DESC:FIELD OF INVENTION

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

BACKGROUND OF THE INVENTION

Ponesimod is a sphingosine 1-phosphate receptor modulator and is chemically known as (2Z,5Z)-5-[3-chloro-4-[(2R)-2,3-dihydroxypropoxy]benzylidene]-3-(2-methylphenyl)-2-(propylimino)-1,3-thiazolidin-4-one which has been approved as a Tablet having dosage strength 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, and 20 mg under the trade name PONVORY® for the treatment of relapsing forms of multiple sclerosis (MS). Ponesimod is structurally represented as follows:

Ponesimod as well as its pharmaceutically acceptable salts were disclosed in USRE43728 E (US ‘728) of Actelion Pharmaceuticals Ltd. Further, discloses the synthesis of Ponesimod of Formula I is as shown below:

This process involves the condensation of 3-Chloro4-hydroxybenzaldehye and ((4R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol in presence of ADDP / TBP, which yields 3-Chloro-4-((4R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)benzaldehyde as oil, and is further purified by silicagel chromatography, followed by condensation with (Z)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one to yield Ponesimod (pale yellow foam).

US 9,340,518 B2 (US ‘518) of Actelion Pharmaceuticals Ltd discloses the synthesis of Ponesimod of Formula I is as shown below:

IN 202141050891 A discloses the process for the preparation of Ponesimod of Formula I, is as shown below:

The present inventors have repeated the prior-art process and found that process yields Ponesimod having undesirable diol impurity and required number of purification steps to remove diol impurity. The structure of diol impurity of Formula A is as follows:

US 9,062,014 B2 (US ‘014) of Acetelion Pharmaceuticals discloses Crystalline Forms A, I, II and Amorphous form of Ponesimod and synthesis thereof. Further, discloses the synthesis of Amorphous form using Ponesimod Crystalline Form A.
Further the present inventors have observed that by carrying out these prior art processes, it is difficult to remove diol impurity which thereby results in low yield and low purity.

In view of the above, there is need a process to prepare Brexpiprazole which is cost-effective, industrially applicable with high yields and high purity.

The present inventors have now found a process for preparation of Brexpiprazole which resolves above referred issues and industrially suitable.

OBJECTIVES

Objective of the present invention is to provide a process for the preparation of Ponesimod of Formula I, which is free of diol impurity.

Another objective of the present invention is to provide a process for the preparation of Ponesimod of Formula I using intermediate compounds of Formula II, Formula III & Formula VI, which is economically cost effective and industrially applicable process.

Another objective of the present invention is to provide intermediate compounds of Formula II, Formula III & Formula VI and process for the preparation thereof.

Another objective of the present invention is to provide a process for the preparation of Ponesimod of Formula I, which has higher yield and purity with acceptable level of impurities.

SUMMARY OF THE INVENTION

The present invention provides a process for the preparation of Ponesimod of Formula I:

which comprises:
a. condensing the compound of Formula III,

with compound of Formula IV,

to obtain compound of Formula II; and

b. converting the compound of Formula II to Ponesimod of Formula I.

The present invention also provides a process for the preparation of Ponesimod of Formula I:

which comprises:
a. condensing the compound of Formula III,

with compound of Formula V,

to obtain compound of Formula VI;
;
b. condensing the compound of Formula VI with a compound of Formula VII,

to obtain compound of Formula II; and

c. converting the compound of Formula II to Ponesimod of Formula I.

The present invention also provides use of compound of Formula II,

in the preparation of Ponesimod of Formula I.

The present invention also provides use of compound of Formula III,

in the preparation of Ponesimod of Formula I.

The present invention also provides use of compound of Formula VI,

in the preparation of Ponesimod of Formula I.

The present invention also provides a process for the preparation of Amorphous Ponesimod using spray drying technique.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the present invention provides a process for the preparation of Ponesimod of Formula I, which comprises: condensing the compound of Formula III with compound of Formula IV in presence of a reagent selected from the group comprising of DIAD, DEAD, ADDP and the like, in combination with TPP, TBP and the like; a base; in a solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar solvents, polar-aprotic solvents or mixture of solvents thereof; to obtain a compound of Formula II.

