Synthesis of lanifibranor intermediate

Abstract

The present disclosure is directed to a process for preparing a compound of formula (I), which comprises a palladium-free coupling reaction between N-(4-chloro-2-iodo-phenyl)-1,3-benzothiazole-6-sulfonamide and methyl 5-hexynoate in the presence of a copper catalyst.

Description

[0001] Synthesis of lanifibranor intermediate

[0002] Field of the invention

[0003] The present invention relates to a process for preparing a compound useful in the synthesis of lanifibranor, as well as a process for preparing lanifibranor from said compound.

[0004] Background of the invention

[0005] Lanifibranor or l-(6-benzothiazolylsulfonyl)-5-chloro-lH-indole-2-butanoic acid is a pan- PPAR agonist which is currently in clinical development for the treatment of patients with non-alcoholic steatohepatitis (NASH), for which there is currently no approved therapy.

[0006] Lanifibranor is described in example 117 of WO 2007 / 026097 and has the following structure:

[0007] Its synthesis is described in WO 2007 / 026907 and in J Med Chem 2018, 61(6), 2246- 2265. In the latter reference, the synthesis of lanifibranor comprises (i) reacting 4-chloro- 2-iodoaniline with l,3-benzothiazole-6-sulfonyl chloride to yield N-(4-chloro-2-iodoaniline)- l,3-benzothiazole-6-sulfonamide, (ii) reacting the compound obtained in step (i) with methyl hex-5-ynoate to yield methyl 4-[l-(l,3-benzothiazol-6-ylsulfonyl)-5-chloro-indol-2- yl]-butanoate, and (iii) deprotecting the ester group of the compound obtained in step (ii). The reagents and conditions described for step (ii) are: alkyne, Pd(PPh3)2CI2, Cui, diethylamine, DMF, microwave 130°C.

[0008] It will be appreciated that using a microwave source of heat for performing a chemical reaction is not suited for large-scale production of an active pharmaceutical ingredient (API).

[0009] It will also be appreciated that the high demand and limited supply of palladium over the last years has resulted in a significant deficit in this metal. In addition, the processes which palladium must undergo in its journey from ore to round-bottom flasks are accompanied by environmental consequences that are often underappreciated: the low concentration of palladium in ore (<10 g / tonne), alongside the presence of other first row transition and platinum group metals, means that palladium refining is an energy demanding process which relies also on harmful chemical reagents. It is accordingly desirable to find less toxic and sustainable alternatives to palladium-based catalysts when synthesizing APIs.

[0010] The present invention was made having the above problems in mind.

[0011] Summary of the invention

[0012] In one aspect, the present disclosure relates to a process for preparing a compound of formula (I): which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3-benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of a copper catalyst, wherein said coupling reaction is carried out in the absence of a palladium catalyst.

[0013] In some embodiments, the copper catalyst is a copper(I) catalyst. In some embodiments, the copper catalyst is a copper(II) catalyst.

[0014] In some embodiments, the coupling reaction is carried out in the presence of a base.

[0015] In some embodiments, the coupling reaction is carried out in the presence of a solvent.

[0016] In another aspect, the present disclosure relates to a process for preparing lanifibranor, which comprises: a) preparing a compound of formula (I) by the process as defined above; and b) deprotecting the ester group of the compound of formula (I).

[0017] Description of the invention

[0018] In one aspect, the present disclosure relates to a process for preparing a compound of formula (I): which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3-benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of a copper catalyst, wherein said coupling reaction is carried out in the absence of a palladium catalyst. Within the context of the present invention, the expression "absence of a palladium catalyst" means that no palladium catalyst is used to carry out the coupling reaction. Advantageously, the coupling reaction is carried out under palladium-free condition.

[0019] In some embodiments, wherein the copper catalyst is a copper(I) catalyst or a copper(II) catalyst.

