Solid-state forms of vidofludimus calcium and process for preparation of vidofludimus thereof

Abstract

Aspects of the present application relates to a solid-state forms of Vidofludimus calcium such as amorphous solid dispersion, amorphous form, crystalline form D1, D2, D3 and DC and process for preparation of Vidofludimus and intermediate thereof.

Description

[0001] SOLID-STATE FORMS OF VIDOFLUDIMUS CALCIUM AND

[0002] PROCESS FOR PREPARATION OF VIDOFLUDIMUS THEREOF

[0003] CROSS REFERENCE

[0004] This application claims the priority of Indian provisional applications 202441101398 filed on 20thDecember 2024 and 202541051900 filed on 29thMay 2025.

[0005] FIELD OF THE INVENTION

[0006] Aspects of the present application relates to solid-state forms of Vidofludimus calcium and process for preparation of Vidofludimus and intermediate thereof.

[0007] BACKGROUND OF THE INVENTION

[0008] The drug compound having the adopted name “Vidofludimus calcium” has chemical name: 2-({3-Fluoro-3'-methoxy-[l,l'-biphenyl]-4- yl}carbamoyl)cyclo pent- 1-ene-l -carboxylic acid) calcium salt of formula (I) as below.

[0009] Vidofludimus is currently under clinical trials for the treatment of multiple sclerosis (MS).

[0010] US patent number 8653138 B2 describes crystalline form of Vidofludimus calcium.

[0011] US patent number 12037305 B2 describes crystalline forms A and B of Vidofludimus calcium and preparations thereof.

[0012] However, there remains a need for alternate solid forms of Vidofludimus calcium and preparative processes thereof, exhibiting desired properties such as bioavailability and stability.

[0013] Different forms of Active pharmaceutical ingredients (API) in pharmaceutical compositions can be prepared. In the synthesis of a chemical compound intended for pharmaceutical use, it is necessary to isolate and purify the compound at the completion of the synthetic process and prior to further processing to provide the compound in a pharmaceutical formulation. The isolation and the purification steps, which can be combined or separate consecutive steps, provide the compound as a purified solid with minimal loss of yield during isolation from other components of the reaction mixture and / or during purification to remove impurities from the isolated compound. It is desirable to prepare physically and chemically stable amorphous form / amorphous solid dispersion / crystalline form using regulatory acceptable solvents.

[0014] US patent number 7176241 discloses process for preparation Vidofludimus comprising reaction of 4-bromo-2-fluoroaniline of formula (II) with (3 -methoxyphenyl) boronic acid of formula (III) in presence of palladium- tetrakis(triphenylphosphine) (Pd(PPhs)4), cesium carbonate, 1,2-dimethoxyethane and water to get 3 -fluoro-3 '-methoxy- [l,l'-biphenyl]-4-amine of formula (IV). The compound of formula (IV) is further reacted with 1 -cyclopentene- 1,2- dicarboxylic anhydride of formula (V) in presence of dichloromethane to produce Vidofludimus.

[0015] However, US '241 process has several disadvantages like use of expensive homogenous catalyst such as Pd(PPh3)4. Moreover, the catalyst is non-recoverable and causes potential metal contamination in the product. Further, the prior art process uses 1 -cyclopentene- 1,2-dicarboxylic anhydride of formula (V), which is not stable at room temperature. Overall, the prior art process is expensive, tedious and cumbersome.

[0016] Hence, there remains a need of improved process for the synthesis of Vidofludimus which is simple, economic and eco-friendly.

[0017] SUMMARY OF THE INVENTION

[0018] First aspect of the present application relates to amorphous solid dispersion comprising Vidofludimus calcium and one or more pharmaceutically acceptable carriers and process for preparation thereof.

[0019] Second aspect of the present application relates to amorphous form of Vidofludimus calcium and process for preparation thereof.

[0020] Third aspect of the present application relates to a crystalline form DI of Vidofludimus calcium and process for preparation thereof.

[0021] Fourth aspect of the present application relates to a crystalline form D2 of Vidofludimus calcium and process for preparation thereof.

[0022] Fifth aspect of the present application relates a crystalline form D3 of Vidofludimus calcium and process for preparation thereof.

[0023] Sixth aspect of the present application relates to a crystalline form DC1 of Vidofludimus calcium and process for preparation thereof.

[0024] Seventh aspect of the present application relates to a pharmaceutical composition comprising a solid-state form of Vidofludimus calcium selected from amorphous solid dispersion, amorphous form, crystalline form DI, crystalline form D2, crystalline form D3, crystalline form DC1 and one or more pharmaceutically acceptable excipients.

[0025] Eighth aspect of the present application relates to use of solid state form of Vidofludimus calcium selected from amorphous solid dispersion, amorphous form, crystalline form DI, crystalline form D2, crystalline form D3, crystalline form DC1 of the present application for the treatment of multiple sclerosis.

[0026] Ninth aspect of the present application relates to a process for the preparation of Vidofludimus and pharmaceutically acceptable salts thereof, comprising; a) reacting the compound of formula (IV) with the compound of formula

[0027] (VI) to produce compound of formula (VII); wherein, R represents C1-C4 alkyl group. b) hydrolyzing the compound of formula (VII) to Vidofludimus; c) optionally, converting the Vidofludimus into pharmaceutically acceptable salts.

[0028] Tenth aspect of the present application relates to a process for the preparation of 3-fluoro-3'-methoxy-[l,l'-biphenyl]-4-amine of formula (IV), comprising; a) reacting compound of formula (VIII) with (3 -methoxyphenyl) boronic acid of formula (HI) in presence of heterogeneous metal catalyst to produce 3-fluoro-3'-methoxy-4-nitro-l,l'-biphenyl of formula (IX), b) reducing compound of formula (IX) to produce 3-fluoro-3'-methoxy-

[0029] [l,l'-biphenyl]-4-amine of formula (IV) wherein, X is Cl, Br or I.