In another aspect of the present invention provides a process for the preparation of Ponesimod of Formula I, which comprises: condensing the compound of Formula III with the compound of Formula V in presence of a reagent selected from the group comprising of DIAD, DEAD, ADDP, and the like and in combination with TPP, TBP and the like; a base; in a solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar solvents, polar-aprotic solvents or mixture of solvents thereof to obtain a compound of Formula VI; followed by condensation with Formula VII in presence of a suitable base, acid, in a solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar solvents, polar-aprotic solvents or mixture of solvents thereof to obtain a compound of Formula II.

In another aspect of the present invention also provides the conversion of compound of Formula II to Ponesimod of Formula I, with hydrogen chloride in an organic solvent, acids selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, trifluoroacetic acid, formic acid, methane sulfonic acid, ethane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid and the like, base selected from the group comprising of organic base or inorganic base; solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar-aprotic solvents, polar solvents or mixture of solvents thereof to give Ponesimod of Formula I.

In another aspect of the present invention, diol impurity of Formula A is less than 0.1% in Ponesimod of Formula I.

In another aspect of the present invention, wherein hydrogen chloride gas is purged in an organic solvent selected from alcohol, ether or ester.

In another aspect of the present invention obtained Ponesimod is in the form of solution, liquid, foamy solid, solid, any crystalline form or amorphous form.

In another aspect of the present invention also provides a process for the preparation of Amorphous Ponesimod comprising treating Ponesimod with a solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar solvents, polar-aprotic solvents or mixture of solvents thereof; spray dried the obtained reaction mixture to yield Ponesimod in Amorphous form.

In another aspect of the present invention, in the preparation of Ponesimod Amorphous form, Ponesimod is in the form of solution, liquid, foamy solid, solid, any crystalline form.

In another aspect throughout the invention, alcohols are selected from the group comprising of methanol, ethanol, butanol, t-BuOH, isopropanol and the like; ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; the halogenated solvents are selected from the group comprising of dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ethers are selected from the group comprising of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, isopropyl ether, diisopropyl ether (DIPE), methyl t-butyl ether, dioxane, anisole and the like; esters are selected from the group comprising of ethyl acetate, isopropyl acetate and the like; hydrocarbons are selected from the group comprising of n-hexane, n-heptane, cyclohexane, cycloheptane, benzene, toluene, m-, o- or p-xylene and the like; nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, acrylonitrile and the like; polar solvents are selected from group comprising of water and the like; polar aprotic solvents are selected from the group comprising of N,N-dimethylformamide, dimethylacetamide, dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) and the like.

In another aspect throughout the invention, the mixture of solvents means two or more solvents.

In another aspect throughout the invention, suitable base is selected from the group comprising of organic bases and inorganic bases. Wherein, organic bases are selected from the group comprising of DIPEA, diisobutylamine, Triethylamine (TEA), pyridine, DMAP, NMM and the like; organosilicon base selected from the group comprising of lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like; inorganic bases are selected from the group comprising of alkali metal hydroxides such as Sodium hydroxide, Potassium hydroxide, Lithium hydroxide and the like; alkali metal carbonates and bicarbonates are selected from the group comprising of sodium carbonate, sodium bicarbonate, Potassium carbonate, potassium bicarbonate and the like; alkali metal alkoxides selected from the group comprising of sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium t-butoxide, potassium t-butoxide and the like; and alkali metal amides selected from the group comprising of Sodium amide, Potassium amide and the like.

In another aspect throughout the invention, as used herein the term “halogen” refers to chlorine, bromine, iodine and the like; “tosyl” used in the present invention refers to tolunesulfonyl; “mesyl” used in the present invention refers to methane sulfonyl; “Toluoyl” used in the present invention refers to toluenesulfonyl; and “silyl” used in the present invention refers to trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), t-butyldimethylsilyl (TBDMS) and the like.

In another aspect, obtained Ponesimod and its intermediate compounds can be optionally isolated and optionally purified by conventional methods.

In another aspect throughout the invention, isolation of Ponesimod and its intermediate compounds can be performed by conventional methods such as cooling, removal of solvents, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, filtration, centrifugation and the like.

