Related applications:

This application claims the benefit under Indian Provisional Application Nos. 202241007153, filed on Feb 10, 2022 and 202241041742, filed on Jul 21, 2022; the contents of which are incorporated by reference herein.

Field of the invention:

The present invention relates to a process for the preparation of Ponesimod of formula I and its intermediates thereof. of the invention:

Ponesimod is a sphingosine 1 -phosphate receptor modulator. It was approved and marketed as Ponvory in the United States and Europe in 2021 for the treatment of relapsing forms of multiple sclerosis, by Janssen pharmaceuticals.

Ponesimod is chemically known as (2Z,5Z)-5-[3-chloro-4-[(2R)-2,3- dihydroxypropoxy] benzylidene]-3-(2-methylphenyl)-2-(propylimino)-l,3-thiazoli din-4-one and is represented by the following structural formula I.

Ponesimod and process for its preparation was first disclosed in the US7435828 (the US ‘828 patent) and the disclosed process is schematically depicted in the following scheme: The US 8912340 patent (the US ‘340 patent) discloses a generic process for the preparation of Ponesimod intermediate compound of Formula A, chemically known as 3-(2-methyl phenyl)-2-((Z)-propylimino)thiazolidin-4-one and Formula B, chemically known as 5-(3- Chloro-4-hydroxy-benz-(Z)-ylidene)-2-[(Z)-propyhmino]-3-(o-t olyl)-thiazolidin-4-one.

The disclosed process is schematically depicted in the following scheme:

The US 9340518 patent (the US ‘518 patent) discloses a process for the preparation of Ponesimod intermediate compound of Formula C, chemically known as (R)-3-chloro-4- (2,3-dihydroxypropoxy)-benzaldehyde. The disclosed process is schematically depicted in the following scheme:

Formula C

The reported processes for the preparation of Ponesimod and its intermediates suffer from many disadvantages which include difficulty in achieving desired chemical and enantiomeric purity, tedious & cumber some work up procedures, column chromatographic separations and purifications etc. All these disadvantages affect the overall yield as well as the quality of the final product.

Still there is a need for an alternative process for the preparation of Ponesimod which is economical, easy to scale up and commercially viable. Thus, main objective of the present invention is to provide an alternative process for the preparation of Ponesimod which avoids the shortcomings of the prior art. Summary of the invention:

Accordingly, the present invention provides a process for the preparation of Ponesimod of formula I via novel intermediates.

In accordance with one embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) reacting a compound of formula XII with a compound of general formula XIII in the presence of a base in a suitable solvent to provide a compound of general formula IV, b) condensing the compound of general formula IV with a compound of formula VI in the presence of a base in a suitable solvent to provide a compound of general formula II, and c) converting the compound of general formula II into Ponesimod of formula I or its pharmaceutically acceptable salts.

In accordance with another embodiment, the present invention provides a process for the preparation of compound of formula IVa, which comprises, a) reacting 1,2-diol compound of formula XVIII with 2,2-dimethoxypropane in the presence of a suitable copper catalyst and a solvent to provide a compound of formula Xlllb, and b) condensing the compound of formula Xlllb with a compound of formula XII in the presence of a suitable base and a solvent to provide a compound of formula IVa.

In accordance with another embodiment, the present invention provides a process for the preparation of compound of formula VI, which comprises a) reacting a compound of formula XIX with carbon disulfide in the presence of a suitable base to provide an o-tolylisothiocynate of formula XX, b) reacting the o-tolylisothiocynate of formula XX with n-propylamine in the presence of a suitable solvent to provide a compound of formula XXI; and c) cyclizing the compound of formula XXI obtained in step-(b) with 2-chloro-acetyl chloride in the presence of a suitable base and a solvent to provide a compound of formula VI. In accordance with another embodiment, the present invention provides an alternate process for the preparation of compound of formula VI, which comprises a) reacting n-propylamine with carbon disulfide in the presence of a suitable base to provide a n-propyl isothiocyanate of formula XXII, b) reacting the n-propyl isothiocyanate of formula XXII with a compound of formula XIX in the presence of a suitable solvent to provide a compound of formula XXI, and c) cyclizing the compound of formula XXI obtained in step-(b) with 2-chloro-acetyl chloride or 2-bromo-acetyl bromide in the presence of a suitable base and a solvent to provide a compound formula VI.

In accordance with another embodiment, the present invention provides a process for the preparation of Ponesimod of formula I, which comprises,

1) preparing a compound of formula IVa, or a compound of formula VI according the present invention process; and

2) converting the compound of formula IVa or a compound of formula VI into Ponesimod of formula I.

In accordance with another embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) condensing a compound of formula V with a compound of general formula IV in the presence of a base in a suitable solvent to provide a compound of general formula in, b) reacting the compound of general formula III with n-propylhalide to provide a compound of general formula II, and c) converting the compound of general formula II into ponesimod of formula I or its pharmaceutically acceptable salts.

In accordance with another embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) reacting compound of formula XII with alkyl or aryl sulfonyl halide in the presence of a base in a suitable solvent to provide a compound of general formula XIV, b) condensing the compound of general formula XIV with a compound of formula VI to provide a compound of general formula VII, and c) converting the compound of general formula VII into ponesimod of formula I or its pharmaceutically acceptable salts.