[0030] Eleventh aspect of the present application relates to a process for the preparation of Vidofludimus and pharmaceutically acceptable salts, comprising; a) reacting 4-bromo-2-fluoroaniline of formula (II) with (3- methoxyphenyl) boronic acid of formula (III) in presence of heterogeneous metal catalyst to produce 3 -fluoro-3 '-methoxy- [1,1'- biphenyl]-4-amine of formula (IV), b) reacting the compound of formula (IV) with the compound of formula

[0031] (VI) to produce compound of formula (VII), wherein, R represents C1-C4 alkyl group. c) hydrolyzing the compound of formula (VII) to Vidofludimus, d) optionally converting the Vidofludimus into pharmaceutically acceptable salts wherein heterogeneous metal catalyst is selected from supported palladium, supported palladium oxide (PdO) or supported palladium hydroxide (Pd(OH)2) such as Pd / C, Pd(OH)2 / C, SiliaCat DPP-Pd, PdO on graphene oxide, Pd / Al2O3, Pd / BaSO4 and the like.

[0032] BRIEF DESCRIPTION OF THE DRAWING

[0033] Figure 1 is an illustrative X-ray powder diffraction (hereinafter referred as XRPD) pattern of amorphous solid dispersion of Vidofludimus calcium with copovidone (1:3, w / w) prepared by the method of example 1.

[0034] Figure 2 is an illustrative XRPD pattern of amorphous solid dispersion of Vidofludimus calcium with PVP K-30 (1:3, w / w) prepared by the method of example 2.

[0035] Figure 3 is an illustrative XRPD pattern of amorphous solid dispersion of Vidofludimus calcium with HPMC (1:3, w / w) prepared by the method of example 3.

[0036] Figure 4 is an illustrative XRPD pattern of amorphous solid dispersion of Vidofludimus calcium with Soluplus (1:3, w / w) prepared by the method of example 4.

[0037] Figure 5 is an illustrative XRPD pattern of amorphous solid dispersion of Vidofludimus calcium with methyl cellulose (1:3, w / w) prepared by the method of example 5.

[0038] Figure 6 is an illustrative XRPD pattern of amorphous solid dispersion of Vidofludimus calcium with HPMC-AS (1:3, w / w) prepared by the method of example 6.

[0039] Figure 7 is an illustrative XRPD pattern of amorphous solid dispersion of Vidofludimus calcium with ethyl cellulose (1:3, w / w) prepared by the method of example 7.

[0040] Figure 8 is an illustrative XRPD pattern of crystalline form DI of

[0041] Vidofludimus calcium prepared by the method of example 8.

[0042] Figure 9 is an illustrative XRPD pattern of crystalline form D2 of

[0043] Vidofludimus calcium prepared by the method of example 9.

[0044] Figure 10 is an illustrative XRPD pattern of crystalline form D3 of

[0045] Vidofludimus calcium prepared by the method of example 10.

[0046] Figure 11 is an illustrative XRPD pattern of amorphous form of Vidofludimus calcium prepared by the method of example 11.

[0047] Figure 12 is an illustrative XRPD pattern of crystalline form DC1 of Vidofludimus calcium prepared by the method of example 12.

[0048] DETAILED DESCRIPTION

[0049] As used herein, the term “solid dispersion” denotes a homogeneous solid containing at least two components of different chemical identity, which components are intimately mixed with one another at a molecular level. For example, such solid dispersion is obtained when two components are present as solute in a liquid solution in a solvent and obtained as a residue upon solvent evaporation.

[0050] As used herein, the term "comprising" means the elements recited, or their equivalent in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. All ranges recited herein include the endpoints, including those that recite a range "between" two values.

[0051] The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1.

[0052] First aspect of the present application relates to amorphous solid dispersion comprising Vidofludimus calcium and one or more pharmaceutically acceptable carriers.

[0053] In embodiments, the pharmaceutically acceptable carrier may be any suitable carrier known in the art. Specifically, the pharmaceutically acceptable carrier may include but not limited to vinylpyrrolidone-vinyl acetate copolymer (co-povidone); polyvinyl pyrrolidone (PVP); polymethacrylate - based copolymers; polyvinylcaprolactam-based copolymers; cyclodextrins; chitosan; polyvinyl alcohol; alginic acid; hydroxypropyl methylcellulose (also referred as HPMC or hypromellose) such as HPMC E3; hydroxypropyl methylcellulose acetate succinate (also referred as HPMC -AS or hypromellose acetate succinate) such as L, M, and H grades of HPMC -AS; Eudragit; hydroxypropyl cellulose (Also referred as HPC); methylcellulose (also referred as MC); ethyl cellulose, hypromellose phthalate (also referred as HPMC-P); soluplus; cellulose acetate phthalate; polysaccharides; heteropolysaccharides (pectins); poloxamers; poloxamines; ethylene vinyl acetates; polyethylene glycols; propylene glycols; polyvinylacetates; phosphatidylcholines (lecithins); miglyols; polylactic acid; polyhydroxybutyric acid; neucilin, dextrans and mixture thereof.

[0054] In embodiments, more specifically the pharmaceutically acceptable carrier is selected from a group of copovidone, PVP-K30, HPMC, soluplus, methyl cellulose, HPMC-AS, ethyl cellulose and mixture thereof.

[0055] In embodiments, silicon dioxide may be added to the amorphous solid dispersions of the present application.

[0056] In embodiments, amorphous solid dispersions of the present application is physically and chemically stable for at least three months at 40°C / 75%RH.

[0057] In embodiments, amorphous solid dispersion comprising Vidofludimus calcium and pharmaceutically acceptable carrier, wherein the ratio of Vidofludimus calcium and pharmaceutically acceptable carrier is 1:0.1 to 1:5, w / w.

[0058] In alternate embodiment, amorphous solid dispersion comprising Vidofludimus calcium and pharmaceutically acceptable carrier, wherein the ratio of Vidofludimus calcium and pharmaceutically acceptable carrier is 1: 1 to 1:3, w / w.

[0059] In yet another alternate embodiment, the present application provides a process for the preparation of amorphous solid dispersion comprising Vidofludimus calcium and one or more pharmaceutically acceptable carriers, comprising the steps of providing a solution of Vidofludimus calcium and one or more pharmaceutically acceptable carriers in a solvent and removing the solvent.

[0060] In embodiments, the solvent may be selected from a group of methanol, ethanol, 2-propanol, 1-butanol, 2-butanol, 1-pentanol, 2-pentanol, 3-pentanol, acetone, methylene chloride, chloroform, or mixtures thereof. Preferably, the solvent is a mixture of methanol and methylene chloride.