In another aspect of the present invention, the Ponesimod obtained by removing the solvent by using suitable techniques which may be used for the removal of the solvent include evaporation techniques such as a Büchi® Rotavapor®, spray drying, agitated thin film drying, freeze drying (lyophilization) and the like or any other suitable technique of downward atmospheric distillation, the solvent may be removed. The solvent may be removed optionally adjusting/the optimizing atmospheric pressure as well as temperatures.
In another aspect of the present invention, Freeze drying (lyophilization) may be carried out by freezing a solution of Ponesimod at low temperatures and reducing the pressure required to remove the solvent from the frozen solution of Ponesimod, wherein temperatures that may be required to freeze the solution, depending on the solvent chosen to make the solution of Ponesimod.

In another aspect of the present invention, after removing the solvent, the obtained compound (which may be in the form of liquid, solid, semi-solid, gel) is subjected to melting, thereafter cooling to isolate the stable solid form of Ponesimod.

In another aspect of the present invention provides a pharmaceutical composition comprising Ponesimod and at least one pharmaceutically acceptable excipient. As used herein, the term “pharmaceutical composition” or “pharmaceutical formulation” include tablets, pills, powders, liquids, suspensions, emulsions, granuels, capsules, suppositories, or injection preparations.

The Abbreviations used throughout the invention are as follows:
ADDP : 1,1-(Azodicarbonyl)dipiperidine
DEAD : Diethyl azodicarboxylate
DIAD : Diisopropyl azodicarboxylate
DMAP : Dimethylaminopyridine
TBP : tributylphosphine
TPP : triphenylphosphine
N,N-DIPEA / DIPEA: N,N-Diisopropylethylamine
N,N-DMF / DMF: N,N-Dimethyl formamide
NMM : N-Methyl morpholine

The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.

Examples
Reference example 1:
A solution of 3-(2-methylphenyl)-2-[(Z)-propylimino]-thiazolidin-4-one (87 mg, 0.351 mmol), 3-chloro-4-((4R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-benzaldehyde (190 mg) and sodium acetate (58 mg) in acetic acid (4 mL) is stirred at 110°C for 4 hours. water is added (50 µL) and stirring is continued at 110°C for 1 hour. The reaction mixture is cooled to 25-35°C, diluted with ethyl acetate (75 mL), washed with sat. aq. Sodium bicarbonate, followed by water, and evaporated. The residue is dissolved in methanol (20 mL) and sodium methylate is added (150 mg). The resulting solution is allowed to stand for 40 min at 25-35°C before it is diluted with ethyl acetate, washed with 10% aq. citric acid, and twice with water. The organic extracts are evaporated and the residue is purified on prep. TLC plates using toluene / ethyl acetate 1:3 to give Ponesimod (98 mg) as a pale yellow foam.

Reference example 2:

To a suspension of (2Z,5Z)-5-(3-chloro-4-hydroxy-benzylidene)-2-propylimino-3-o-tolyl-thiazolidin-4-one (10.00 g, 1.00 eq.) in ethanol (47.2 mL) is added (R)-3-chloro-1,2-propanediol (3.37 g, 1.18 eq.) at 20°C. Potassium tert-butoxide (3.39 g, 1.13 eq.) is added in portions at 20°C. The resulting fine suspension is stirred at 20°C. for 25 min before being heated to reflux (88°C.). The reaction mixture is stirred at this temperature for 24 h before IPC (conversion specification ?96.0%). After cooling down to 60°C., acetonitrile (28.6 mL) and water (74.9 mL) are added. The resulting clear solution is cooled from 60°C. to 0°C. over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.010 g, 0.001 eq; crystalline form C can be prepared as described in WO 2010/046835) are added at 50°C. The suspension is heated from 0°C. to 50°C., cooled to 0°C. over 6 h and stirred at this temperature for 12 h. The product is filtered and washed with a mixture of acetonitrile (23.4 mL) and water (23.4 mL) at 0°C. The product is dried under vacuum at 45°C. for 24 h to afford a pale yellow solid.
Diol impurity: 1.64% (detected by HPLC)