In accordance with another embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) reacting a compound of formula V with a compound of formula XII to provide a compound of formula IX, b) reacting the compound of formula IX with alkyl or aryl sulfonyl halide in the presence of a base in a suitable solvent to provide a compound of general formula VIII, c) reacting the compound of general formula VIII with n-propylhalide to provide a compound of general formula VII, and d) converting the compound of general formula VII into ponesimod of formula I or its pharmaceutically acceptable salts.

In accordance with another embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) reacting a compound of formula XI with a compound of general formula XIII in the presence of a base in a suitable solvent to provide a compound of general formula X, b) converting the compound of general formula X into the compound of general formula II by reacting with a suitable chlorinating agent; and c) converting the compound of general formula II into ponesimod of formula I or its pharmaceutically acceptable salts.

In accordance with another embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) condensing the compound of formula XV with a compound of formula V or a compound of formula VI to provide a corresponding compound of formula XVI or compound of formula XVII, b) converting the compound of formula XVI and compound of formula XVII into the compound of formula IIA, and c) converting the compound of formula IIA into ponesimod of formula I or its pharmaceutically acceptable salts.

In accordance with another embodiment, the present invention provides novel intermediate compound of formula IIA, III, IVA, VII, VIII, IX, X, XVI and XVII.

In accordance with another embodiment, the present inventions provides use of novel compounds of formula IIA, III, IVA, VIIA, VIIB, VIII, IX, X, XVI and XVII as an intermediate in the preparation of ponesimod of formula I or its pharmaceutically acceptable salts.

In accordance another embodiment, the present invention provides a process for the purification of ponesimod or its pharmaceutically acceptable salts which comprises of crystallizing ponesimod or its pharmaceutically acceptable salts from a suitable solvent or mixture thereof.

In accordance with further embodiment, the present invention provides pharmaceutical composition comprising ponesimod or its pharmaceutically acceptable salts prepared according to the process of the present invention and at least one pharmaceutically acceptable excipients.

Detailed description of the invention:

Accordingly, the present invention provides a process for the preparation of Ponesimod of formula I via novel intermediates.

The term “suitable base/base” used herein the present invention until unless specified is selected from inorganic bases like “alkali metal hydroxides” such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; “alkali metal carbonates” such sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; “alkali metal hydrides” such as sodium hydride, potassium hydride, lithium hydride and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide and the like, ammonia and organic bases such as triethylamine, methylamine, ethylamine, sodium acetate, potassium acetate, l,8-diazabicycle[5.4.0]undec7-ene (DBU), 1,5- diazabicyclo(4.3.0)non-5-ene (DBN), lithiumdiisopropylamine (LDA), n- butyl lithium, tribenzylamine, isopropyl amine, diisopropylamine (DIP A), diisopropylethyl amine (DIPEA), N-methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (DMAP), morpholine, pyridine, 2,6-lutidine, 2,4,6-collidine, imidazole, 1- methylimidazole, 1 ,2,4-triazole, 1 ,4-diazabicyclo [2.2.2]octane (DABCO) or mixtures thereof.

The term “suitable solvent” used herein the present invention until unless specified is selected from, but are not limited to “alcoholic solvents” such as methanol, ethanol, isopropyl alcohol, n-propanol, butanol and the like; “ester solvents” such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, “ether solvents” such as tetrahydrofuran, diethyl ether, methyl tert-butyl ether, dioxane and the like; “hydrocarbon solvents” such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and the like; “chloro solvents” such as dichloromethane, ethylene dichloride, carbon tetrachloride, chloroform and the like; “polar aprotic solvents” such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, N- methyl pyrrolidone and the like; “nitrile solvents” such as acetonitrile and the like; “ketone solvents” such as acetone, methyl isobutyl ketone, methyl ethylketone and the like; and water.

The term “Cu catalyst” used in the present invention until unless specified is selected from, but are not limited to Q1SO4 anhydrous, CUSO4.3H2O, CUSO4.5H2O, CUSO4.7H2O, CuCl, CuBr, Cui, CU2O, CU(0AC)2 and the like. The term “suitable acid” used herein the present invention until unless specified is selected from, but are not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid etc; organic acids such as formic acid, acetic acid, maleic acid, malic acid, tartaric acid, oxalic acid, trifluoroacetic acid, methane sulfonic acid, p-toluene sulfonic acid and the like.

In a first embodiment, the present invention provides a process for the preparation of

Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) reacting a compound of formula XII with a compound of general formula XIII in the presence of a base in a suitable solvent to provide a compound of general formula IV; wherein R is selected from oxirane or 2, 2-dialkyl- 1,3 -dioxo lane and X is halogen; b) condensing the compound of general formula IV with a compound of formula VI in the presence of a base in a suitable solvent to provide a compound of general formula II, wherein R is selected from oxirane or 2, 2-dialkyl- 1,3 -dioxo lane, and c) converting the compound of general formula II into Ponesimod of formula I or its pharmaceutically acceptable salts. The starting compounds of formula XII & XIII are known in the art and commercially available; the same can be prepared by the known methods.