[0061] In embodiments, a solution of Vidofludimus calcium and one or more pharmaceutically acceptable carriers may be prepared at any suitable temperatures, such as about 0°C to about the reflux temperature of the solvent used. Stirring and heating may be used to reduce the time required for the dissolution process.

[0062] In embodiments, a solution of Vidofludimus calcium and one or more pharmaceutically acceptable carriers may be filtered to make it clear and free of unwanted particles. In embodiments, the obtained solution may be optionally treated with an adsorbent material, such as carbon and / or hydrose, to remove colored components, etc., before filtration.

[0063] In an embodiment, removal of solvent may be carried out by methods known in the art or any procedure disclosed in the present application. In preferred embodiments, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.

[0064] In an embodiment, removal of solvent may be carried out by solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor or spray drying.

[0065] It was found that amorphous solid dispersion of Vidofludimus calcium of the present application has good physico-chemical properties. The amorphous solid dispersion of the present application may be easily formulated into a pharmaceutical composition comprising Vidofludimus calcium along with one or more pharmaceutically acceptable carriers.

[0066] Second aspect of the present application provides amorphous form of Vidofludimus calcium.

[0067] In embodiments, amorphous form of Vidofludimus calcium of the present application is physically and chemically stable at least for three months at 40°C / 75%RH.

[0068] In other embodiment, amorphous form of Vidofludimus calcium further characterized by XRPD pattern as illustrated in figure-11.

[0069] In another embodiment, the present application provides a process for the preparation of amorphous form of Vidofludimus calcium, comprising the steps of providing a solution of Vidofludimus calcium in a solvent and removing the solvent thereof, wherein, removing of solvent may be carried out by methods known in the art or any procedure disclosed in the present application.

[0070] In yet another embodiment, removal of solvent may include, but not limited to: solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Buchi Rotavapor, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD) and the like.

[0071] It was found that amorphous form of Vidofludimus calcium of the present application has good physico-chemical properties. The amorphous form of the present application may be easily formulated into a pharmaceutical composition comprising Vidofludimus calcium along with one or more pharmaceutically acceptable carriers.

[0072] Third aspect of the present application provides crystalline form DI of Vidofludimus calcium characterized by XRPD pattern as illustrated in figure-8.

[0073] In embodiment, the present invention provides a process for preparation of crystalline form DI of Vidofludimus calcium, comprising: a) providing a solution of Vidofludimus calcium in 2-methoxyethanol; b) isolating the crystalline form DI of Vidofludimus calcium.

[0074] Fourth aspect of the present application provides crystalline form D2 of Vidofludimus calcium characterized by XRPD pattern as illustrated in figure-9.

[0075] In embodiment, the present invention provides a process for preparation of crystalline form D2 of Vidofludimus calcium, comprising: a) providing a solution of Vidofludimus free acid and calcium hydroxide in 2-propanol; b) isolating the crystalline form D2 of Vidofludimus calcium.

[0076] Fifth aspect of the present application provides crystalline form D3 of Vidofludimus calcium characterized by XRPD pattern as illustrated in figure- 10.

[0077] In embodiment, the present invention provides a process for preparation of crystalline form D3 of Vidofludimus calcium, comprising: a) providing a solution of Vidofludimus free acid and calcium hydroxide in a mixture of methanol and n-butanol; b) isolating the crystalline form D3 of Vidofludimus calcium.

[0078] Sixth aspect of the present application provides crystalline form DC1 of Vidofludimus calcium characterized by XRPD pattern as illustrated in figure- 12.

[0079] In embodiment, the present invention provides a process for preparation of crystalline form DC1 of Vidofludimus calcium, comprising: a) providing a solution of Vidofludimus calcium and caffeine in methanol; b) isolating the crystalline form DC1 of Vidofludimus calcium.

[0080] Seventh aspect of the present application relates to a pharmaceutical composition comprising a solid-state form of Vidofludimus calcium selected from amorphous solid dispersion with one or more pharmaceutically acceptable carriers such as copovidone, PVP-K30, HPMC, soluplus, methyl cellulose, HPMC-AS and ethyl cellulose, amorphous form, crystalline form DI, crystalline form D2, crystalline form D3, crystalline form DC1 and one or more pharmaceutically acceptable excipients.

[0081] In embodiments, the pharmaceutical composition of the present application may be formulated as: solid oral dosage forms such as, powders, granules, pellets, tablets, and capsules; liquid oral dosage forms such as, syrups, suspensions, dispersions, and emulsions; and injectable preparations such as, solutions, dispersions, and freeze dried compositions. Formulations may be in the forms of immediate release, delayed release, or modified release. Further, immediate release compositions may be conventional, dispersible, chewable, mouth dissolving, or flash melt preparations, and modified release compositions that may comprise hydrophilic or hydrophobic, or combinations of hydrophilic and hydrophobic, release rate controlling substances to form matrix or reservoir or combination of matrix and reservoir systems. The compositions may be prepared using any one or more of techniques such as direct blending, dry granulation, wet granulation, and extrusion and spheronization.

[0082] Compositions may be presented as uncoated, film coated, sugar coated, powder coated, enteric coated, and modified release coated.

[0083] Pharmaceutically acceptable excipients that are useful in the present application include, but are not limited to: diluents such as starches, pregelatinized starches, lactose, powdered celluloses, microcrystalline celluloses, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinylpyrrolidones, hydroxypropyl celluloses, hydroxypropyl methyl celluloses, pre-gelatinized starches, and the like; disintegrants such as starches, sodium starch glycolate, pre- gelatinized starches, crospovidones, croscarmellose sodium, colloidal silicon dioxide, and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate, and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic, cationic, or neutral surfactants; complex forming agents such as various grades of cyclodextrins and resins; and release rate controlling agents such as hydroxypropyl celluloses, hydroxymethyl celluloses, hydroxypropyl methylcelluloses, ethylcelluloses, methylcelluloses, various grades of methyl methacrylates, waxes, and the like. Other pharmaceutically acceptable excipients that are useful include, but are not limited to, film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants, and the like.

[0084] Eighth aspect of the present application relates to use of solid state form of Vidofludimus calcium selected from amorphous solid dispersion, amorphous form, crystalline form DI, crystalline form D2, crystalline form D3, crystalline form DC1 of the present application for the treatment of multiple sclerosis.

