WO2020079541A1 - Process for preparation of elafibranor - Google Patents

Process for preparation of elafibranor Download PDF

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Publication number
WO2020079541A1
WO2020079541A1 PCT/IB2019/058643 IB2019058643W WO2020079541A1 WO 2020079541 A1 WO2020079541 A1 WO 2020079541A1 IB 2019058643 W IB2019058643 W IB 2019058643W WO 2020079541 A1 WO2020079541 A1 WO 2020079541A1
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Prior art keywords
compound
formula
elafibranor
reacting
present
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PCT/IB2019/058643
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French (fr)
Inventor
Sushanta Mishra
Sri Hari GALLA
Abhay NIMONKAR
Samir Naik
Shekhar Bhaskar Bhirud
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Glenmark Pharmaceuticals Limited; Glenmark Life Sciences Limited
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Publication of WO2020079541A1 publication Critical patent/WO2020079541A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/27—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring having amino groups linked to the six-membered aromatic ring by saturated carbon chains
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton

Definitions

  • the present invention relates to a process for the preparation of elafibranor, optical isomers, geometric isomers, racemate, tautomers and salts thereof.
  • 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.
  • NASH non alcoholic steatohepatitis
  • the structure of elafibranor is depicted by formula
  • 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.
  • the present invention provides a process for the preparation of elafibranor, a compound of formula I, comprising:
  • the present invention provides a compound of formula IX,
  • the present invention provides a process for the preparation of a compound of formula IX,
  • Figure 1 is a characteristic XRPD of Elafibranor (I).
  • Figure 2 is 1H NMR of Elafibranor benzyl amine salt (IX).
  • the present invention provides a process wherein, elafibranor, a compound of formula I is obtained as depicted in scheme I,
  • the present invention provides a process for the preparation of elafibranor, a compound of formula I,
  • the compound of formula II may be formed by reacting acetone with chloroform in presence of an organic or an inorganic base.
  • the compound of formula II may be formed in situ by reacting acetone with chloroform in presence of an organic or an inorganic base.
  • the organic or inorganic base may be selected from the group as discussed supra.
  • 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.
  • the compound of formula IP may be reacted with the compound of formula IV,
  • the compound of formula III may be formed by reacting acetone with chloroform in presence of an organic or an inorganic base.
  • the compound of formula III may be formed in situ by reacting acetone with chloroform in presence of organic or inorganic base.
  • the organic base is selected from the group consisting of amines, organolithiums, tetraalkylammonium hydroxides, phosphonium hydroxides and the like.
  • 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.
  • the cyclic aliphatic amine is selected from the group consisting of cyclohexyl amine, dicyclohexyl amine, piperidine, piperazine and the like.
  • the trialkyl amine is selected from the group consisting of triethylamine, diisoporpylethylamine (DIPEA) and the like.
  • 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.
  • the C1-C6 aliphatic amine may be selected from the group consisting of methyl amine, propyl amine, n-butylamine and the like.
  • C6-C12 aryl alkylamine may be selected from the group consisting of benzyl amine, phenyl ethyl amine, and the like.
  • the C6-C12 aryl amine may be selected from the group consisting of aniline and the like.
  • the organolithium is selected from the group consisting of methyllithium, n-butyllihtium, t-butyllithium and the like.
  • the tetraalkylammonium hydroxide is selected from the group consisting of tetrabutylammonium hydroxide (TBAH), tetramethylammonium hydroxide and the like.
  • TBAH tetrabutylammonium hydroxide
  • tetramethylammonium hydroxide tetramethylammonium hydroxide
  • the phosphonium hydroxide is selected from the group consisting of tetrabutyl phosphonium hydroxide and the like.
  • 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.
  • 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.
  • 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.
  • 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.
  • the metal alkoxide is selected from the group consisting of sodium methoxide, potassium t-butoxide, sodium ethoxide and the like.
  • 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.
  • the compound of formula II or the compound of formula PI may be prepared by reacting acetone with chloroform in presence of a base.
  • 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.
  • 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.
  • 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.
  • 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.
  • the organic or inorganic base may be selected from the group as discussed supra.
  • the strong acid may be selected from the group consisting of hydrochloric acid, boron trifluoride, boron trioxide, p-toluene sulfonic acid and the like.
  • the compound of formula V may be reacted with the compound of formula VI in presence of hydrochloric acid.
  • 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,
  • the level of Z isomer is less than 5% w/w.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • elafibranor a compound of formula I, is purified, by the process comprising:
  • the acid used in step‘ii’ may be selected from hydrochloric acid, nitric acid, acetic acid sulfuric acid and the like.
