DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
PROCESS FOR PREPARATION OF OZANIMOD

FIELD OF THE INVENTION
The present application provides intermediates of Ozanimod, process for the preparation of Ozanimod and intermediates of Ozanimod.

BACKGROUND OF THE INVENTION
The drug compound having the adopted name Ozanimod, has a chemical name (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1Hinden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile, and is represented by the structure of formula I

Ozanimod is an investigational immunomodulatory drug currently in phase III clinical trials for the therapy of relapsing multiple sclerosis (RMS) and ulcerative colitis.
Racemic Ozanimod, its synthetic process and its pharmaceutical compositions are described in US patent No. 8,481,573 B2 (US ‘573). Ozanimod (S) and (R) isomers, synthetic processes and their pharmaceutical compositions are described in US patent No. 8,362,048 B2 (US ‘048).
The US ‘573 describes a process for preparation of racemic Ozanimod. The process is schematically represented below.

The US ‘048 describes a process for preparation of Ozanimod (S) and (R) isomers. The process is schematically represented below.

The prior-art processes herein described above suffer from drawbacks such as use of hazardous reagents like NaH and/or more process steps or low yield. Hence there is a continuing need to develop simplified and improved process for preparing Ozanimod which is suitable for commercial manufacturing in high purity and yield.

SUMMARY OF THE INVENTION
The present application provides intermediates of Ozanimod, process for the preparation of Ozanimod and intermediates of Ozanimod.
In the first aspect, the present application provides a compound of formula IV, its acid addition salts and its isomers thereof.

wherein P1 and P2 are independently hydrogen or a protecting group.
In the second aspect, the present application provides a process of resolution of compound of formula IV into its (S) or (R) isomer

Where in P1 and P2 are independently hydrogen or a protecting group; comprising treating the racemic mixture of compound of formula IV with a suitable chiral acid.
In the third aspect, the present application provides a process for preparation of Ozanimod (R)-isomer, comprising:
a) reacting a compound of formula V with ethanolamine in presence of a suitable base to form a racemic mixture of compound of formula IV, and optionally protecting the racemic mixture of compound of formula IV with one or more suitable protecting groups

b) treating the racemic mixture of compound of formula IV with a suitable chiral acid to form (R)-isomer of compound of formula IV

c) reacting the (R)-isomer of compound of formula IV with hydroxylamine in presence of a suitable base to form compound of formula III

d) reacting the compound of formula III with a compound of formula IX to form compound of formula II

e) optionally deprotecting the compound of formula II to form Ozanimod (R)-isomer of formula I

In the fourth aspect, the present application provides novel compounds of formula V, formula IVa, formula IVb and compound of formula IVc and their isomers thereof

In the fifth aspect, the present application provides a pharmaceutical composition comprising Ozanimod prepared by the processes of the present application and one or more pharmaceutically acceptable excipient.

DETAILED DESCRIPTION
The present application provides intermediates of Ozanimod, process for the preparation of Ozanimod and intermediates of Ozanimod.
In one aspect, the present application providesa process of resolution ofcompound of formula IV into its (S) or (R) isomer

wherein P1 and P2 are independently hydrogen or a protecting group; comprising treating the racemic mixture of compound of formula IV with a suitable chiral acid.
The process involves treating the racemic compound of formula IV with a suitable chiral acid in a suitable solvent. The suitable chiral acid is selected from the group comprising tartaric acid, dibenzoyltartaric acid, di-p-toluoyltartaric acid, aspartic acid, camphorsulfonic acid, glutamic acid, malic acid, mandelic acid, pyroglutamic acid and valine.
The suitable solvent is selected from the group comprising ethanol, methanol, isopropyl alcohol, acetone, ethylacetate, tetrahydrofuran, acetonitrile, toluene and water or mixtures thereof.
The racemic compound of formula IV, solvent and the chiral acid are mixed and stirred for about 10 minutes to about 10 hours at a temperature of about 0 °C to about 100 °C.
The mixture is filtered and the filtrate may be concentrated. The residue is dissolved in a suitable water immiscible solvent such as dichloromethane. The solvent layer may be washed with sodium bicarbonate solution and the organic layer may be concentrated to get the desired isomer of the compound of formula IV.
In a specific aspect, the present application provides a process for preparation of (R)-isomer of compound of formula IVa comprising treating the racemic compound of formula IVa with a suitable chiral acid,