[0085] Ninth aspect of the present application relates to a process for the preparation of Vidofludimus and pharmaceutically acceptable salts thereof, comprising; a) reacting the compound of formula (IV) with the compound of formula (VI) to produce compound of formula (VII), wherein, R represents C1-C4 alkyl group b) hydrolyzing the compound of formula (VII) to Vidofludimus, c) optionally converting the Vidofludimus to pharmaceutically acceptable salts.

[0086] In embodiments, step-a) may be carried out in presence of an acid amine coupling agent. In other embodiments, the acid amine coupling agent may be selected from propylphosphonic anhydride (T3P), N,N'-dicyclohexylcarbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), O-(7-azabenzotriazol-l- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol- l-yl-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU) and benzotriazol- 1-yl-oxy-tris-pyrrolidinophosphonium hexafluorophosphate

[0087] (PyBOP). In a specific embodiment, the acid amine coupling agent is propylphosphonic anhydride. Alternatively, step-a) may be carried out in presence of chlorinating agent such as thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride and the like.

[0088] In embodiments, the step-a) may be carried out in presence of a base selected from pyridine, trialkylamine such as triethylamine, diisopropylethylamine, dimethylamine and the like. In a specific embodiment, the base may be pyridine. The above step-a) may be carried out in presence of a solvent that includes but is not limited to polar aprotic solvents such as dimethyl formamide (DMF), dimethylacetamide (DMA), N-methyl pyrrolidone (NMP) and the like; ester solvents such as ethyl acetate, methyl acetate, propyl acetate and the like; ether solvents such as tetrahydrofuran, methyl tert-butyl ether and the like; ketone solvents such as acetone, ethyl methyl ketone and the like; aromatic hydrocarbon solvents such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane and the like; nitrile solvent such as acetonitrile, propionitrile and the like; and mixtures thereof. In a specific embodiment, the step a) may be carried out in ethyl acetate as solvent.

[0089] In embodiments of the step-b), the hydrolysis may be carried out in presence of a base or an acid. In a specific embodiment, the hydrolysis may be carried out in presence of a base. The base may be selected from an organic base or an inorganic base. In a more specific embodiment, the base may be an inorganic base. In a furthermore specific embodiment, the base may be a hydroxide base.

[0090] In a specific embodiment, a process for the preparation of Vidofludimus and pharmaceutically acceptable salts thereof, comprising; a) reacting the compound of formula (IV) with the compound of formula (Via) to produce compound of formula (Vila), b) hydrolyzing the compound of formula (Vila) to obtain Vidofludimus, c) optionally, converting the Vidofludimus to its pharmaceutically acceptable salts.

[0091] Tenth aspect of the present application relates to a process for the preparation of 3-fluoro-3'-methoxy-[l,T-biphenyl]-4-amine of formula (IV), comprising; a) reacting compound of formula (VIII) with (3 -methoxyphenyl) boronic acid of formula (HI) in presence of heterogeneous metal catalyst to produce 3-fluoro-3'-methoxy-4-nitro-l,l'-biphenyl of formula (IX), wherein, X is Cl, Br or I b) reducing compound of formula (IX) to produce 3-fluoro-3'-methoxy-

[0092] [l,l'-biphenyl]-4-amine of formula (IV)

[0093] In one embodiment, 3-fluoro-3'-methoxy-4-nitro-l, l'-biphenyl of formula (IX) which is obtained in step-a) may optionally be isolated.

[0094] In one embodiment, the heterogeneous metal catalyst in step-a) includes but not limited to supported palladium, palladium oxide (PdO) or palladium hydroxide (Pd(OH)2) catalysts such as Pd / C, Pd(OH)2 / C, SiliaCat DPP-Pd, PdO on graphene oxide, Pd / AFOs. Pd / BaSO4 and the like.

[0095] In one embodiment, the solvent in step-a) and step-b) includes but not limited to ether solvents such as tetrahydrofuran, methyl tert-butyl ether, 1,4- dioxane and the like; alcohol solvents such as methanol, ethanol, 1 -propanol, isopropyl alcohol, n-butanol and the like; ester solvents such as ethyl acetate, methyl acetate and the like; polar aprotic solvents such as dimethyl formamide (DMF), dimethylacetamide (DMAc), N-methyl pyrrolidone (NMP) and the like; nitrile solvent such as acetonitrile, propionitrile and the like; water and mixtures thereof. In a specific embodiment, the solvent in step-a) may be a mixture of 1, 4- dioxane and water. In a specific embodiment, the solvent in step-b) may be ethyl acetate.

[0096] In one embodiment, step-a) and step-b) reaction may be carried out between about 10°C and about 100°C. The reaction mixture obtained may be stirred for 10 to 24 hours at the required temperature.

[0097] In one embodiment, step-a) reaction may be carried out in presence of a base selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium phosphate, potassium phosphate and the like. In a specific embodiment, potassium carbonate may be used as a base in step-a).

[0098] In one embodiment, the reduction reaction in step-b) may be carried out using a suitable reducing agent that includes but not limited to sodium dithionite, sulfur, sodium sulfide, sodium hydrogen sulfide and the like; hydrogen in presence of metal catalysts such as Pd / C, Pt / C, Raney Ni, Pd / BaSC , Pd / CaCOs and the like; stoichiometric metal reducing agents such as Fe, Zn, SnCh and the like; boron reagents such as bis(pinacolato)diboron (B2PHI2), B2(OH)4 and the like; transfer hydrogenation reagents such as NaBFU, formic acid and the like. In a specific embodiment, the reducing agent is hydrogen in presence of metal catalyst such as Pd / C. In a preferred embodiment, a process for the preparation of 3-fluoro-3'- methoxy-[l,l'-biphenyl]-4-amine of formula (IV), comprising; a) reacting 4-bromo-2-fluoro-l -nitrobenzene of formula (Villa) with (3- methoxyphenyl) boronic acid of formula (III) to produce 3-fluoro-3'- methoxy-4-nitro-l,l'-biphenyl of formula (IX), b) reducing compound of formula (IX) to produce compound of formula (IV)

[0099] Eleventh aspect of the present application relates to a process for the preparation of Vidofludimus and pharmaceutically acceptable salts thereof, comprising: a) reacting 4-bromo-2-fluoroaniline of formula (II) with (3- methoxyphenyl) boronic acid of formula (III) in presence of heterogeneous metal catalyst to produce 3 -fluoro-3 '-methoxy- [1,1'- b) reacting the compound of formula (IV) with the compound of formula (VI) to produce compound of formula (VII), wherein, R represents C1-C4 alkyl group c) hydrolyzing the compound of formula (VII) to Vidofludimus, d) optionally converting the Vidofludimus into pharmaceutically acceptable salts wherein heterogeneous metal catalyst is selected from supported palladium, supported palladium oxide (PdO) or supported palladium hydroxide (Pd(OH)2) such as Pd / C, Pd(OH)2 / C, SiliaCat DPP-Pd, PdO on graphene oxide, Pd / Al2O3, Pd / BaSO4 and the like.