The step a) of aforementioned process involves the reaction of a compound of formula XII with a compound of general formula XIII, wherein R is selected from oxirane or 2,2- dialkyl-l,3-dioxolane; where alkyl is selected from methyl, ethyl or propyl and X is halogen selected from Cl, Br, I and F; in the presence of a base in a suitable solvent under appropriate reaction conditions to provide a compound of general formula IV, wherein R is selected from oxirane or 2, 2-dialkyl- 1,3 -dioxolane. The said reaction may be carried out in the presence of an additional catalyst such as iodine source selected from iodine, potassium iodide and the like. The suitable base is selected from inorganic bases such as alkali metal hydroxides, alkali metal carbonates/bicarbonates, alkali metal alkoxides and alkali metal hydrides and/or mixtures thereof; and the suitable solvent is selected from alcohols, polar aprotic solvents and/or mixtures thereof. The step a) reaction is carried out at a suitable temperature of about 25°C to about reflux temperature of the solvent used for a sufficient period of time till completion of the reaction, preferably for about 15 to 20 hrs at reflux temperature.

In a preferred embodiment, the reaction of a compound of formula XII with a compound of formula XIII, wherein R is 2, 2-dimethyl- 1,3 -di oxolane and X is Cl, represented by formula Xllla, in the presence of a base such as potassium carbonate in a polar aprotic solvent such as dimethylformamide to provide a compound formula IV, wherein R is 2, 2-dimethyl- 1,3- dioxolane, represented by formula IVa.

Formula Xllla Formula IVa

The step b) of aforementioned process involves the condensation of compound of general formula IV with a compound of formula VI in the presence of a base selected from organic or inorganic bases, in a suitable solvent under appropriate reaction conditions to provide a compound of general formula II, wherein R is selected from oxirane or 2, 2-dialkyl- 1,3- dioxolane. The suitable base is selected from sodium acetate, potassium acetate, triethylamine, diisopropylamine (DIPA), diisopropylethyl amine (DIPEA), N- methylmorpholine (NMP), N-ethylmorpholine, piperidine, dimethyl amino pyridine (DMAP), morpholine, pyridine, 2,6-lutidine and/or mixtures thereof; and the solvent is selected from alcohols, hydrocarbon solvents, acetic acid and/or mixture thereof. The step b) reaction is carried out at a suitable temperature of about 30°C to about reflux temperature of the solvent used for a sufficient period of time till completion of the reaction, preferably at a temperature of about 60°C to about 90°C for about 4 to 6 hours.

In a preferred embodiment, the condensation of a compound of formula IV, wherein R is 2,2-dimethyl-l,3-dioxolane represented by formula IVa with a compound of formula VI, in the presence of a base such as sodium acetate in an alcohol solvent such as isopropanol to provide a compound of formula II, wherein R is 2,2-dimethyl-l,3-dioxolane and is represented by following formula Ila,

Formula Ila

In an embodiment, the compound of formula II is isolated as a solid. Further isolation/crystallization of the compound of formula Ila can be carried out by dissolving the compound of formula Ila in a suitable solvent such as alcohols at a suitable temperature of about 30°C to reflux temperature, followed by precipitating the compound of formula Ila by addition of water or aliphatic hydrocarbons such as xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and/or mixtures thereof. The compound of formula Ila alternatively purified by recrystallisation from a suitable solvent such as ketones, preferably acetone.

In an embodiment, the present provides a process for purification/crystallization of a compound of formula Ila, which comprises,

1) dissolving a compound of formula Ila in a suitable solvent;

2) adding a suitable anti-solvent to step 1) solution; and

3) isolating pure compound of formula Ila. The dissolution of compound of formula Ila in a suitable solvent such as alcohols, preferably ethanol or isopropanol in step 1) is carried out by heating it to a suitable temperature of about 30°C to about reflux temperature of the solvent used; in step 2) the addition of suitable anti-solvent selected from water or hydrocarbons such as xylene, cyclohexane, hexane, heptane, n-pentane, petroleum ether and/or mixtures thereof is carried out at the same temperature of step a); and the isolation of pure compound of formula Ila from step 2) reaction can be carried out by the methods known in the art; for example, cooling the reaction mass, stirring followed by filtration.

The step c) of aforementioned process involves the conversion of the compound of general formula II into Ponesimod of formula I can be carried out by treating the compound of formula II with a base or an acid in a suitable solvent under appropriate reaction conditions. Optionally, Ponesimod of formula I is further converted into pharmaceutically acceptable salt by reaction with a suitable acid in a suitable solvent.

In a preferable embodiment, the conversion of compound of formula II, wherein R is 2,2- dimethyl- 1,3 -di oxolane represented by following formula Ila in to Ponesimod of formula I is carried out by treating the compound of formula II with a suitable acid such as hydrochloric acid in a suitable chloro solvent such as dichloromethane at a suitable temperature of about 20°C to about 40°C for a time period from about 8 to 12 hours.

In another embodiment, the present invention provides a process for the preparation of compound of formula IVa,

Formula IVa which comprises; a) reacting 1,2-diol compound of formula XVIII, wherein X is halogen or -OSO2R1; where Ri is selected from alkyl group or aryl group with or without substitution;

Formula XVIII with 2,2-dimethoxypropane in the presence of a suitable copper catalyst and a solvent to provide a compound of formula Xinb, wherein X is as defined above; and

Formula Xlllb b) condensing the compound of formula Xlllb with a compound of formula XII,

Formula XII in the presence of a suitable base and a solvent to provide a compound of formula IVa.