[0020] In some embodiments, the copper catalyst is a copper(I) catalyst. Suitable copper (I) catalysts include copper(I) bromide, copper(I) chloride, copper(I) iodide, copper(I) acetate, copper(I) oxide, tetrakisacetonitrile copper(I) triflate, bis(triphenylphosphine)copper(I) borohydride, and mixtures thereof.

[0021] In some embodiments, the copper catalyst is a copper(II) catalyst. Suitable copper(II) catalysts include copper(II) sulfate, copper(II) trifluoromethanesulfonate, copper(II) oxide, copper(II) bromide, copper(II) chloride, copper(II) iodide, copper(II) acetate, copper acetylacetonate and mixtures thereof.

[0022] In some embodiments, the coupling reaction is carried out in the presence of from about 0.1 to about 2.0 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 0.1 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 0.2 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 0.3 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 0.4 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 0.5 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 0.6 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 0.7 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 0.8 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 0.9 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.0 equivalent of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.1 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.2 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.3 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.4 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.5 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.6 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.7 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.8 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 1.9 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of 2.0 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of from about 0.2 to about 1.4 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of from about 0.3 to about 1.3 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of from about 0.4 to about 1.2 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of from about 0.5 to about 1.1 equivalents of copper catalyst. In some embodiments, the coupling reaction is carried out in the presence of from about 0.5 to about 1.5 equivalents of copper catalyst.

[0023] In some embodiments, the coupling reaction is carried out in the presence of a base. Suitable bases include cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butylate, potassium tert-butylate, sodium acetate, diisopropylamine, triethylamine, trans-diaminocyclohexane, l,8-diazabicyclo[5.4.0]undec-7-ene, pyridine, 4- (dimethylamino)pyridine and mixtures thereof. In some embodiments, the coupling reaction is carried out in the absence of a base.

[0024] In some embodiments, the reactants are added successively to the solvent at the start of the coupling reaction. In some embodiments, some reactants are added after the reaction has started, for example 30 minutes, 1 hour, 1.5 hours, 2 hours, 2,5 hours or 3 hours after the reaction has started.

[0025] In some embodiments, additional copper catalyst can be added to the reaction after it has started. The addition can be carried out in one or more stages, with, for example, up to about 8.0 equivalents of copper catalyst being added.

[0026] In some embodiments, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. In some embodiments, the coupling reaction is carried out at a temperature of at least 70°C. Advantageously, the coupling reaction is carried out at a temperature of at least 75°C, advantageously of at least 80°C, advantageously of at least 85°C, advantageously of at least 90°C, advantageously of at least 91°C, advantageously of at least 92°C, advantageously of at least 93°C, advantageously of at least 94°C, advantageously of at least 95°C, advantageously of at least 96°C, advantageously of at least 97°C, advantageously of at least 98°C, advantageously of at least 99°C, advantageously of at least 100°C, advantageously of at least 101°C, advantageously of at least 102°C, advantageously of at least 103°C, advantageously of at least 104°C, advantageously of at least 105°C, advantageously of at least 106°C, advantageously of at least 107°C, advantageously of at least 108°C, advantageously of at least 109°C, advantageously of at least 110°C, advantageously of at least 111°C, advantageously of at least 112°C, advantageously of at least 113°C, advantageously of at least 114°C, advantageously of at least 115°C, advantageously of at least 116°C, advantageously of at least 117°C, advantageously of at least 118°C, advantageously of at least 119°C, advantageously of 120°C. In some embodiments, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out at a temperature in the range from about 75°C to about 120°C, advantageously from about 80°C to about 120°C, advantageously from about 85°C to about 120°C, advantageously from about 90°C to about 120°C, advantageously from about 95°C to about 120°C, advantageously from about 100°C to about 120°C, advantageously from about 105°C to about 120°C, advantageously from about 110°C to about 120°C.