The racemic compound of formula IVa, acetonitrile and a suitable chiral acid such as di-p-toluolyl-L-(+)-tartaric acid are mixed and stirred for about 10 minutes to about 10 hours at a temperature of about 0 °C to about 100 °C.
The mixture is filtered and the filtrate is concentrated. The residue is dissolved in a suitable water immiscible solvent such as dichloromethane. The solvent layer is washed with sodium bicarbonate solution and the organic layer may be concentrated to get the (R) isomer of the compound of formula IVa.
The (S)-isomer of the compound of formula IVa can also be prepared using a suitable chiral acid and with the similar approach described for (R)-isomer.
In another aspect, the present application provides a process for preparation of Ozanimod (R)-isomer, comprising:
a) reacting a compound of formula V with ethanolamine in presence of a suitable base to form a racemic mixture of compound of formula IV, and optionally protecting the racemic mixture of compound of formula IV with one or more suitable protecting groups

wherein P1 and P2 are independently hydrogen or a protecting group;
b) treating the racemic mixture of compound of formula IV with a suitable chiral acid to form (R)-isomer of compound of formula IV

c) reacting the (R)-isomer of compound of formula IV with hydroxylamine in presence of a suitable base to form compound of formula III

d) reacting the compound of formula III with a compound of formula IX to form compound of formula II

e) optionally deprotecting the compound of formula II to form Ozanimod (R)-isomer of formula I

The step (a) of the process involves reaction of compound of formula V with ethanolamine in presence of a suitable base such as triethylamine or diethyl isopropyl amine or N,N-Diisopropylethylamine and a suitable solvent such as N,N-dimethylformamide or N,N-dimethylacetamide. The compound of formula V can be prepared by the process described in this application or any of the processes described in the art.
The compound of formula V, the solvent, the base and ethanolamine are mixed and the resulted mixture may be stirred for about 1 hour to about 24 hours at a temperature of about 30 °C to about 150 °C.
After completion of the reaction the reaction mixture was added to water and the resultant mixture is extracted with a suitable water immiscible solvent such as dichloromethane and the organic layer is concentrated to obtain the compound of formula IV.
The free amine functional group and the free hydroxy functional group of the compound of formula IV may optionally be protected using a suitable protecting group such as tert-butyloxycarbonyl (BOC group), benzyloxy carbonyl, trimethylsilyl or tert-butyl dimethylsilyl to produce the protected compound of formula IV.
The step (b) of the process involves treating the racemic compound of formula IV with a suitable chiral acid in a suitable solvent. The suitable chiral acid is selected from the group comprising tartaric acid, dibenzoyltartaric acid, di-p-toluoyltartaric acid, aspartic acid, camphorsulfonic acid, glutamic acid, malic acid, mandelic acid, pyroglutamic acid and valine.
The suitable solvent is selected from the group comprising ethanol, methanol, isopropyl alcohol, acetone, ethylacetate, tetrahydrofuran, acetonitrile, toluene and water or mixtures thereof.
The racemic compound of formula IV, solvent and the chiral acid are mixed and stirred for about 10 minutes to about 10 hours at a temperature of about 0 °C to about 100 °C.
The mixture is filtered and the filtrate may be concentrated. The residue is dissolved in a suitable water immiscible solvent such as dichloromethane. The solvent layer may be washed with sodium bicarbonate solution and the organic layer may be concentrated to get the (R) isomer of the compound of formula IV.
The step (c) of the process involves reaction of the (R)-isomer of compound of formula IV with hydroxylamine in presence of a suitable base such as trimethylamine, diethyl isopropyl amine or N,N-Diisopropylethylamine and a suitable solvent such as methanol, ethanol, isopropanol, THF to form compound of formula III.
The compound of formula IV, the solvent, the base and hydroxylamine are mixed and the resulted mixture may be stirred for about 15 minutes to about 12 hours at a temperature of about 20 °C to about 130 °C.
After completion of the reaction the reaction the mixture was concentrated under reduced pressure and the residue is added to a suitable water immiscible solvent such as dichloromethane. The organic layer may be washed with aqueous sodium bicarbonate solution and the organic layer is concentrated to obtain the compound of formula III.
The step (d) of the process involves reaction of the (R)-isomer of compound of formula III with a compound of formula IX or a salt thereof in presence of a suitable base such as triethylamine, N,N-diisopropylethylamine (DIPEA), pyridine, piperidine, 1,8-Diazabicyclo[5.4.0[undec-7-ene (DBU), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI), 4-Dimethylaminopyridine (DMAP); a suitable coupling agent such as (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium oxide hexafluorophosphate (HATU), 1-hydroxybenzotriazole (HOBT), hydroxyazabenzotriazole (HOAT), and hydroxy succinimide (HOSu); and a suitable solvent such as acetone, acetonitrile, ethylacetate, dimethylformamide, N-methylpyrrolidine, dimethylsulfoxide, tetrahydrofuran, chlorobenzene and toluene to form compound of formula II.
The amount of compound of formula IX or its salt to be used may generally be within a range of 0.8 to 3.0 molar ratio relative to the compound of formula III. The reaction temperature may vary depending on the kinds of the solvent and the base used, but may be generally within a range of from about 30 °C to about 120 °C. The reaction time varies depending on the solvent and base used and on the reaction temperature, but may be generally within a range of from about 5 minutes to about 20 hours. After completion of the reaction the reaction mass may be poured into water optionally containing sodium bicarbonate and the aqueous mass is extracted with a suitable water immiscible solvent followed by washings and the organic layer may be concentrated to isolate the compound of formula II.
If the compound of formula II contains any protecting group then the compound may be treated with a suitable acid such as aqueous hydrochloric acid in presence of a suitable solvent such as acetone, THF or 1,4-dioxane to produce the (R)-isomer of Ozanimod.
Racemic Ozanimod and Ozanimod (S)-isomer can also be prepared using racemic compound of formula IV or the (S)-isomer of the compound of formula IV and with the method described above for the preparation of the (R)-isomer of Ozanimod.
The compound of formula IV or its isomers can be prepared by the following synthetic route