[0100] In one embodiment, the solvent in step-a) includes but not limited to alcohol solvents such as methanol, ethanol, 1 -propanol, isopropyl alcohol, n- butanol, tert-butanol and the like; polar aprotic solvents such as dimethyl formamide (DMF), dimethylacetamide (DMA), N-methyl pyrrolidone (NMP) and the like; ester solvents such as ethyl acetate, methyl acetate, propyl acetate and the like; ether solvents such as tetrahydrofuran, methyl tert-butyl ether and the like; ketone solvents such as acetone, ethyl methyl ketone and the like; aromatic hydrocarbon solvents such as toluene, xylene and the like; halogenated hydrocarbons such as dichloromethane and the like; aliphatic hydrocarbon solvents such as n-pentane, n-hexane, n-heptane and the like; nitrile solvent such as acetonitrile, propionitrile and the like; water and mixtures thereof. In a specific embodiment, alcohol solvent such as methanol, ethanol, 1 -propanol, isopropyl alcohol, n-butanol, tert-butanol and the like; water; and mixture thereof.

[0101] The above step-a) may be carried out between about 10°C and about 100°C. The reaction mixture obtained in step-a) may be stirred for 10 to 24 hours at the required temperature.

[0102] The above step-a) may be carried out in presence of a base selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, sodium phosphate, potassium phosphate and the like. In a specific embodiment, potassium carbonate is used as a base in step a).

[0103] In one specific embodiment, the present application relates to a process for preparation of Vidofludimus and pharmaceutically acceptable salts thereof, comprising the steps of; a) reacting compound of formula (VIII) with (3 -methoxyphenyl) boronic acid of formula (HI) in presence of heterogeneous metal catalyst to produce 3-fluoro-3'-methoxy-4-nitro-l,l'-biphenyl of formula (IX), wherein, X is Cl, Br or I b) reducing compound of formula (IX) to produce 3-fluoro-3'-methoxy- [l,l'-biphenyl]-4-amine of formula (IV) c) reacting the compound of formula (IV) with the compound of formula

[0104] (VI) to produce compound of formula (VII); wherein, R represents C1-C4 alkyl group d) hydrolyzing the compound of formula (VII) to Vidofludimus; e) optionally converting the Vidofludimus to pharmaceutically acceptable salts.

[0105] Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.

[0106] EXAMPLES

[0107] Example-1: Process for the preparation of amorphous solid dispersion of Vidofludimus calcium with copovidone.

[0108] Vidofludimus calcium (500 mg) and copovidone (1500 mg) were dissolved in a mixture of methylene chloride and methanol (76 mL, 3: 1 (v / v)) at 25-30°C. The obtained solution was distilled completely under reduced pressure at 70°C and then dried for 1 hour to get the solid compound.

[0109] PXRD diagram: Figure- 1

[0110] Example-la: Stability of amorphous solid dispersion of Vidofludimus calcium with copovidone

[0111] The amorphous solid dispersion of Vidofludimus calcium with copovidone (1:3, w / w), as prepared in example 1, was kept at 25°C / 60% RH and 40°C / 75% RH and 2-8°C in closed conditions and found to be stable, both physically and chemically, after three months.

[0112] Example-2: Process for the preparation of amorphous solid dispersion of

[0113] Vidofludimus calcium with PVP K-30.

[0114] Vidofludimus calcium (500 mg) and PVP K-30 (1500 mg) were dissolved in a mixture of methylene chloride and methanol (76 mL, 3: 1 (v / v)) at 25-30°C. The obtained solution was distilled completely under reduced pressure at 70°C and then dried for 24 hours to get the solid compound.

[0115] PXRD diagram: Figure-2

[0116] Example-2a: Stability of amorphous solid dispersion of Vidofludimus calcium with PVP K-30

[0117] The amorphous solid dispersion of Vidofludimus calcium with PVP K-30 (1:3, w / w), as prepared in example 2, was kept at 25°C / 60% RH and 40°C / 75% RH and 2-8°C in closed conditions and found to be stable, both physically and chemically, after three months.

[0118] Example-3: Process for the preparation of amorphous solid dispersion of Vidofludimus calcium with HPMC.

[0119] Vidofludimus calcium (500 mg) and HPMC (1500 mg) were dissolved in a mixture of methylene chloride and methanol (76 mL, 3: 1 (v / v)) at 25-30°C. The obtained solution was distilled completely under reduced pressure at 70°C and then dried for 5 hours to get the solid compound.

[0120] PXRD diagram: Figure-3

[0121] Example-3a: Stability of amorphous solid dispersion of Vidofludimus calcium with HPMC

[0122] The amorphous solid dispersion of Vidofludimus calcium with HPMC (1:3, w / w), as prepared in example 3, was kept at 25°C / 60% RH and 40°C / 75% RH and 2-8°C in closed conditions and found to be stable, both physically and chemically, after three months.

[0123] Parameter

[0124] Example-4: Process for the preparation of amorphous solid dispersion of Vidofludimus calcium with Soluplus.

[0125] Vidofludimus calcium (500 mg) and Soluplus (1500 mg) were dissolved in a mixture of methylene chloride and methanol (76 mL, 3: 1 (v / v)) at 25-30°C. The obtained solution was distilled completely under reduced pressure at 70°C and then dried for 24 hours to get the solid compound.

[0126] PXRD diagram: Figure-4

[0127] Example-4a: Stability of amorphous solid dispersion of Vidofludimus calcium with Soluplus

[0128] The amorphous solid dispersion of Vidofludimus calcium with Soluplus (1:3, w / w), as prepared in example 4, was kept at 25°C / 60% RH and 40°C / 75% RH and 2-8°C in closed conditions and found to be stable, both physically and chemically, after three months.