[0027] In some embodiments, the coupling reaction is carried out in the presence of a solvent. Suitable solvents include water, methanol, ethyl acetate, acetonitrile, an ether such as methyltetra hydrofuran or dioxane, toluene, pyridine, dimethylsulfoxide, dimethylformamide and a mixture thereof. In some embodiments, suitable solvents can be water / ether mixture or a water / methanol mixture.

[0028] In some embodiments, the coupling reaction is carried out in the presence of a ligand. Suitable ligangs include phenanthroline, N,N'-dimethylethylenediamine, N,N',N"- trimethyldiethylenetriamine, 2-(2-pyridyl)pyridine, di(2-picolyl)amine , glyoxal bis(2- hydroxyanil) and mixtures thereof.

[0029] In some embodiments, the coupling reaction is carried out for at least 10 minutes, at least 15 minutes, at least 20 minutes, advanategously at least 30 minutes, advanategously at least 45 minutes, advantageously at least 1 hour, advantageously at least 1.5 hours, advantageously at least 2 hours, advantageously at least 2.5 hours, advantageously at least 3 hours, advantageously at least 3.5 hours, advantageously at least 4 hours, advantageously at least 4.5 hours, advantageously at least 5 hours, advantageously at least 5.5 hours, advantageously at least 6 hours, advantageously at least 6.5 hours, advantageously at least 7 hours, advantageously at least 7.5 hours, advantageously at least 8 hours, advantageously at least 8.5 hours, advantageously at least 9 hours, advantageously at least 9.5 hours, advantageously at least 10 hours, advantageously at least 10.5 hours, advantageously at least 11 hours, advantageously at least 11.5 hours, advantageously at least 12 hours, advantageously at least 12.5 hours, advantageously at least 13 hours, advantageously at least 13.5 hours, advantageously at least 14 hours, advantageously at least 14.5 hours, advantageously at least 15 hours, advantageously at least 15.5 hours, advantageously at least 16 hours, advantageously at least 16.5 hours, advantageously at least 17 hours, advantageously at least 17.5 hours, advantageously at least 18 hours, advantageously at least 18.5 hours, advantageously at least 19 hours, advantageously at least 19.5 hours, advantageously at least 20 hours.

[0030] In one embodiment, the coupling reaction is carried out for 10 minutes to 20 hours, advantageously for 10 minutes to 6 hours, advantageously for 10 minutes to 5.5 hours, advantageously for 10 minutes to 5 hours, advantageously for 10 minutes to 4.5 hours, advantageously for 10 minutes to 4 hours, advantageously for 10 minutes to 3.5 hours, advantageously for 10 minutes to 3 hours, advantageously for 10 minutes to 2.5 hours, advantageously for 10 minutes to 2 hours, advantageously for 10 minutes to 1.5 hours, advantageously for 10 minutes to 1 hour.

[0031] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) bromide. Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 30 minutes to about 2.5 hours.

[0032] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 2.5 hours.

[0033] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of tetrakisacetonitrile copper(I) triflate. Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 15 minutes to about 1.5 hours.

[0034] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(II) trifluoromethanesulfonate. Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 30 minutes to about 4 hours.

[0035] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(II) bromide. Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 30 minutes to about 20 hours.

[0036] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and ethyl acetate as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 4 hours.

[0037] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and acetonitrile as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3 hours.

[0038] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and pyridine as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3 hours.

[0039] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and 2- methyltetrahydrofuran as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 4 hours.

[0040] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of cesium carbonate as suitable base, phenanthroline as suitable ligand and a water / 2- methyltetra hydrofuran mixture as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3 hours.

[0041] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 4 hours.

[0042] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of sodium carbonate as suitable base, phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 5 hours.

[0043] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of sodium acetate as suitable base, phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3 hours.

[0044] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of triethylamine as suitable base, phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 5 hours.

[0045] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of N,N-diisopropylethylamine as suitable base, phenanthroline as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 5 hours. In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of N,N-diisopropylethylamine as suitable base, N,N'-dimethylethylenediamine as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 5 hours.