Purification of (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one
Recrystallisation I: The crude (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 g) is dissolved in acetonitrile (30 mL) at 70° C. The reaction mixture is cooled from 70°C. to 0°C. over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50°C. The suspension is heated up to 52°C., cooled to 0°C. over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10°C. (2×12.8 mL).
Recrystallisation II: The wet product is dissolved in acetonitrile (27.0 mL) at 70° C. The reaction mixture is cooled from 70°C. to 0°C. over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50°C. The suspension is heated up to 52°C., cooled to 0°C. over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10°C. (2×11.3 mL).
Recrystallisation III: The wet product is dissolved in acetonitrile (24.3 mL) at 70°C. The reaction mixture is cooled from 70°C. to 0°C. over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50° C. The suspension is heated up to 52°C., cooled to 0°C. over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10°C. (2×10.1 mL).
Recrystallisation IV: The wet product is dissolved in acetonitrile (21.9 mL) at 70°C. The reaction mixture is cooled from 70°C. to 0°C. over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50°C. The suspension is heated up to 52°C., cooled to 0°C. over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10°C. (2×9.1 mL).
Recrystallisation V: The wet product is dissolved in acetonitrile (19.7 mL) at 70°C. The reaction mixture is cooled from 70°C. to 0°C. over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50°C. The suspension is heated up to 52°C., cooled to 0°C. over 6 h and agitated at this temperature for 2 h. The product is filtered and washed with acetonitrile at -10°C. (2×8.2 mL).
Recrystallisation VI: The wet product is dissolved in acetonitrile (23.9 mL) at 70° C. Water (20 mL) is added at 70°C. The reaction mixture is cooled from 70°C. to 0°C. over 2 h. During the cooling ramp, (2Z,5Z)-5-(3-chloro-4-((R)-2,3-dihydroxypropoxy)benzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one seeds of crystalline form C (0.0075 g, 0.00075 eq.) are added at 50°C. The suspension is heated up to 52°C., cooled to 0°C. over 6 h and agitated at this temperature for 2 h. The product is filtered and washed twice with a mixture of acetonitrile (4.5 mL) and water (4.5 mL) at -10°C. The product is dried under vacuum at 45°C. for 24 h to afford a pale yellow solid; yield: 7.0 g (70%).
Diol impurity: 0.27% (detected by HPLC)

Example 1: Preparation of (Z)-5-(Z)-3-chloro-4-hydroxybenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one of Formula IV

To the 3-Chloro-4-hydroxy benzaldehyde (70 gm), added sodium acetate (70 gm), acetic acid (800 ml) at 25-35°C and stirred the reaction mixture for 2 hours 30 minutes to 3 hours. To the obtained clear solution, added (Z)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (100 gm), heated to 55-65°C and stirred for 7 hours to 8 hours. Added water, stirred, filtered the solid and dried under vacuum to yield (Z)-5-(Z)-3-chloro-4-hydroxybenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (125 gm).
Purity by HPLC: 98%

Example 2: Preparation of (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one

To the (Z)-5-(Z)-3-chloro-4-hydroxybenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (100 gm), added toluene (1000 ml), (S)-(1,4-dioxaspiro[4.5]decan-2-yl)methanol (66 gm) at 25-35°C. To the obtained reaction mixture, added TPP (100 gm), cooled to 5-15°C, added DIAD (100 gm) and heated to 40-45°C, stirred, cooled to 25-35°C. Added sodium hydroxide solution (400 ml), hexane, stirred, filtered the solid, dried under vacuum at 50°C for 15 hours to 17 hours to yield (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (110 gm)
Purity by HPLC: 97%

Example 3: Preparation of Ponesimod

To the (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (100 gm), added MeOH (400 ml) at 25-35°C, stirred, cooled to 15-20°C, added methanolic HCl (300 ml), stirred for 3 hours to 5 hours at 25-35°C, added sodium bicarbonate solution (500 ml). Filtered the obtained solid and washed with water, added acetonitrile (300 ml), heated to 60-70°C. Cooled to 25-35°C and stirred for 2 hours to 3 hours, filtered, dried the obtained solid in vacuum at 40-50°C for 15 hours to 16 hours to yield Ponesimod (64 gm).
Purity by HPLC: 99.88%
Diol impurity: Not detected

Example 4: Preparation of (R)-4-((1,4-dioxaspiro[4,5]-decan-2-yl)methoxy)-3-chlorobenzaldehyde of Formula VI(a)