The starting compound of formula XVIII is known in the art and can be prepared by the method disclosed in the art.

In step a) of the forgoing process, the reaction of 1,2-diol compound of formula XVIII, wherein X is halogen; for example chlorine, bromine, iodine or fluorine, or -OS2R1, wherein Ri is selected from alkyl or aryl group with or without substitution; for example; benzenesulfonyl, toluene sulfonyl, nitrobenzene sulfonyl, methane sulfonyl and the like; with 2,2-dimethoxypropane is carried out in the presence of copper catalyst and a solvent under appropriate reaction conditions to provide a compound of formula Xlllb. The suitable copper catalyst is selected from CUSO4 anhydrous, CUSO4.3H2O, CUSO4.5H2O, CUSO4.7H2O, CuCl, CuBr, Cui, CU2O, Cu(0Ac)2 etc. The suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, nitrile solvents, ketone solvents and water. The said reaction carried out at a suitable temperature of about 15°C to 45°C for a sufficient period of time till completion of the reaction, preferably for about 1 to 2 hrs at about 25°C to about 35°C.

In a preferred embodiment, the reaction of 1 ,2-diol compound of formula XVIII, wherein X is chloro with 2,2-dimethoxypropane is carried out in the presence of CUSO4.5H2O in acetone to provide a compound of formula Xlllb, wherein X is chloro. In step b) of the foregoing process, condensation of the compound of formula Xlllb with a compound of formula XII is carried out in the presence of a suitable base and a solvent under appropriate reaction conditions to provide a compound of formula IVa. The suitable base is selected from inorganic bases, organic bases or mixtures thereof. The suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, nitrile solvents, ketone solvents and water. The said reaction is carried out at a suitable temperature of about 25°C to about reflux temperature of the solvent used, for a sufficient period of time till completion of the reaction, preferably for about 16 to 24 hrs at reflux temperature.

In a preferred embodiment, the condensation of compound of formula Xlllb, wherein X is chloro, with a compound of formula XII is carried out in the presence of a base such as potassium carbonate in polar aprotic solvent such as dimethylformamide to provide a compound formula IVa.

In another embodiment, the present invention provides a process for the preparation of compound of formula VI, which comprises, a) reacting a compound of formula XIX,

Formula XIX with carbon disulfide in the presence of a suitable base to provide a o-tolyliso thiocynate of formula XX,

Formula XX b) reacting the compound of formula XX with n-propylamine in the presence of a suitable solvent to provide a compound of formula XXI, and

Formula XXI c) cyclizing the compound of formula XXI obtained in step-(b) with 2-chloro-acetyl chloride in the presence of a suitable base and a solvent to provide a compound formula VI.

The starting compound of formula XIX is known in the art and commercially available. The same can be prepared by the methods disclosed in the art or procured from the available commercial sources.

In step a) of the forgoing process, the reaction of compound of formula XIX with carbon disulfide is carried out in the presence of suitable base and a solvent under appropriate reaction conditions to provide o-tolylisothiocynate of formula XX. The suitable base is selected from inorganic bases, organic bases or mixtures thereof. The said reaction carried out at a suitable temperature of about 0-30°C for a sufficient period of time till completion of the reaction, preferably for about 16 to 24 hrs.

In a preferred embodiment, the reaction of compound of formula XIX with carbon disulfide is carried out in the presence of inorganic base such as potassium carbonate in water to provide o-tolylisothiocynate of formula XX.

In step b) of the foregoing process, the reaction of compound of formula XX with n- propylamine is carried out in the presence of a suitable solvent under appropriate reaction conditions to provide a compound of formula XXI. The suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, nitrile solvents, ketone solvents and water; preferably, chloro solvent such as dichloromethane. The said reaction is carried out at a suitable temperature of about 0-30°C for a sufficient period of time till completion of the reaction, preferably for about 1 to 2 hrs. In step c) of the foregoing process, cyclization of the compound of formula XXI obtained in step-(b) with 2-chloro-acetyl chloride is carried out in the presence of a suitable base and a solvent under appropriate reaction conditions to provide a compound formula VI. The suitable base is selected from inorganic bases, organic bases or mixtures thereof. The suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, nitrile solvents, ketone solvents and water. The said reaction carried out at a suitable temperature of about -10°C to about 20°C for a sufficient period of time till completion of the reaction, preferably for about 30 minutes to 2 hrs.

In a preferred embodiment, cyclization of the compound of formula XXI with 2-chloro- acetyl chloride carried out in the presence of organic base such as triethylamine in dichloromethane to provide a compound formula VI.

In an embodiment, the preparation of compound of formula VI can be carried out without isolation of compound of formula XX and XXI.

In another embodiment, the present invention provides an alternate process for the preparation of compound of formula VI,

Formula VI which comprises; a) reacting n-propylamine with carbon disulfide in the presence of a suitable base to provide a n-propyl isothiocyanate of formula XXII,

Formula XXII b) reacting the n-propyl isothiocyanate of formula XXII with a compound of formula XIX,

Formula XIX in the presence of a suitable solvent to provide a compound of formula XXI, and

Formula XXI c) cyclizing the compound of formula XXI obtained in step-(b) with 2-chloro-acetyl chloride or 2-bromo-acetyl bromide in the presence of a suitable base and a solvent to provide compound formula VI.

