylpropan-2-ol (8.8g, 0.05mol) was added to a suspension of compound IV (10. Og, 0.033mol) in acetone (lOOml). The reaction mixture was stirred at about 0°C to about 5°C for about 30min and pulverized sodium hydroxide (6.6g, 0. l65mol) was added in lots over the course of about 3h. The reaction mixture was stirred overnight at about 20°C to about 25°C. After completion of the reaction, acetone was removed under vacuum to afford a residue which was dissolved in water; acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was separated and concentrated under vacuum to yield crude oil. The crude oil was dissolved in ethyl acetate, benzyl amine (3.94 g, 0.036mmol) was added to it, refluxed for about lh and stirred overnight. The solid obtained was filtered, washed with ethyl acetate and dried in air oven. The dry solid was added in water, basified using aq sodium hydroxide under stirring. The reaction mass was washed with dichloromethane, distilled to remove traces of dichloromethane and acidified using dil. Hydrochloric acid under stirring. The solid was filtered, washed with water and dried in an air oven to obtain 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3-oxopr op-l- en-l-yl}phenoxy)-2-methylpropanoic acid (elafibranor, I) as a pale yellow solid (7.6 g, 59% yield; purity >99.5%; Z-isomer less than 2% w/w) 1H NMR CDCh d ppm: 1.55 (s, 6H), 2.29 (s, 6H), 2.55 (s, 3H), 7.31 (d, J = 8.55Hz, 2H), 7.44 (s, 2H), 7.73 (d); , J = 15.5Hz, 1H), 7.97 (d, J = 8.55Hz, 2H), 12.97 (s, 1H). [0124] Example 5: Preparation of 2-(2,6-dimethyl-4-{(lE)-3-[4-(methylsulfanyl)phenyl]-3- oxoprop-l-en-l-yl}phenoxy)-2-methylpropanoic acid (Elafibranor, I)

l,l,l-trichloro-2-methylpropan-2-ol (8.8g, 0.05mol) was added to a suspension of compound IV (10. Og, 0.033mol) in acetone (lOOml). The reaction mixture was stirred at about 0°C to about 5°C for about 30min and pulverized sodium hydroxide (6.6g, 0. l65mol) was added in lots over the course of about 3h. The reaction mixture was stirred overnight at about 20°C to about 25°C. After completion of the reaction, acetone was removed under vacuum to afford a residue which was dissolved in water; acidified with hydrochloric acid and extracted with ethyl acetate. The organic layer was separated and concentrated under vacuum to yield crude oil. The crude oil was dissolved in ethyl acetate, benzyl amine (3.94 g, 0.036mmol) was added to it, refluxed for about lh and stirred overnight. The solid obtained was filtered, washed with ethyl acetate and dried in air oven. The dry solid was added in water, acidified using dil. Hydrochloric acid under stirring. The solid was filtered, washed with water and dried in an air oven to obtain 2-(2,6-dimethyl-4-{(lE)-3-[4- (methylsulfanyl)phenyl]-3-oxoprop-l-en-l-yl}phenoxy)-2-methy lpropanoic acid (elafibranor, I) as a pale yellow solid (7.4 g, 57% yield; purity >99.5%; Z-isomer less than 2% w/w) 1H NMR CDCh d ppm: 1.55 (s, 6H), 2.29 (s, 6H), 2.55 (s, 3H), 7.31 (d, J = 8.55Hz, 2H), 7.44 (s, 2H), 7.73 (d); , J = 15.5Hz, 1H), 7.97 (d, J = 8.55Hz, 2H), 12.97 (s, 1H).

XRD peaks of Elafibranor (I):