[0046] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of N,N-diisopropylethylamine as suitable base, N,N',N"-trimethyldiethylenetriamine as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3.5 hours.

[0047] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of N,N-diisopropylethylamine as suitable base, di(2-picolyl)amine as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3.5 hours.

[0048] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of N,N-diisopropylethylamine as suitable base, 2-(2-pyridyl)pyridine as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3.5 hours.

[0049] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of N,N-diisopropylethylamine as suitable base, glyoxal bis(2-hydroxyanil) as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3.5 hours.

[0050] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc). Advantageously, the coupling reaction is carried out in the presence of N,N-diisopropylethylamine as suitable base, triphenylphosphine as suitable ligand and toluene as suitable solvent. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3.5 hours.

[0051] In one specific embodiment, the present disclosure concerns a process for preparing a compound of formula (I), which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3- benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of copper(I) acetate (CuOAc), phenanthroline as suitable ligand and toluene as suitable solvent, then a suitable base, for example DIPEA, is added at least 30 minutes after the coupling reaction has started. Advantageously, the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C. Advantageously, the coupling reaction is carried out for about 10 minutes to about 3.5 hours.

[0052] In one aspect, the present disclosure relates to a process for preparing lanifibranor, which comprises: a) preparing a compound of formula (I) by the process as defined above; and b) deprotecting the ester group of the compound of formula (I).

[0053] In some embodiments, deprotection of the ester group in step b) is carried out by techniques well known in the art, for example by hydrolysing said ester group and treating the resulting compound with an acid.

[0054] The invention is illustrated by the following, non-limiting examples.

[0055] Examples

[0056] All the examples are directed to the synthesis of methyl 4-[l-(l,3-benzothiazol-6- ylsulfonyl)-5-chloro-indol-2-yl]-butanoate.

[0057] Abbreviations

[0058] CuOAc = copper(I) acetate DIPEA = N,N-diisopropylethylamine

[0059] DMEDA = N,N'-dimethylethylenediamine

[0060] DMSO = dimethylsulfoxide eq = equivalent

[0061] EtOAc = ethyl acetate

[0062] HPLC = high-performance liquid chromatography

[0063] LC-MS = liquid chromatography-mass spectrometry

[0064] MeTHF = 2-methyltetrahydrofuran

[0065] PPh3= triphenylphosphine

[0066] Example 1

[0067] 1.0 eq (1.0 g) of N-(4-chloro-2-iodo-phenyl)-l,3-benzothiazole-6-sulfonamide, 1.05 eq of methyl 5-hexynoate, 2.0 eq of cesium carbonate, 1.0 eq of copper(I) bromide and 0.2 eq of phenanthroline were successively added to toluene (12 v / w). The reaction mixture was stirred at 110°C for 2h30. The product was filtered on Celite®, washed with toluene, and the solvents were evaporated from the filtrate to give crude product in 83% isolated yield. LC-MS analysis showed a conversion rate of the starting sulfonamide of >99%.

[0068] Example 2

[0069] Crude product was obtained in 68% isolated yield following the procedure of example 1 but using CuOAc instead of CuBr and stirring the mixture at 110°C for 10 min. LC-MS analysis showed a conversion rate of the starting sulfonamide of >99%.

[0070] Example 3

[0071] Crude product was obtained in 73% isolated yield following the procedure of example 1 but using tetrakisacetonitrile copper(I) triflate instead of CuBr and stirring the mixture at 110°C for lh. LC-MS analysis showed a conversion rate of the starting sulfonamide of >99%.

[0072] Example 4

[0073] Crude product was obtained in 32% isolated yield following the procedure of example 2 but using 0.2 eq of CuOAc and stirring the mixture at 110°C for 6h. LC-MS analysis showed an 84% conversion rate of the starting sulfonamide.