  • the acid used in step‘ii’ may be hydrochloric acid.
  • the present invention provides elafibranor, the compound of formula I with purity of at least 99.0%, as determined by HPLC.
  • the present invention provides elafibranor, the compound of formula
  • the present invention provides elafibranor, the compound of formula I with purity of at least 99.9%, as determined by HPLC.
  • the present invention provides base addition salt of elafibranor, the compound of formula I,
  • the present invention provides a process for elafibranor, the compound of formula I,
  • the base may be selected from organic or inorganic base.
  • the organic base may be selected from the group as discussed supra.
  • 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.
  • DIPEA diisopropylethyl amine
  • the inorganic base may be selected from the group as discussed supra.
  • the present invention provides a process for elafibranor, the compound of formula I,
  • the present invention provides a process for elafibranor, a compound of formula I,
  • the present invention provides a process for elafibranor, a compound of formula I,
  • 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.
  • 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.
  • the organic solvent may be selected from the group consisting of esters, aromatic hydrocarbon, ketones, aliphatic ether and the like.
  • the ester solvent may be selected from the group consisting of ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate and the like.
  • the ketone solvent is selected from the group consisting of acetone and the like.
  • the aliphatic ether solvent is selected from the group consisting of diethyl ether, tetrahydrofuran, and the like.
  • the aromatic hydrocarbon solvent is selected from the group consisting of toluene, xylene and the like.
  • the acid may be selected from the group consisting of hydrochloric acid, acetic acid, sulfuric acid, nitric acid and the like.
  • the present invention provides a process for elafibranor, a compound of formula I,
  • 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.
  • the present invention provides a process for elafibranor, a compound of formula I,
  • 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.
  • crude elafibranor may be obtained by reacting compound of formula IV with the compound of formula II or the compound of formula III.
  • the present invention provides a benzyl amine salt of elafibranor, a compound of formula IX
  • the present invention provides a benzyl amine salt of elafibranor, a compound of formula IX
  • the present invention provides a crystalline benzyl amine salt of elafibranor, a compound of formula IX,
  • the present invention provides a process for the preparation of a compound of formula IX,
  • reaction of elafibranor, a compound of formula I, with benzyl amine may be carried out in a solvent.
  • the solvent may be selected from the group as discussed supra.
  • the solvent used in step‘a’ may be selected from the group as discussed supra.
  • reaction of elafibranor, a compound of formula I, with benzyl amine may be carried out at reflux temperature.
  • the present invention provides a process for elafibranor, the compound of formula I,
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • the present invention provides elafibranor, a compound of formula I,
  • the level of Z isomer is less than 5% w/w.
  • the present invention provides elafibranor, a compound of formula I, wherein, the level of Z isomer is less than 2% w/w.
  • the present invention provides elafibranor, a compound of formula I, wherein, the level of Z isomer is less than 1% w/w.
  • 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.
  • the present invention provides elafibranor, a compound of formula I, wherein, the Z isomer is substantially absent.
  • 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.
  • the present invention provides crystalline elafibranor, the compound of formula I,
  • XRPD X-ray powder diffraction
  • the present invention provides elafibranor, a compound of formula I,
  • the present invention provides elafibranor, a compound of formula I,
  • 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.
  • 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.
  • the present invention provides a process wherein elafibranor, a compound of formula I is obtained as depicted in scheme II,
  • 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.
  • the compound of formula VI may be reacted with the compound of formula VII,
  • 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.
  • the acid may be selected from the group as discussed supra.
  • 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.
  • the organic or inorganic base may be selected from the group as discussed supra.
  • the present invention provides a process for elafibranor, the compound of formula I,
  • elafibranor the compound of formula I obtained in step b is isolated by any method known in the art as discussed supra.
  • 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.
  • the present invention provides a compound of formula VII,
  • HPLC High performance liquid chromatography
  • Example 2 2-(2,6-dimethyl-4- ⁇ (lE)-3-[4-(methylsulfanyl)phenyl]-3-oxoprop-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.
  • chloroform 4.4g, 0.036mol
  • acetone was removed under vacuum. The residue was dissolved in water (lOOml), acidified with hydrochloric acid (HC1) and extracted with ethyl acetate.
  • 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.
  • acetone was removed under vacuum to afford a residue which was dissolved in water; acidified with hydrochloric acid and extracted with ethyl acetate.
  • 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.
  • 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.
  • 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.
  • 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.