[0129] Example-5: Process for the preparation of amorphous solid dispersion of Vidofludimus calcium with methyl cellulose.

[0130] Vidofludimus calcium (500 mg) and methyl cellulose (1500 mg) were dissolved in a mixture of methylene chloride and methanol (76 mL, 3: 1 (v / v)) at 25-30°C. The obtained solution was distilled completely under reduced pressure at 70°C and then dried for 24 hours to get the solid compound.

[0131] PXRD diagram: Figure-5. Example-5a: Stability of amorphous solid dispersion of Vidofludimus calcium with methyl cellulose.

[0132] The amorphous solid dispersion of Vidofludimus calcium with methyl cellulose (1:3, w / w), as prepared in example 5, was kept at 25°C / 60% RH and 40°C / 75% RH and 2-8°C in closed conditions and found to be stable, both physically and chemically, after three months.

[0133] Example-6: Process for the preparation of amorphous solid dispersion of Vidofludimus calcium with HPMC-AS.

[0134] Vidofludimus calcium (500 mg) and HPMC-AS (1500 mg) were dissolved in a mixture of methylene chloride and methanol (76 mL, 3:1 (v / v)) at 25-30°C. The obtained solution was distilled completely under reduced pressure at 70°C and then dried for 20 hours to get the solid compound.

[0135] PXRD diagram: Figure-6.

[0136] Example-6a: Stability of amorphous solid dispersion of Vidofludimus calcium with HPMC-AS

[0137] The amorphous solid dispersion of Vidofludimus calcium with HPMC-AS (1:3, w / w), as prepared in example 6, was kept at 25°C / 60% RH and 40°C / 75% RH and 2-8°C in closed conditions and found to be stable, both physically and chemically, after three months. Example-7: Process for the preparation of amorphous solid dispersion of Vidofludimus calcium with ethyl cellulose.

[0138] Vidofludimus calcium (500 mg) and ethyl cellulose (1500 mg) were dissolved in a mixture of methylene chloride and methanol (76 mL, 3:1 (v / v)) at 25-30°C. The obtained solution was distilled completely under reduced pressure at 70°C and then dried for 16 hours to get the solid compound.

[0139] PXRD diagram: Figure-7

[0140] Example-7a: Stability of amorphous solid dispersion of Vidofludimus calcium with ethyl cellulose.

[0141] The amorphous solid dispersion of Vidofludimus calcium with ethyl cellulose (1:3, w / w), as prepared in example 7, was kept at 25°C / 60% RH and 40°C / 75% RH and 2-8°C in closed conditions and found to be stable, both physically and chemically, after three months.

[0142] Example-8: Process for the preparation of Vidofludimus calcium crystalline form DI

[0143] Vidofludimus calcium (2 gm) and 2-methoxyethanol (10 mL) were discharged into a glass vial and raised the temperature of the mixture to 60°C. The reaction mixture was stirred for 1 hour at 60°C and cooled to -10°C and stirred for 24 hours at same temperature. Methyl tert-butyl ether (10 mL) was added to the above slurry and stirred for 15 min. The obtained solid was filtered and then dried for 3 hours to get the solid material.

[0144] PXRD diagram: Figure-8.

[0145] PEAK Positions: 7.4, 12.13, 12.36, 13.23, 13.84, 14.07, 15.02, 15.91, 17.24, 18.13, 18.83, 19.32, 20.59, 20.95, 21.34, 21.5, 21.88, 23.03, 23.28, 24.12, 24.36, 24.87, 25.36, 25.56, 26.06, 26.71, 27.16, 27.97, 28.32, 29.28, 29.51 degrees 2-theta. Example-9: Process for the preparation of Vidofludimus calcium crystalline form D2

[0146] Vidofludimus free acid (100 mg) and calcium hydroxide (40 mg) were added to 2-propanol (2 mL) and raised the temperature of the mixture to 70°C. The reaction mixture was stirred for 1 hour at 70°C and cooled to 60°C and stirred for 1 hour at same temperature. The obtained solid was filtered to get the solid material.

[0147] PXRD diagram: Figure-9.

[0148] Peak Positions: 7.17, 8.81, 10.07, 14.54, 13.9, 16.18, 17.92, 23.05, 26.82 and 28.59 degrees 2-theta.

[0149] Example-10: Process for the preparation of Vidofludimus calcium crystalline form D3

[0150] Vidofludimus free acid (100 mg) and calcium hydroxide (40 mg) were added to a mixture of methanol and n-butanol (2mL, 1: 1 (v / v)) and raised the temperature of the mixture to 70°C. The reaction mixture was stirred for 1 hour at 70°C for 1 hour. The obtained solid was filtered and then dried to get the solid material. PXRD diagram: Figure-10.

[0151] Peak Positions: 7.17, 8.81, 10.07, 14.54, 13.9, 16.18, 17.92, 23.05, 26.82 and 28.59 degrees 2-theta.

[0152] Example-11: Process for the preparation of amorphous form of Vidofludimus calcium

[0153] Vidofludimus calcium (10 gm) was dissolved in a mixture of methylene chloride and methanol (2400 mL, 3: 1 (v / v)). The clear solution was filtered under reduced pressure at 25-30°C. The filtered solution was spray dried (Inlet 70°C, feed rate 8 gm / min) and then dried the obtained compound for 2 hours to get the title compound.

[0154] PXRD diagram: Figure-11.

[0155] Example-lla: Stability of amorphous form of Vidofludimus calcium.

[0156] The amorphous form of Vidofludimus calcium as prepared in example 11, was kept at 25°C / 60% RH and 40°C / 75% RH and 2-8°C in closed conditions and found to be stable, both physically and chemically, after three months.

[0157] Example-12: Process for the preparation of Vidofludimus calcium form DC1

[0158] Vidofludimus calcium (50 mg) and caffeine (20 mg) were added to methanol (0.25 mL). The obtained mixture was stirred for 15 days at 25-30°C. The solid was filtered and then dried to get the title compound.

[0159] PXRD diagram: Figure-12.

[0160] Peak Positions: 4.63, 7.52, 9.29, 9.61, 10.27, 11.71, 11.9, 12.44, 13.63, 14.07, 14.65, 15.15, 15.95, 17.49, 18.82, 19.23, 19.67, 20.16, 20.36, 20.68, 21.3, 22.02, 22.82, 23.51, 24.09, 25.05, 25.69, 26.02, 26.99, 27.57, 28.27, 28.58, 29.28, 30.08, 30.46, 31.13, 33.06, 34.55, 36.39, 37.16 and 39.39 degrees 2-theta.