[0074] Example 5

[0075] Crude product was obtained in 52% isolated yield following the procedure of example 1 but using copper(II) trifluoromethanesulfonate instead of CuBr and stirring the mixture at 110°C for 4h. LC-MS analysis showed an 81% conversion rate of the starting sulfonamide. Example 6

[0076] Crude product was obtained in 22% isolated yield following the procedure of example 1 but using CuBr2instead of CuBr and stirring the mixture at 110°C for 20h. LC-MS analysis showed a 65% conversion rate of the starting sulfonamide.

[0077] Comparative example 1

[0078] The procedure of example 1 was followed using copper dust instead of CuBr and stirring the mixture at 110°C for lh30. Whilst LC-MS analysis showed a 67% conversion rate of the starting sulfonamide, no traces of the targeted ester were detected by HPLC.

[0079] Example 7

[0080] Crude product was obtained in 74% isolated yield (before purification) following the procedure of example 2 but with stirring of the mixture at 80°C for 2h30. LC-MS analysis showed a 98% conversion rate of the starting sulfonamide.

[0081] Comparative example 2

[0082] The procedure of example 2 was followed using dry ethanol instead of toluene and stirring the mixture at 80°C for 2h. Whilst LC-MS analysis showed a conversion rate of the starting sulfonamide >99%, the yield in crude product was a mere 1%.

[0083] Comparative example 3

[0084] The procedure of example 2 was followed using DMSO instead of toluene and stirring the mixture at 80°C for 2h30. Whilst LC-MS analysis showed a 66% conversion rate of the starting sulfonamide, the yield in crude product was a mere 1%.

[0085] Example 8

[0086] Crude product was obtained in 47% isolated yield following the procedure of example 2 but using ethyl acetate instead of toluene and stirring the mixture at 80°C for 4h. LC-MS analysis showed a conversion rate of the starting sulfonamide of >99%.

[0087] Example 9

[0088] Crude product was obtained in 58% isolated yield following the procedure of example 2 but using acetonitrile instead of toluene and stirring the mixture at 80°C for 2h. LC-MS analysis showed a conversion rate of the starting sulfonamide of >99%.

[0089] Example 10

[0090] Crude product was obtained in 50% isolated yield following the procedure of example 2 but using pyridine instead of toluene and stirring the mixture at 80°C for 3h. LC-MS analysis showed a conversion rate of the starting sulfonamide of >99%. Example 11

[0091] Crude product was obtained in 67% isolated yield following the procedure of example 2 but using MeTHF instead of toluene and stirring the mixture at 80°C for 2h30. LC-MS analysis showed a conversion rate of the starting sulfonamide of >99%.

[0092] Example 12

[0093] Crude product was obtained in 58% isolated yield following the procedure of example 11 but using a water / MeTHF mixture (1:2 v / v) instead of MeTHF and stirring the mixture at 80°C for 3h. LC-MS analysis showed a conversion rate of the starting sulfonamide of >99%.

[0094] Example 13

[0095] Crude product was obtained in 57% isolated yield following the procedure of example 2 but without using cesium carbonate and stirring the mixture at 80°C for 4h. LC-MS analysis showed a 79% conversion rate of the starting sulfonamide. Addition of 2.0 eq of cesium carbonate and strirring of the mixture at 80°C for a further 2h improved the yield in crude product to 74% with a conversion rate of the starting sulfonamide of >99%.

[0096] Example 14

[0097] Crude product was obtained in 44% isolated yield following the procedure of example 2 but using sodium carbonate instead of cesium carbonate and stirring the mixture at 80°C for 5h. LC-MS analysis showed a 68% conversion rate of the starting sulfonamide.

[0098] Example 15

[0099] Crude product was obtained in 53% isolated yield following the procedure of example 2 but using sodium acetate instead of cesium carbonate and stirring the mixture at 80°C for 3h. LC-MS analysis showed a 72% conversion rate of the starting sulfonamide.