To the 3-Chloro-4-hydroxy benzaldehyde (20 gm), added Toluene (200 ml), (S)-(1,4-dioxaspiro[4.5]decan-2-yl)methanol (32 gm), TPP (50 gm) at 25-35°C. Cooled to 5-15°C, added DIAD (50 gm), heated to 40-50°C, stirred for 5 hours to 7 hours. Cooled to 25-35°C, layers were separated, and washed the organic layer with sodium hydroxide solution, distilled off the solvent. The obtained foamy residue was purified by column chromatography using ethylacetate / hexane to yield (R)-4-((1,4-dioxaspiro[4,5]-decan-2-yl)methoxy)-3-chlorobenzaldehyde (31.6 gm).

Example 5: Preparation of (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one

To the (R)-4-((1,4-dioxaspiro[4,5]-decan-2-yl)methoxy)-3-chlorobenzaldehyde (13.5 gm), added sodium acetate (6 gm), acetic acid (80 ml) at 25-35°C and stirred for 2 hours 30 minutes to 3 hours. To the obtained clear solution, added (Z)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 gm), heated to 75-85°C and stirred for 7 hours to 8 hours, added water (150 ml). Filtered the obtained precipitated solid and washed with water, dried under vacuum at 45-55°C for 10 hours to 12 hours to yield (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (17.3 gm).
Purity by HPLC: 97%

Example 6: Preparation of Ponesimod

To the (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (10 gm), added MeOH (40 ml) at 25-35°C, stirred, cooled to 15-20°C, added Methanolic HCl (30 ml), stirred for 3 hours to 5 hours at 25-35°C, added NaHCO3 solution (50 ml). Filtered the obtained solid and washed with water (50 ml), added acetonitrile (30 ml) at 25-35°C, heated to 60-70°C. Cooled to 25-35°C and stirred for 2 hours to 3 hours, filtered the solid, washed with acetonitrile (5 ml) and dried the solid in vacuum at 35-45°C for 15 hours to 16 hours to yield Ponesimod (6.5 gm).
Diol impurity: Not detected
Purity by HPLC: 99.87%

Example 7: Preparation of Amorphous Ponesimod

To the Ponesimod (120 gm), added MDC (500 ml) at room temperature, heated to 40°C, stirred for 30 minutes to 45 minutes. Filtered the obtained clear solution and spray dried at 40°C, dried the obtained spray dried solid at 45°C for 15 hours to yield Amorphous Ponesimod (102 gm).

Example 8: Preparation of Amorphous Ponesimod

To the (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (100 gm), added MeOH (400 ml) at 25-35°C, stirred, cooled to 15-20°C, added methanolic HCl (300 ml), stirred for 3 hours to 5 hours at 25-35°C, distilled off methanol completely under vacuum, added MDC (500 ml), NaHCO3 solution (500 ml). Separated the layers and organic layer washed with water, spray dried to yield Amorphous Ponesimod (72 gm).

Example 9: Preparation of (Z)-5-(Z)-3-chloro-4-hydroxybenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one of Formula IV

To the 3-Chloro-4-hydroxy benzaldehyde (120 gm), added sodium acetate (100 gm), acetic acid (1600 ml) at 25-35°C and stirred the reaction mixture for 30 minutes. To the obtained clear solution, added (Z)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (200 gm), stirred for 15 minutes, heated to 90-110°C and stirred for 3 hours to 4 hours, Cooled to 50-70°C. Added water, stirred, filtered the solid and washed with water. To the obtained wet compound, added isopropyl alcohol, heated to 70-90°C, stirred for 30 minutes, cooled to room temperature, filtered the solid and washed with isopropyl alcohol. Dried the obtained solid under vacuum to yield (Z)-5-(Z)-3-chloro-4-hydroxybenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (218 gm).
Purity by HPLC: 95%

Example 10: Preparation of (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one