In step a) of the forgoing process, the reaction of n-propylamine with carbon disulfide in the presence of a suitable base is carried out under appropriate reaction conditions to provide an n-propyl isothiocyanate of formula XXII. The suitable base is selected from inorganic bases, organic bases or mixtures thereof. The said reaction carried out at a suitable temperature of about 0-30°C for a sufficient period of time till completion of the reaction, preferably for about 16 to 24 hrs.

In a preferred embodiment, the reaction of n-propylamine with carbon disulfide carried out in the presence of inorganic base such as potassium carbonate in water to provide n-propyl isothiocyanate of formula XXII.

In step b) of the foregoing process, the reaction of n-propyl isothiocyanate of formula XXII with a compound of formula XIX is carried out in the presence of a suitable solvent under appropriate reaction conditions to provide a compound of formula XXI. The suitable solvent is selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, nitrile solvents, ketone solvents and water; preferably, chloro solvent such as dichloromethane. The said reaction is carried out at a suitable temperature of about 0-30°C for a sufficient period of time till completion of the reaction, preferably for about 1 to 2 hrs.

The step c) of the foregoing process involving cyclization of the compound of formula XXI obtained in step-(b) with 2-chloro-acetyl chloride or 2-bromo-acetyl bromide to provide compound of formula VI is carried out as described in step c) of the previous embodiment of the present invention. In an embodiment, the preparation of compound of formula VI is carried out without isolation of compound of formula XXI and XXII.

In another embodiment, the present invention provides a process for the preparation of Ponesimod of formula I, which comprises,

1) preparing the compound of formula VI or the compound of formula IVa according to the present invention process as described above; and

2) converting the compound of formula VI or the compound of formula IVa into Ponesimod of formula I.

The conversion of compound of formula VI or the compound of formula IVa into Ponesimod of step 2) of aforementioned process is carried out by the methods disclosed herein the present invention or by the methods known in the art.

In an embodiment, the preparation of Ponesimod carried out without isolation of one or more intermediates; or carried out as one-pot process without isolation of any intermediates.

The Ponesimod of formula I prepared as per the above process is further purified using a suitable solvent selected from alcoholic solvents, ester solvents, ether solvents, hydrocarbon solvents, chloro solvents, polar aprotic solvents, nitrile solvents, ketone solvents, water and mixtures thereof by conventional purification methods such as recrystallisation, slurrying and solvent/anti-solvent techniques.

In another embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) condensing a compound of formula V with a compound of general formula IV in the presence of a base in a suitable solvent to provide a compound of general formula III, wherein R is selected from oxirane or 2, 2-dialkyl- 1,3 -dioxo lane, b) reacting the compound of general formula III with n-propylhalide to provide a compound of general formula II, wherein R is selected from oxirane or 2,2-dialkyl-l,3- dioxolane, and

Formula II c) converting the compound of general formula II into ponesimod of formula I or its pharmaceutically acceptable salts.

The starting compounds of formula V or formula IV (wherein R is selected from oxirane or 2, 2-dialkyl- 1,3 -di oxolane) are known in the art and can be prepared by the known methods or as per the process described herein the present invention.

The step a) of aforementioned process involves the condensation of a compound of formula V with a compound of general formula IV in the presence of base selected from organic or inorganic base, in a suitable solvent under appropriate reaction conditions to provide a compound of general formula III, wherein R is selected from oxirane or 2,2-dialkyl-l,3- dioxolane.

The step b) of aforementioned process involves the reaction of the compound of general formula III with n-propylhalide to provide a compound of general formula II, wherein R is selected from oxirane or 2, 2-dialkyl- 1,3 -di oxolane. The step b) reaction can suitably carried out in the presence of a suitable base in a suitable solvent under appropriate reaction conditions.

The step c) of aforementioned process involves the conversion of the compound of general formula II into ponesimod of formula I can be carried out by treating the compound of formula II with a base in a suitable solvent under appropriate reaction conditions. Optionally, ponesimod of formula I is further converted into pharmaceutically acceptable salt by reaction with a suitable acid in a suitable solvent. In a further embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) reacting a compound of formula XII with alkyl or aryl sulfonyl halide in the presence of a base in a suitable solvent to provide a compound of general formula XIV, wherein Ri is alkyl or aryl;

Formula XII Formula XIV b) condensing the compound of general formula XIV with a compound of formula VI to provide a compound of general formula VII, wherein Ri is alkyl or aryl; and c) converting the compound of general formula VII into ponesimod of formula I or its pharmaceutically acceptable salts.

The starting compound of formula XII is known in the art and commercially available; the same can be prepared by the known methods or procured from the available commercial sources.

The step a) of aforementioned process involves the reaction of a compound of formula XII with alkyl or aryl sulfonyl chloride, for example methane sulfonyl chloride or toluene sulfonyl chloride and the like; in the presence of a base in a suitable solvent under appropriate reaction conditions to provide a compound of general formula XIV.