[0100] Example 16

[0101] Crude product was obtained in 75% isolated yield following the procedure of example 2 but using triethylamine instead of cesium carbonate and stirring the mixture at 80°C for 5h. LC-MS analysis showed a 97% conversion rate of the starting sulfonamide.

[0102] Example 17

[0103] Crude product was obtained in 70% isolated yield following the procedure of example 16 but using 1.0 eq of triethylamine. LC-MS analysis showed a 92% conversion rate of the starting sulfonamide.

[0104] Example 18

[0105] Crude product was obtained in 78% isolated yield following the procedure of example 16 but using 0.5 eq of triethylamine. LC-MS analysis showed a 92% conversion rate of the starting sulfonamide. Example 19

[0106] Crude product was obtained in 81% isolated yield following the procedure of example 2 but using 0.5 eq of DIPEA instead of cesium carbonate and stirring the mixture at 80°C for 3h30. LC-MS analysis showed a 92% conversion rate of the starting sulfonamide.

[0107] Example 20

[0108] Crude product was obtained in 38% isolated yield following the procedure of example 19 but using DMEDA instead of phenanthroline. LC-MS analysis showed a 90% conversion rate of the starting sulfonamide.

[0109] Example 21

[0110] Crude product was obtained in 39% isolated yield following the procedure of example 19 but using N,N',N"-trimethyldiethylenetriamine instead of phenanthroline. LC-MS analysis showed an 84% conversion rate of the starting sulfonamide.

[0111] Example 22

[0112] Crude product was obtained in 58% isolated yield following the procedure of example 19 but using di(2-picolyl)amine instead of phenanthroline. LC-MS analysis showed a 90% conversion rate of the starting sulfonamide.

[0113] Example 23

[0114] Crude product was obtained in 68% isolated yield following the procedure of example 19 but using 2-(2-pyridyl)pyridine instead of phenanthroline. LC-MS analysis showed a 90% conversion rate of the starting sulfonamide.

[0115] Example 24

[0116] Crude product was obtained in 62% isolated yield following the procedure of example 19 but using glyoxal bis(2-hydroxyanil) instead of phenanthroline. LC-MS analysis showed a 79% conversion rate of the starting sulfonamide.

[0117] Example 25

[0118] Crude product was obtained in 64% isolated yield following the procedure of example 17 but using PPh3instead of phenanthroline. LC-MS analysis showed an 80% conversion rate of the starting sulfonamide.

[0119] Example 26

[0120] 1.0 eq (1.0 g) of N-(4-chloro-2-iodo-phenyl)-l,3-benzothiazole-6-sulfonamide, 1.05 eq of methyl 5-hexynoate, 1.0 eq of CuOAc and 0.2 eq of phenanthroline were successively added to toluene (12 v / w). The reaction mixture was stirred at 80°C for 30 min. 0.5 eq of DIPEA was then added, and the reaction mixture was stirred at 80°C for 3h. At that point, LC-MS of an aliquot of the reaction product showed a 92% conversion rate of the starting sulfonamide. 0.15 eq of CuOAc was then added and the reaction mixture was stirred at 80°C for lh30. The mixture was filtered on Celite®, washed with toluene, and the solvents were evaporated from the filtrate to give crude product in 86% isolated yield. LC-MS analysis showed a conversion rate of the starting sulfonamide of >98%.

[0121] Example 27

[0122] 10 g (1 eq) of N-(4-chloro-2-iodoaniline)-l,3-benzothiazole-6-sulfonamide, 2.86 g CuOAc (1 eq), 1.42 g of DIPEA (0.5 eq) and 0.798 g of phenantroline (0.2 eq) were added to a solution of methyl hex-5-ynoate (3.06g, 1.05eq) in 120 mL of anhydrous toluene. The mixture was stirred at 800 rpm and degassed by argon bubbling for 10 min at 25 °C. The mixture was then heated at 80°C in a perforated plate while maintaining stirring at 800 rpm under a light argon flow. Analytical monitoring was performed by HPLC and showed incomplete conversion of the starting sulfonamide.