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Abstract

The present invention provides a process for elafibranor, the process comprising reacting compound of formula II or the compound of formula III with a compound of formula IV. The present invention also involve purification of elafibranor by reacting elafibranor with benzyl amine to form compound of formula IX and treating compound of formula IX with acid to form elafibranor.

Description

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,
Figure imgf000002_0001
[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,
Figure imgf000003_0001
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,
Figure imgf000003_0002
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,
Figure imgf000003_0003
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,
Figure imgf000003_0004
comprising:
a) reacting elafibranor, a compound of formula I,
Figure imgf000004_0001
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,
Figure imgf000004_0002
Scheme I.
[0012] In one embodiment, the present invention provides a process for the preparation of elafibranor, a compound of formula I,
Figure imgf000004_0003
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,
Figure imgf000005_0001
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,
Figure imgf000005_0002
II may be reacted with the compound of formula IV,
Figure imgf000005_0003
optionally in presence of a base, to obtain elafibranor, the compound of formula I,
Figure imgf000005_0004
[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,
Figure imgf000006_0001
may be reacted with the compound of formula IV,
Figure imgf000006_0002
to obtain elafibranor, the compound of formula I,
Figure imgf000006_0003
[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,
Figure imgf000008_0001
may be reacted with the compound of formula VI,
Figure imgf000008_0002
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,
Figure imgf000009_0001
may be reacted with the compound of formula VI,
Figure imgf000009_0002
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,
Figure imgf000009_0003
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,
Figure imgf000010_0001
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,
Figure imgf000010_0002
with benzyl amine to form a compound of formula IX,
Figure imgf000010_0003
and
ii) treating the compound of formula IX with an acid to form elafibranor, the compound of formula
I,
Figure imgf000011_0001
[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,
Figure imgf000011_0002
[0062] In one embodiment, the present invention provides a process for elafibranor, the compound of formula I,
Figure imgf000011_0003
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,
Figure imgf000012_0001
[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,
Figure imgf000012_0002
comprising:
a) reacting elafibranor, the compound of formula I, with sodium hydroxide to form sodium salt of elafibranor, a compound of formula VIII,
Figure imgf000012_0003
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,
Figure imgf000013_0001
comprising:
a) reacting elafibranor, the compound of formula I, with benzyl amine to form benzyl amine salt of elafibranor, a compound of formula IX,
Figure imgf000013_0002
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,
Figure imgf000013_0003
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,
Figure imgf000014_0001
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,
Figure imgf000014_0002
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
Figure imgf000015_0001
[0081] In one embodiment, the present invention provides a benzyl amine salt of elafibranor, a compound of formula IX
Figure imgf000015_0002
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,
Figure imgf000015_0003
[0083] The present invention provides a process for the preparation of a compound of formula IX,
Figure imgf000016_0001
comprising the steps of:
a) reacting elafibranor, a compound of formula I,
Figure imgf000016_0003
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,
Figure imgf000016_0002
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,
Figure imgf000017_0001
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,
Figure imgf000017_0002
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,
Figure imgf000018_0001
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,
Figure imgf000018_0002
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,
Figure imgf000018_0003
wherein, the level of one or more impurities represented by A, B, C, and D,
Figure imgf000019_0001
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 &
Figure imgf000020_0001
Scheme II.
[0107] In one embodiment, a compound of formula VII,
Figure imgf000020_0002
is obtained by reacting the compound of formula II,
Figure imgf000020_0003
II
or the compound of formula III,
Figure imgf000020_0004
with the compound of formula V,
Figure imgf000021_0001
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,
Figure imgf000021_0002
may be reacted with the compound of formula VII,
Figure imgf000021_0003
to obtain elafibranor, the compound of formula I,
Figure imgf000021_0004
[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,
Figure imgf000022_0001
comprising the steps of:
a) reacting a compound of formula II or a compound of formula IP, with a compound of formula
V,
Figure imgf000022_0002
and
b) reacting a compound of formula VI with a compound of formula VII,
Figure imgf000022_0003
to obtain elafibranor, the compound of formula I,
Figure imgf000022_0004
[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,
Figure imgf000023_0001
[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-oxoprop-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-oxoprop-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-methylpropanoic 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):
Figure imgf000026_0001