The step b) of aforementioned process involves the condensation of a compound of general formula XIV with a compound of formula VI to provide a compound of general formula VII, wherein Ri is alkyl or aryl. The step b) reaction is suitably carried out in the presence of a base in a suitable solvent under appropriate reaction conditions. The step c) of aforementioned process involves the conversion of compound of general formula VII into ponesimod of formula I and carried out by reacting the compound of general formula VII with (R)-(-)-2,2-dimethyl-l,3-dioxolane-4-methanol in the presence of a base in a suitable solvent under appropriate reaction conditions. Optionally, ponesimod of formula I is further converted into pharmaceutically acceptable salt by reaction with a suitable acid in a suitable solvent.

In a further embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) reacting a compound of formula V with a compound of formula XII to provide compound of formula IX, b) reacting the compound of formula IX with alkyl or aryl sulfonyl halide in the presence of a base in a suitable solvent to provide a compound of general formula VIII, wherein Ri is alkyl or aryl;

Formula VIII c) reacting the compound of general formula VIII with n-propylhalide to provide a compound of general formula VII, wherein Ri is alkyl or aryl; and

Formula VII d) converting the compound of general formula VII into ponesimod of formula I or its pharmaceutically acceptable salts. The starting compound of formula V is known in the art and can be prepared by the known methods or as per the process described herein by the present invention.

The step a) of aforementioned process involves the reaction of compound of formula V with a compound of formula XII to provide a compound of formula IX. The step a) reaction is suitably carried out in the presence of a base in a suitable solvent under appropriate reaction conditions.

The step b) of aforementioned process involves the reacting the compound of formula IX with alkyl or aryl sulfonyl halide in the presence of a base in a suitable solvent under appropriate reaction conditions to provide a compound of general formula VIII, wherein R i is alkyl or aryl.

The step c) of aforementioned process involves the reaction of the compound of general formula VIII with n-propylhalide to provide a compound of general formula VII, wherein Ri is alkyl or aryl. The step c) reaction is suitably carried out in the presence of a base in a suitable solvent under appropriate reaction conditions.

The step d) of aforementioned process involves the conversion of compound of general formula VII into ponesimod of formula I and carried out by reacting the compound of general formula VII with (R)-(-)-2,2-dimethyl-l,3-dioxolane-4-methanol in the presence of a base in a suitable solvent under appropriate reaction conditions. Optionally, ponesimod of formula I is further converted into pharmaceutically acceptable salt by reaction with a suitable acid in a suitable solvent.

In a further embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) reacting a compound of formula XI with a compound of general formula XIII in the presence of a base in a suitable solvent to provide a compound of general formula X, wherein R is selected from oxirane or 2, 2-dialkyl- 1,3 -dioxo lane,

Formula XI Formula XIII Formula X b) converting the compound of general formula X into the compound of general formula II, wherein R is oxirane or 2, 2-dialkyl- 1 ,3-di oxolane by reacting with a suitable chlorinating agent, and c) converting the compound of general formula II into ponesimod of formula I or its pharmaceutically acceptable salts.

The starting compound of formula XI is known in the art and can be prepared by the known methods or as per the process described herein by the present invention.

The step a) of aforementioned process involves the reaction of a compound of formula XI with a compound of general formula XIII, wherein R is selected from oxirane or 2,2- dialkyl-l,3-dioxolane in the presence of a base in a suitable solvent under appropriate reaction conditions to provide a compound of general formula X, wherein R is oxirane or

2.2-dialkyl- 1 ,3 -di oxolane.

The step b) of aforementioned process involves conversion of compound of general formula X into the compound of general formula II, wherein R is oxirane or 2,2-dialkyl-

1.3-dioxolane by reacting with a suitable chlorinating agent, for example N- chlorosuccinimide in the presence or absence of a base in a suitable solvent under appropriate reaction conditions.

The step c) of aforementioned process involves conversion of the compound of general formula II into ponesimod of formula I and carried out by reacting with a base in a suitable solvent under appropriate reaction conditions. Optionally, ponesimod of formula I is further converted into pharmaceutically acceptable salt by reaction with a suitable acid in a suitable solvent.

In a further embodiment, the present invention provides a process for the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts, which comprises: a) condensing the compound of formula XV with a compound of formula V or compound of formula VI to provide a corresponding compound of formula XVI or a compound of formula XVII, b) converting the compound of formula XVI and compound of formula XVII into the compound of formula IIA, and

Formula IIA c) converting the compound of formula IIA into ponesimod of formula I or its pharmaceutically acceptable salts.

The starting compound of formula XV is known in the art and can be prepared by the known methods or as per the process described herein by the present invention. The step a) of aforementioned process involves the condensation of compound of formula

XV with a compound of formula V or compound of formula VI can be carried out in the presence of a base in a suitable solvent under appropriate reaction conditions to provide a corresponding compound of formula XVI or compound of formula XVII.

The step b) of aforementioned process involves conversion of compound of formula XVI and compound of formula XVII into compound of formula IIA. The compound of formula

XVI is first converted into compound of formula XVII by reacting with n-propylhalide in the presence of a base in a suitable solvent under appropriate condition; then compound of formula XVII subjected to chiral sharpless epoxidation under appropriate reaction conditions to provide compound of formula IIA.

