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1. (WO2019025017) PROCESS FOR THE PREPARATION OF ELAFIBRANOR AND NOVEL SYNTHESIS INTERMEDIATES
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Claims

1. A process for the preparation of elafibranor which comprises:

a. mixing com ounds (II) and (III)


(II)

wherein

X is an alkali— or a alkali-earth metal

R is -CHO or


wherein the dotted line indicates the bond by which said group is linked to the remaining part of the molecule; in an aprotic solvent, which is optionally in admixture with a protic co-solvent, in the presence of a strong base;

preferably heating the mixture of step (a) and, when R is -CHO, adding 4' (methylthio)acetophenone of formula V)


to the mixture;

c. acidifying the mixture after step (b) with an acidic solution to achieve elafibranor; and

d. optionally isolating and optionally purifying elafibranor thus obtained. A one-pot process comprising the following steps:

a', in an aprotic solvent comprising compound (II) or (Ila),

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optionally in the presence of a protic co-solvent and in the presence of a strong base, preferably sodium or potassium hydroxide,;

b'. preferably heating the mixture and adding (III) and, when R is -CHO, also (V);

c'. acidifying the mixture after step (b') with an acidic solution to achieve elafibranor; and

d'. optionally isolating and optionally purifying elafibranor thus obtained. The process according to claims 1 or 2, characterized in that step (b) and (b') are carried out at a temperature of 20 to 70°C, preferably of 45 to 60°C, more preferably of 50 to 55°C.

The process according to claims 2 or 3, characterized in that it comprises:

a" . dissolving a compound of formula Ila)


wherein R is as defined in claim 1, in an aprotic solvent, optionally in the presence of a protic co-solvent and in the presence of a strong base preferably selected from sodium hydroxide and potassium hydroxide, to obtain the compound of formula (II) as defined in claim 1 ;

heating the mixture of step (a") at a temperature of 20 to 70°C, preferably of 45 to 60°C, more preferably of 50 to 55°C, and adding a solution of 2-halo-2-methylpropanoic acid (III), when R is -CHO, also 4'-(methylthio)acetophenone (V);

acidifying the mixture after step (b") with an acidic solution to achieve elafibranor, and

optionally isolating and optionally purifying elafibranor thus obtained.

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The process according to any one of the preceding claims, characterized in that the aprotic solvent is selected from hydrocarbons C5- C12- alkanes, alkenes, cycloalkanes and cycloalkenes; aromatic solvents such as toluene and xylenes; halogenated solvents; ketones; esters; heterocyclic solvents such as pyridine; and ethers such as tetrahydrofurane (THF), diethyl ether (Et20), methyl tert-butyl ether (MTBE), diisopropyl ether (DIPE), dibutyl ether (Bu20) and 1,2-dimethoxy ethane (DME).

The process according to claim 5, characterized in that the aprotic solvent is THF or 1,4-dioxane.

The process according to any one of the preceding claims, characterized in that the polar solvent is selected from dimethylformamide (DMF), dimethylacetamide (DMA), acetonitrile, dimethyl sulfoxide (DM SO), sulfolane, N-methyl-2-pyrrolidone (NMP), l,3-dimethyl-2-imidazolidinone (DMI), hexamethylphosphoramide (HMPA), N,N'-dimethylpropyleneurea (DMP, water, alcohols, diols and their mixtures, acetonitrile, sulfolane.

The process according to claim 7, characterized in that the protic solvent is n-propanol or 1,4-butandiol.

The process according to any one of the preceding claims, characterized in that R is -CHO.

The process according to any one of the preceding claims, characterized in that the strong base is selected from hydroxides, alkoxydes, hydrides, amides, diethylamides, diisopropylamides, tetramethylpiperidides and hexamethyl disilazides of alkali metals and alkaline earth metals or strong organic bases such as Ν,Ν-diisopropylethylamine, DBU, DBN, quinuclidine, DABCO, Barton base or other guanidine derivatives, and phosphazene bases.

The process according to claim 10, characterized in that the strong base is sodium or potassium hydroxide.

The process according to claim 11, characterized in that the strong base is solid sodium salt.

The process according to claim 12, characterized in that said solid sodium hydroxide, is in the form of powder, pellets, flakes, or beads.

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A compound selected from formula (II) and (IV)


(II) (IV)

wherein

- X is Na

- R is -CHO or


15. The compound according to claim 14, wherein R is -CHO.

16. Use of at least a compound according to claim 14 or 15, as a synthesis intermediate.

17. Use according to claim 16 as a synthesis intermediate for the preparation of elafibranor.

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