Claims

Claims
1. A process for the preparation of elafibranor, a compound of formula I,
Figure imgf000027_0001
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,
Figure imgf000027_0002
optionally, in presence of a base in a solvent;
and
b) optionally, purifying elafibranor, the compound of formula I.
2. The process according to claim 1, wherein the compound of formula IV,
Figure imgf000027_0003
is obtained by reacting a compound of formula V with a compound of formula VI,
Figure imgf000027_0004
3. The process according to claim 1, wherein the compound of formula II or the compound of formula III is prepared by reacting acetone with chloroform in presence of a base.
4. The process according to claim 1 , wherein the compound of formula II or the compound of III is formed in situ by reacting acetone with chloroform in presence of a base.
5. The process according to claim 3, wherein the base is 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.
6. The process according to claim 1, wherein 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
Figure imgf000028_0001
and
ii) treating the compound of formula IX with an acid to form elafibranor, the compound of formula
I,
Figure imgf000028_0002
7. The process according to claim 6, wherein the acid used in step‘ii’ is hydrochloric acid.
8. A compound of formula IX,
Figure imgf000028_0003
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.
9. The process according to claim 6, 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.
10. A process for the preparation of a compound of formula IX,
Figure imgf000029_0001
comprising:
a) reacting elafibranor, a compound of formula I,
Figure imgf000029_0002
with benzyl amine to obtain the compound of formula IX; and
b) isolating the compound of formula IX.
PCT/IB2019/058643 2018-10-16 2019-10-10 Process for preparation of elafibranor WO2020079541A1 (en)

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Citations (1)

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Publication number Priority date Publication date Assignee Title
CN106674069A (en) * 2016-12-06 2017-05-17 上海博志研新药物技术有限公司 GFT505 and preparation method for intermediate thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106674069A (en) * 2016-12-06 2017-05-17 上海博志研新药物技术有限公司 GFT505 and preparation method for intermediate thereof

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Title
M.R. SAIDI: "Dithiocarbamic acids and thiols as nucleophiles in the Bargellini reaction", SCIENTIA IRANICA, 2 May 2012 (2012-05-02), pages 302, XP055703337, Retrieved from the Internet <URL:https://doi.org/10.1016/j.scient.2011.09.021> *

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