To the (Z)-5-(Z)-3-chloro-4-hydroxybenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (150 gm), added toluene (1500 ml), (S)-(1,4-dioxaspiro[4.5]decan-2-yl)methanol (73 gm) at 25-35°C. To the obtained reaction mixture, added TPP (127 gm), cooled to 5-15°C, added DIAD (118 gm) and heated to 50-70°C, stirred, cooled to 25-35°C. Added sodium hydroxide solution (450 ml), layers were separated, organic layer washed with sodium hydroxide and Water, concentrated the organic layer completely under vacuum below 55°C. The obtained residue was cooled to 25-35°C, added hexane, stirred, filtered the solid. To the obtained wet solid, added 50% aq.MeOH, stirred for 30 minutes to 45 minutes, filtered and dried under vacuum at 50°C for 15 hours to 18 hours to yield (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (180 gm)
Purity by HPLC: 97%

Example 11: Preparation of Ponesimod

To the (Z)-5-((Z)-4-(((R)-1,4-dioxaspiro[4,5]decan-2-yl)methoxy)-3-chlorobenzylidene)-2-(propylimino)-3-(o-tolyl)thiazolidin-4-one (150 gm), added MeOH (675 ml) cooled to 10-15°C, added 40% Aq.HCl (30 ml), stirred for 3 hours to 4 hours at 10-15°C, distilled the solvent, added MDC (1500 ml), cooled to 5-15°C, added Na2CO3 solution (50 ml). Layers were separated and organic layer washed with water, concentrate the organic layer. The obtained residue was cooled to 25-35°C, added MDC, heated to 35-45°C, cooled to 25-35°C, added DIPE and maintained for 1 hour to 2 hours. Filtered the obtained solid and washed with DIPE, added acetonitrile (600 ml), heated to 65-75°C, stirred for 10 minutes to 15 minutes, filtered, cooled, stirred for 1 hour to 2 hours at 25-35°C, cooled to 5-15°C, stirred for 10 minutes to 15 minutes. Filtered the solid, washed with acetonitrile (75 ml) and dried the solid in vacuum at 35-45°C for 15 hours to yield Ponesimod (100 gm).
Diol impurity: Not detected
,CLAIMS:We Claim:

1. A process for the preparation of Ponesimod of Formula I:

which comprises:
a. condensing the compound of Formula III,

with compound of Formula IV,

to obtain compound of Formula II; and

b. converting the compound of Formula II to Ponesimod of Formula I.

2. A process for the preparation of Ponesimod of Formula I:

which comprises:
a. condensing the compound of Formula III,

with compound of Formula V,

to obtain compound of Formula VI;
;
b. condensing the compound of Formula VI with a compound of Formula VII,

to obtain compound of Formula II; and

c. converting the compound of Formula II to Ponesimod of Formula I.

3. The process as claimed in claim 1, wherein step a) condensation of compound of Formula III with compound of Formula IV is carried out in presence of a reagent selected from the group comprising of DIAD, DEAD, ADDP; in combination with TPP, TBP.

4. The process as claimed in claim 2, wherein step a) condensation of compound of Formula III with compound of Formula V is carried out in presence of a reagent selected from the group comprising of DIAD, DEAD, ADDP; in combination with TPP, TBP.

5. The process as claimed in claims 1 & 2, wherein conversion of compound of Formula II to Ponesimod of Formula I is carried out by treating the compound of Formula II with acid selected from the group comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid; base selected from the group comprising of organic base or inorganic base; solvent selected from the group comprising of halogenated solvents, alcohols, ketones, ethers, esters, hydrocarbons, nitriles, polar-aprotic solvents, polar solvents or mixture of solvents thereof.

6. The process as claimed in claim 2, wherein step b) condensation of compound of Formula VI with a compound of Formula VII is carried out in presence of a suitable base selected from organic or inorganic base; acid is selected from the group comprising of hydrochloric acid, hydrobromic acid, acetic acid.
7. The process as claimed in claims 5 & 6, wherein organic bases are selected from the group comprising of DIPEA, diisobutylamine, TEA, pyridine, DMAP, NMM, LiHMDS, NaHMDS, KHMDS; inorganic bases are selected from the group comprising of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate.

8. The compound of Formula II,

used in the preparation of Ponesimod of Formula I.

9. The compound of Formula III,

used in the preparation of Ponesimod of Formula I.

10. The compound of Formula VI,

used in the preparation of Ponesimod of Formula I.

Dated this 19th day of June, 2024

Dr. RATHNAKAR REDDY KURA
DIRECTOR
HETERO LABS LIMITED