The step c) of aforementioned process involves the conversion of the compound of formula IIA into Ponesimod of formula I can be carried out by reacting with a base in a suitable solvent under appropriate reaction conditions. Optionally, Ponesimod of formula I is further converted into pharmaceutically acceptable salt by reaction with a suitable acid in a suitable solvent.

In a further embodiment, the present invention provides a novel compounds of formula II, formula III, formula IVA (R is oxirane), formula VII, formula VIII, formula IX, formula X, formula XVI and formula XVII.

In a further embodiment, the present invention provides use of compounds of formula II, III, IVA (R is oxirane), VII, VIII, IX, X, XVI and XVII as an intermediate in the preparation of Ponesimod of formula I or its pharmaceutically acceptable salts.

In a further embodiment, the present invention provides a process for the purification of Ponesimod or its pharmaceutically acceptable salts which comprises of crystallizing Ponesimod or its pharmaceutically acceptable salts from suitable solvent or mixture thereof.

In a further embodiment, the present invention provides pharmaceutical composition comprising Ponesimod prepared according to the process of the present invention and at least one pharmaceutically acceptable excipients. Examples:

The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.

Example-1: Preparation of (47?)-4-(chloromethyl)-2,2-dimethyl-l,3-dioxolane (Xllla):

To clean and dry RBF, acetone (1 L), (2R)-3-chloropropane-l,2-diol (100 g), 2,2- dimethoxypropane (200 g) followed by CUSO4.5H2O (1.0 g) was added at 25-30°C and stirred for 2 hours. After completion of the reaction, acetone was distilled off completely under reduced pressure below 40°C. Ethyl acetate and DM water was added to the obtained residue at 25-30 C, stirred and both layers were separated. The aqueous layer extracted with ethyl acetate; the organic layers washed with water followed by sodium chloride solution, dried over sodium sulfate and distilled off under vacuum below 40°C to get the title compound. Yield: 95 g.

Example-2: Preparation of 3-chloro-4-((4R)-2,2-dimethyl-[l,3]dioxolan-4-yl methoxy)- benzaldehyde (IVa):

To a clean and dry RBF, 3-chloro-4-hydroxybenzaldehyde (25 g), dimethyl formamide (250 ml), potassium carbonate (44 g), and (4/ )-4-(chloromethyl)-2,2-dimethyl- l ,3- dioxolane (72 g) was added at 25-30°C and stirred for 10 mins. The reaction mass was heated to 155-160 C and stirred for 18 hrs at the same temperature. After completion of reaction, the reaction mass was cooled to 25-30°C, filtered and washed with ethyl acetate. DM water and ethyl acetate was added to the filtrate, stirred and the layers were separated. The aqueous layer extracted with ethyl acetate; the organic layers combined, washed with water, followed by sodium chloride solution, dried over sodium sulphate and then distilled off completely under reduced pressure at 40-45°C to get the title compound. Yield: 66 g.

Example-3: Preparation of o-tolyl isothiocynate (XX):

To a solution of potassium carbonate (515 g) in water (2 L) at 0-5°C, o-toluidine (200 g) followed by carbondisulfide (275 g) were added drop wise at 0-5 °C and stirred for 16 hrs at 25-30°C. Then, potassium carbonate (257 g) was added lot wise to the reaction mass followed by sodium persulfate solution (444 g in 1 L water) and was added dropwise at 0- 5°C. The reaction mass temperature was raised to 25-30°C and stirred for 2 hrs. After reaction completion, the reaction mass was filtered and pet ether (500 ml) was added to the filtrate and stirred. Both organic and aqueous layers were separated; the aqueous layer extracted with pet ether; the organic layers combined; washed with water followed by sodium chloride solution and dried over sodium sulphate then distilled off completely under reduced pressure to get the title compound. Yield: 195 g.

Example-4: Preparation of (Z)-2-(propylimino)-3-o-tolylthiazolidin-4-one (VI):

To a solution of o-tolylisothiocynate (10 g) in di chloromethane (100 ml), n- propylamine (5.23 g) was added dropwise at 20°C under nitrogen atmosphere and stirred for 30 mins. Then, chloroacetyl chloride (9.15 g) was added dropwise to the reaction mass at -5 to 0°C followed by triethylamine (14.2 g) and stirred for 30 mins at -5-0°C. After reaction completion, hydrochloric acid (300 ml) was added to reaction mass then stirred for 15 mins. Both organic and aqueous layers separated; aqueous layer washed with dichloromethane and the pH was adjusted to 8.0 with sodium bicarbonate solution. Then the reaction mass was extracted into dichloromethane and distilled off the solvent to get the title compound. Yield: 15.3 g.