[0161] Example-13: Process for the preparation of 3-fluoro-3'-methoxy-[l,l'- biphenyl]-4-amine of formula (IV)

[0162] (3 -Methoxyphenyl) boronic acid of formula (III) (57.17 g), potassium carbonate (47.98 g) and 10% Pd / C (1.1 g) were added to a stirred solution of 4-bromo-2- fluoroaniline of formula (II) (55 g) in a mixture of methanol and water (1100 ml, 3: 1 v / v). The obtained reaction mixture was sparged with nitrogen for 30-60 min and then heated at 70-75°C under nitrogen atmosphere for 18 hours. The reaction mixture was diluted with methanol (550 ml) and stirred for 15 min. The reaction mixture was filtered through a Celite bed and the obtained filtrate was concentrated under reduced pressure at 45-50°C. The obtained residue was dissolved in dichloromethane (687.5 ml). The dichloromethane solution was washed with water twice, followed by brine, dried over anhydrous sodium sulfate and finally concentrated under reduced pressure at 40-45°C. The obtained solid was triturated with hexane (550 ml), filtered and then dried under reduced pressure to obtain 3-fluoro-3'-methoxy-[l,r-biphenyl]-4-amine of formula (IV) as an off-white solid.

[0163] Yield: 56.5 g, purity: 98.49% by HPLC.

[0164] Example-14: 3-Fluoro-3'-methoxy-4-nitro-l,r-biphenyl of formula (IX)

[0165] To a stirred solution of 4-bromo-2-fluoro-l -nitrobenzene (3 g) in 1,4-dioxane (45 mL) and water (15 mL) was added K2CO3 (2.25 g), (3 -methoxyphenyl) boronic acid of formula (III) (2.06 g) and 10% Pd / C (0.06 g) at 25-35°C. The obtained reaction mixture was sparged with nitrogen for 30-60 min and then heated at 80-85°C under nitrogen atmosphere for 6 h. The reaction mixture was cooled to 25-35°C and a second lot of (3 -methoxyphenyl) boronic acid of formula (III) (0.206 g) was added. The obtained reaction mixture was then heated at 80-85°C for 16 h. The reaction mixture was cooled to 25-35°C and a third lot of (3 -methoxyphenyl) boronic acid of formula (III) (0.206 g) was added. The obtained reaction mixture was heated at 80-85 °C for 4-5 h. The reaction mixture was cooled to 25 -35 °C and filtered under suction through a Celite bed, which was then washed with ethyl acetate (90 mL). The organic layer in the combined filtrate and washings was separated and concentrated under reduced pressure below 45°C to obtain a viscous liquid. This crude product was purified by column chromatography using silica gel (100-200 mesh) and 5% EtOAc-hexane to get title compound.

[0166] Yield: 2.6 g, purity by HPLC: 99.26%.

[0167] 'H NMR (400 MHz, CDCh): 5 8.14 (t, J = 8.0 Hz, 1H), 7.49-7.50 (m, 1H), 7.46- 7.48 (m, 1H), 7.41 (t, 7 = 8.0 Hz, 1H), 7.18-7.19 (m, 1H), 7.10 (t, J = 2.4 Hz, 1H), 7.01 (ddd, J = 0.8, 2.4 and 8.0 Hz, 1H), 3.88 (s, 3H).

[0168] 19F NMR (376 MHz, CDCh): 5 116.55 (IF)

[0169] 13C NMR (100 MHz, CDCh): 5 160.23, 157.17, 154.53, 149.11, 138.96, 130.36, 126.62, 122.92, 119.64, 116.77, 114.70, 113.13, 55.43.

[0170] Example-15: 3-Fluoro-3'-methoxy-4-nitro-l,l'-biphenyl of formula (IX)

[0171] To a stirred solution of 4-chloro-2-fluoro-l -nitrobenzene (0.5 g) in 1,4-dioxane (7.5 mL) and water (2.5 mL) was added K2CO3 (0.464 g), (3 -methoxyphenyl) boronic acid of formula (HI) (0.510 g) and 10% Pd / C (0.01 g) at 25-35°C. The obtained reaction mixture was sparged with nitrogen for 30-60 min and then heated at 80-85°C under nitrogen atmosphere for 6 h. The reaction mixture was filtered under suction through a Celite bed, which was then washed with ethyl acetate (15 mL). The organic layer in the combined filtrate and washings was separated and concentrated under reduced pressure below 45 °C to obtain a viscous liquid. This crude product was purified by column chromatography using silica gel (100-200 mesh) and 5% EtOAc-hexane to obtain title compound. Yield: 0.15 g; purity by HPLC: 99.21%.

[0172] Example-16: 3-Fluoro-3'-methoxy-[l, 1' -biphenyl] -4-amine of formula (IV)

[0173] To a stirred solution of 3-fluoro-3'-methoxy-4-nitro-l,T-biphenyl of formula (IX) (2.5 g) in ethyl acetate (37.5 mL) at 25-35°C was added 10% Pd / C (0.1 g). The resulting mixture was sparged with hydrogen for 30 min and then hydrogenated at 25-35°C for 16-18 h using a hydrogen balloon. The reaction mixture was filtered through a Celite bed, which then washed with ethyl acetate (75 mL). The filtrate and washings were combined and concentrated under reduced pressure at 45 °C to obtain a viscous liquid, which was mixed with hexane (12.5 mL). The obtained mixture was concentrated under reduced pressure below 45°C to obtain an orange colored solid. This was then stirred with hexane (15 mL) for 10 min at 25-35 °C and filtered under suction. The filter residue was washed with hexane (7.5 mL), and dried to obtain title compound.

[0174] Yield: 1.75 g; purity by HPLC: 98.61%.