[0123] 572 mg of CuOAc (0.2 eq) were then added to the reaction medium after 2h30 and 4h. After 6h at 80°C, HPLC analysis showed that the reaction was complete. The mixture was cooled down to 25°C and diluted with 100 mL of water and 100 mL of EtOAc. The insoluble suspension was removed by filtration and the solid residue was washed with 2x20 mL of EtOAc. The aqueous layer was extracted with 2x100 mL of EtOAc. The combined organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure (42°C, 3.5 mbar) to give 10.86 g of the title compound as a brown solid (84% yield).

[0124] An aliquot of 4.02 g of brown solid was purified by flash chromatography on silica gel (40g SiO2cartridge, elution 100% CH2CI2) to yield 2.93g of the title compound as a white solid (93% purification yield; overall yield = 78%).

[0125] Example 28

[0126] 15 g (33.28 mmol; 1 eq) of N-(4-chloro-2-iodo-phenyl)-l,3-benzothiazole-6-sulfonamide, 6.30 g (49.92 mmol; 1.05 eq) of methyl 5-hexynoate, 21.69 g (66.56 mmol; 2.00 eq) of cesium carbonate, 4.77 g (33.28 mmol; 1.00 eq) of copper(I) bromide and 1.2 g (6.66 mmol; 0.2 eq) of phenanthroline were successively added to 180 mL of toluene. The reaction mixture was stirred at 110°C for 2h30. LC-MS analysis showed a conversion rate of the starting sulfonamide of >99%. The product was then filtered on Celite®, washed with 400 mL of toluene, and the solvents were evaporated from the filtrate to give 12.6 g of crude product (83% yield). The crude product was purified by column chromatography (SiO2200g cartridge) using cyclohexane / EtOAc (10% to 40% EtOAc in 12V) as the eluent to give 10.46 g of title compound (70% overall yield).

[0127] Aspects of the present disclosure are further illustrated by reference to the following, nonlimiting embodiments. 1. A process for preparing a compound of formula (I): which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3-benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of a copper catalyst, wherein said coupling reaction is carried out in the absence of a palladium catalyst.

[0128] 2. The process of paragraph 1, wherein the copper catalyst is a copper(I) catalyst or a copper(II) catalyst.

[0129] 3. The process of paragraph 1 or paragraph 2, wherein the copper(I) catalyst is selected among copper(I) bromide, copper(I) chloride, copper(I) iodide, copper(I) acetate, copper(I) oxide, tetrakisacetonitrile copper(I) triflate, bis(triphenylphosphine)copper(I) borohydride, and mixtures thereof.

[0130] 4. The process of paragraph 1 or paragraph 2, wherein the copper(II) catalyst is selected from copper(II) sulfate, copper(II) trifluoromethanesulfonate, copper(II) oxide, copper(II) bromide, copper(II) chloride, copper(II) iodide, copper(II) acetate, copper acetylacetonate, and mixtures thereof.

[0131] 5. The process of any preceding paragraph, wherein the coupling reaction is carried out in the presence of from 0.1 to 2.0 equivalents of copper catalyst.

[0132] 6. The process of any preceding paragraph, wherein the coupling reaction is carried out in the presence of a base.

[0133] 7. The process of paragraph 6, wherein the base is selected from cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butylate, potassium tert-butylate, sodium acetate, diisopropylamine, triethylamine, trans-dia mi nocyclohexane, 1,8- diazabicyclo[5.4.0]undec-7-ene, pyridine and 4-(dimethylamino)pyridine.

[0134] 8. The process of paragraph 7, wherein the base is cesium carbonate.

[0135] 9. The process of any of paragraphs 1 to 5, wherein the coupling reaction is carried out in the absence of a base.

[0136] 10. The process of any preceding paragraph, wherein the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C.