Example-5: Preparation of n-propyl isothiocyanate (XXII):

To a solution of potassium carbonate (466 g) in water (1 L), n-propylamine (100 g) followed by carbon disulfide (256 g) was added drop wise to the reaction mass at 0-5°C; then the reaction mass temperature was raised to 25-30°C and stirred for 18 hours. Potassium carbonate (232 g) followed by solution of sodium persulfate (402 g) was drop wise added to the reaction mass at 0-5°C. Then the reaction mass temperature was raised to o

25-30 C and stirred for 4 hours. After reaction completion, the reaction mass was filtered and petroleum ether (300 ml) was added to the filtrate. The organic and aqueous layers separated from the filtrate; aqueous layer extracted with Pet. Ether; the organic layers combined; washed with water followed by sodium chloride solution, dried over sodium sulphate and distilled off completely under reduced pressure at 40°C to get the title compound. Yield: 80 g. Example-6: Preparation of (Z)-2-(propylimino)-3-o-tolylthiazolidin-4-one (VI):

To a solution of n-propyl isothiocyanate (10 g) in dichloromethane (100 ml), o-toluidine (12.5 g) was added dropwise at 20°C under nitrogen atmosphere and the stirred for 30 mins. The reaction mass was cooled to -5-0°C and chloroacetyl chloride (9.15 g) followed by pyridine (16.2 g) was added and stirred for 30 mins at -5-0°C. After the reaction completion, the reaction mass was quenched with hydrochloric acid and stirred for 10-15 mins. Organic and aqueous layers separated; aqueous layer washed with dichloromethane and pH was adjusted to 8.0 with sodium bicarbonate. Then the reaction mass extracted with dichloromethane and concentrated to get the title compound. Yield: 10 g.

Example-7: Preparation of (2Z,5Z)-5-(4-(((R)-2,2-dimethyl-l,3-dioxolan-4-yl) methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-o-tolylthiaz olidin-4-one (Ila):

To a solution of o-tolylisothiocynate (10 g) in di chloromethane (100 ml), n-propyl amine (5.23 g) was added dropwise at 20°C under nitrogen atmosphere and the maintained for 30 mins. Chloroacetyl chloride (9.15 g) was added dropwise at -5 to 0°C, followed by triethylamine (14.2 g) and stirred for 30 mins. After the reaction completion, the reaction mass was distilled off completely at 60°C. Isopropanol (110 ml), sodium acetate (7 g), 3- chloro-4-((4R)-2,2-dimethyl-[l,3]dioxolan-4-yl methoxy) -benzaldehyde (IVa) (20 g) was added to the residue at 60°C, stirred for 30 mins and further stirred for 6 hours at 80-85°C. After completion of the reaction, the reaction mass was cooled to 25-30°C, filtered, and the filtrate was distilled off completely. Ethanol (60 ml) was added to the obtained compound, heated to 70°C; DM water (60 ml) was added to it and stirred for 30 mins. Then the reaction mass was cooled to 25-30°C and stirred for 14 hrs. The obtained solid was filtered and dried to get the title compound. Yield: 12.5 g.

Example-8: Preparation of (2Z,5Z)-5-(4-(((R)-2,2-dimethyl-l,3-dioxolan-4-yl) methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-o-tolylthiaz olidin-4-one (Ila):

To a solution of n-propyl isothiocyanate (10 g) in dichloromethane (100 ml), o- toluidine (14 g) was added dropwise at 20°C under nitrogen atmosphere and the reaction mass was maintained for 30 mins. The reaction mass was cooled to -5 to 0°C and chloroacetyl chloride (13.3 g) was dropwise added to it at -5 to 0°C, followed by pyridine (16.2 g) and stirred for 30 mins. After completion of the reaction, the reaction mass was distilled off completely at 60°C. Ethanol (110 ml), sodium acetate (10.3 g), 3-chloro-4- ((4R)-2,2-dimethyl-[l,3]dioxolan-4-yl methoxy)-benzaldehyde (IVa) (29 g) was added to the residue at 60°C, stirred for 20 mins and further stirred for 6 hours at 80-85°C. After completion of the reaction, the reaction mass was cooled to 25-30°C, filtered, and the filtrate was distilled off completely. Ethanol (60 ml) was added to the obtained residue, heated to 70°C; DM water (60 ml) was added and stirred for 30 mins. Then the reaction mass was cooled to 25-30°C and stirred for 14 hrs. The obtained solid was filtered and dried to get the title compound. Yield: 12 g.

Example-9: Preparation of Ponesimod (I):

(2Z,5Z)-5-(4-(((R)-2,2-dimethyl-l,3-dioxolan-4-yl)methoxy )-3-chlorobenzylidene)-2- (propylimino)-3-o-tolylthiazolidin-4-one (IVa) (10 g) was dissolved in dichloromethane (100 ml) at 25-30°C. The reaction mass was cooled to 0-5°C; Con. Hydrochloric acid (10 ml) was added to it and stirred for 12 hrs at 25-30°C. After reaction completion, water (30 ml) was added to the reaction mass and stirred for 20 mins. Both organic and aqueous layers were separated; the aqueous layer washed with dichloromethane and pH was adjusted to 7.5-8.5 with sodium carbonate. Then the reaction mass extracted into dichloromethane, washed with water followed by sodium chloride solution, dried over sodium sulphate and distilled off under reduced pressure at 40-45°C. Ethanol (30 ml) was added to the obtained crude, heated to 70-75°C, and DM water (30 ml) was added to it and stirred for 30 mins. The reaction mass was cooled to room temperature and stirred for 3 hrs. The solid obtained was filtered. Ethanol (30 ml) was added to the obtained wet solid, heated to 70-75°C and DM water (30 ml) was added and stirred for 30 mins. Then the reaction mass was cooled to 25-30°C and stirred for 4 hrs. The obtained solid was filtered and dried under vacuum to get the title compound. Yield: 5 g.; Purity by HPLC: > 99 %