[0175] Example-17: One-pot synthesis of 3-fluoro-3'-methoxy-[l, 1' -biphenyl] -4- amine of formula (IV)

[0176] To a stirred solution of 4-bromo-2-fluoro- 1 -nitrobenzene (0.5 g) in 1,4-dioxane (7.5 mL) and water (2.5 mL) was added K2CO3 (0.364 g), (3 -methoxyphenyl) boronic acid of formula (III) (0.414 g) and 10% Pd / C (0.01 g) at 25-35°C. The obtained reaction mixture was sparged with nitrogen for 30-60 min and then heated at 80-85°C under nitrogen atmosphere for 6 h. The reaction mixture was cooled to 25-35°C and sparged with hydrogen for 30 min. Thereafter, the reaction mixture was hydrogenated at 25-30 °C for 36-40 h using a hydrogen balloon. The reaction mixture was filtered through a Celite bed, which was washed with ethyl acetate (15 mL). The filtrate and washings were combined and concentrated under reduced pressure to obtain a viscous liquid. This crude product was purified by column chromatography using silica gel (100-200 mesh) and 5% ethyl acetatehexane to obtain title compound.

[0177] Yield: 0.25 g; purity by HPLC: 95.47%.

[0178] Example-18: Process for the preparation of Vidofludimus methyl ester 3-Fluoro-3'-methoxy-[l,T-biphenyl]-4-amine of formula (IV) (55 g) was dissolved in ethyl acetate (550 ml) and the solution was heated to 75-80°C. A solution of cyclopent- l-ene-l,2-dicarboxylic acid mono methyl ester (64.59 g) in ethyl acetate (110 ml), followed by pyridine (44.04 g) and propylphosphonic anhydride (483.18 ml, 50% solution in ethyl acetate), were added to the above solution. The obtained reaction mixture was stirred at 75-80°C for 4 hours, after which it was cooled to 0-5 °C and stirred for 1 hour at same temperature. The precipitated solid was filtered, washed with ethyl acetate and then dried under reduced pressure to get title compound as a yellow solid (Lot-1: 50.15 g, purity: 97.41% by HPLC).

[0179] The filtrate and washings were combined, washed first with saturated sodium bicarbonate solution (275 ml) and then with water (2 X330 mL), and finally concentrated under reduced pressure at 45°C. The obtained residue was purified by silica gel column chromatography. The obtained solid was suspended in ethyl acetate (137.5 mL) and stirred at 65-70°C for 2 hours. The mixture was then cooled to 0-5°C, stirred at the same temperature for 1 hour and filtered. The obtained solid was washed with ethyl acetate to afford a second crop of title compound (Lot-2: 9.45 g, purity: 99.4% by HPLC).

[0180] Example-19: Process for the preparation of Vidofludimus

[0181] 10% Aqueous KOH solution (1250 mL) was added to a stirred suspension of Vidofludimus methyl ester (50 g) in a mixture of THF-EtOH (1350 mL, 1: 1 v / v) maintained at 25-35°C. The obtained reaction mixture was heated to 50-55 °C and stirred at the same temperature for 3-4 hours. The reaction mixture was cooled to 25-35°C and concentrated under reduced pressure below 50°C. The obtained solid was taken into water (500 mL). The resulting suspension was cooled to 0-10°C, and while being maintained at 0-10°C, treated with con. HC1 in order to adjust its pH to 1-2. Thereafter it was stirred for 15 min at 0-10°C and filtered. The obtained solid was washed with water (250 mL), dried under suction, suspended again in water (750 mL), stirred for 2.5 hours at 29°C and filtered. The solid was washed with water (400 mL), dried under suction, suspended in hexane (750 mL), stirred for 2 hours at 29°C and filtered. The obtained wet cake was washed with hexane (250 mL) and dried at 55°C under reduced pressure for 2-3 hours to obtain Vidofludimus (I) as a solid

[0182] Yield: 40.9 g; purity: 98.31% by HPLC.

[0183] Example-20: Process for the preparation of Vidofludimus calcium salt

[0184] A suspension of Vidofludimus (38g) in a mixture of MeOH-DCM (2280 mL, 1:3 v / v) was sonicated for 25 min to obtain a clear solution. To this solution was added a suspension of calcium hydroxide (3.9 g) in MeOH-DCM (380 mL, 1:3 v / v). The obtained reaction mixture was stirred at 25 -35 °C for 18 hours after which it was concentrated under reduced pressure below 16°C to one-third of its original volume. Nitrogen was bubbled through the obtained clear solution until a suspension was obtained, which was then stirred at 25-30°C for 45 min and filtered under suction. The obtained solid was washed with MeOH-DCM (190 mL, 1:3 v / v), dried under suction at 25-35°C for 20 min and then stirred in acetone (570 mL) at 25-35°C for 3 hours. The resulting suspension was filtered. The obtained solid was washed with acetone (190 mL) and dried under suction at 25-35°C for 1 hour. It was further dried under reduced pressure for 2-3 h below 25°C to afford Vidofludimus calcium salt as a white solid

[0185] Yield: 33.406 g; purity: 99.84% by HPLC.

Claims

Claims:

1. A process for the preparation of Vidofludimus and pharmaceutically acceptable salts thereof, comprising; a) reacting the compound of formula (IV) with the compound of formula(VI) to produce compound of formula (VII),wherein, R represents C1-C4 alkyl group b) hydrolyzing the compound of formula (VII) to obtain Vidofludimus, c) optionally, converting the Vidofludimus to pharmaceutically acceptable salts.

2. The process of claim 1, wherein step-a) is carried out in presence of an acid amine coupling agent.

3. The process of claim 2, wherein the acid amine coupling agent is propylphosphonic anhydride (T3P).

4. The process of claim 1, wherein R is methyl.

5. The process for claim 1, wherein the hydrolysis of compound of formula (VII) is carried out in presence of a base.

6. The process of claim 1, wherein the compound of formula (IV) is prepared by a process comprising; a) reacting compound of formula (VIII) with (3 -methoxyphenyl) boronic acid of formula (HI) in presence of heterogeneous metal catalyst to produce 3-fluoro-3'-methoxy-4-nitro-l,T-biphenyl of formula (IX),wherein, X is Cl, Br or I b) reducing compound of formula (IX) to produce 3-fluoro-3'-methoxy-[l,l'-biphenyl]-4-amine of formula (IV)7. The process of claim 6, wherein the heterogeneous metal catalyst is selected from supported palladium, palladium oxide (PdO) and palladium hydroxide (Pd(OH)2).

8. The process of claim 7, wherein the heterogeneous metal catalyst is Pd / C.

9. The process of claim 6, wherein X is Br.

10. The process of claim 6, wherein the compound of formula (IX) is optionally isolated.

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