[0137] 11. The process of any preceding paragraph, wherein the coupling reaction is carried out in the presence of a solvent. 12. The process of paragraph 11, wherein the solvent is selected from ethyl acetate, acetonitrile, an ether such as methyltetrahydrofuran or dioxane, a water / ether mixture, a water / methanol mixture, toluene, pyridine, dimethylsulfoxide and dimethylformamide.

[0138] 13. The process of any preceding paragraph, wherein the coupling reaction is carried out in the presence of a ligand.

[0139] 14. The process of paragraph 13, wherein the ligand is selected from phenanthroline, N,N'-dimethylethylenediamine, N,N',N"-trimethyldiethylenetriamine, 2-(2-pyridyl)pyridine, di(2-picolyl)amine and glyoxal bis(2-hydroxyanil).

[0140] 15. The process of paragraph 14, wherein the ligand is phenanthroline. 16. A process for preparing lanifibranor, which comprises: a) preparing a compound of formula (I) by the process of any of paragraphs 1 to 15; and b) deprotecting the ester group of the compound of formula (I).

[0141] 17. The process of claim 16, wherein step b) comprises hydrolysing the ester group of the compound of formula (I) and treating the resulting compound with an acid.

Claims

CLAIMS1. A process for preparing a compound of formula (I):which comprises coupling N-(4-chloro-2-iodo-phenyl)-l,3-benzothiazole-6-sulfonamide with methyl 5-hexynoate in the presence of a copper catalyst, wherein said coupling reaction is carried out in the absence of a palladium catalyst.

2. The process of claim 1, wherein the copper catalyst is a copper(I) catalyst or a copper(II) catalyst.

3. The process of claim 1 or claim 2, wherein the copper(I) catalyst is selected among copper(I) bromide, copper(I) chloride, copper(I) iodide, copper(I) acetate, copper(I) oxide, tetrakisacetonitrile copper(I) triflate, bis(triphenylphosphine)copper(I) borohydride, and mixtures thereof.

4. The process of claim 1 or claim 2, wherein the copper(II) catalyst is selected from copper(II) sulfate, copper(II) trifluoromethanesulfonate, copper(II) oxide, copper(II) bromide, copper(II) chloride, copper(II) iodide, copper(II) acetate, copper acetylacetonate, and mixtures thereof.

5. The process of any preceding claim, wherein the coupling reaction is carried out in the presence of from 0.1 to 2.0 equivalents of copper catalyst.

6. The process of any preceding claim, wherein the coupling reaction is carried out in the presence of a base.

7. The process of claim 6, wherein the base is selected from cesium carbonate, sodium carbonate, potassium carbonate, sodium tert-butylate, potassium tert-butylate,sodium acetate, diisopropylamine, triethylamine, trans-dia mi nocyclohexane, 1,8- diazabicyclo[5.4.0]undec-7-ene, pyridine and 4-(dimethylamino)pyridine.

8. The process of any of claims 1 to 5, wherein the coupling reaction is carried out in the absence of a base.

9. The process of any preceding claim, wherein the coupling reaction is carried out at a temperature in the range from about 70°C to about 120°C.

10. The process of any preceding claim, wherein the coupling reaction is carried out in the presence of a solvent.

11. The process of claim 10, wherein the solvent is selected from water, methanol, ethyl acetate, acetonitrile, an ether such as methyltetrahydrofuran or dioxane, toluene, pyridine, dimethylsulfoxide, dimethylformamide and a mixture thereof.

12. The process of any preceding claim, wherein the coupling reaction is carried out in the presence of a ligand.

13. The process of claim 12, wherein the ligand is selected from phenanthroline, N,N'- dimethylethylenediamine, N,N',N"-trimethyldiethylenetriamine, 2-(2-pyridyl)pyridine, di(2- picolyl)amine and glyoxal bis(2-hydroxyanil).

14. A process for preparing lanifibranor, which comprises: a) preparing a compound of formula (I) by the process of any of claims 1 to 13; and b) deprotecting the ester group of the compound of formula (I).

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