In another aspect, the present application provides novel compounds which are useful as intermediates for the preparation of Ozanimod.

In another aspect, the present application providesa process for preparation of (S)-isomer of compound of formula IVa, comprising:
(a) reacting 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile(compound of formula VII) with ethanolamine to form a compound of formula VIII

(b) Hydrogenating the compound of formula VIII in presence of a suitable catalyst to (S)-isomer of compound of formula IVa

The Ozanimod obtained according to the processes described in this application may exist as amorphous form or crystalline form.
In another aspect, the present application provides Ozanimod having particle sizes less than about 300 µm, or less than about 100 µm, or less than about 50 µm, or less than about 20 µm, or less than about 10 µm.
The present application provides Ozanimod having a particle size distribution wherein the 10th volume percentile particle size (D10) is less than about 15 µm, the 50th volume percentile particle size (D50) is less than about 35 µm, and/or the 90th volume percentile particle size (D90) is less than about 60 µm.
For example, the present application provides Ozanimod having a particle size distribution wherein the 10th volume percentile particle size (D10) is less than about 5 µm, the 50th volume percentile particle size (D50) is less than about 10 µm, and/or the 90th volume percentile particle size (D90) is less than about 20 µm. The “10th volume percentile” as used herein, unless otherwise defined refers to the size of particles, below which 10% of the measured particle volume lies; “50th volume percentile” as used herein, unless otherwise defined refers to the size of particles, below which 50% of the measured particle volume lies, and “90th volume percentile” as used herein, unless otherwise defined refers to the size of particles, below which 90% of the measured particle volume lies.
Particle size distributions of Ozanimod particles may be measured by any technique known in the art. For example, particle size distributions of Ozanimod particles may be measured using light scattering equipment, such as, for example, a Malvern Master Sizer 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom (helium neon laser source, Ozanimod suspended in light liquid paraffin, size range: 0.01 µm to 3000 µm).
In the third aspect, the present application provides a pharmaceutical composition comprising Ozanimod prepared by the processes of the present application and one or more pharmaceutically acceptable excipient.
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.

DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
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.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, “comprising” means the elements recited, or their equivalents 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. All ranges recited herein include the endpoints, including those that recite a range “between” two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
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. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES
Example-1: Preparation of racemic Ozanimod
Example-1a: Preparation of 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile

1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (5.0 g) and methanol (100 mL) were charged into a 500 mL round bottom flask. The mixture was cooled to -40 °C and sodium borohydride (1.3 g) was added portion wise to the reaction mixture. The reaction mixture allowed to rise to 0 °C and stirred for 2 hours at 0 °C. The reaction mixture was quenched with ice water (5 mL) and the resultant mixture was concentrated at 45 °C under reduced pressure. Saturated ammonium chloride solution (30 mL) was added to the crude reaction mixture and stirred for 10 minutes and the mixture was then extracted with ethylacetate. The organic layer was washed with brine solution (50 mL), dried over sodium sulphate and concentrated under reduced pressure at 45 °C to yield 4.5 g of title compound. HPLC purity: 96.66%; Chiral HPLC purity: 49.97%, 50.03%.

Example-1b: Preparation of 1-chloro-2,3-dihydro-1H-indene-4-carbonitrile (compound of formula V)

1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile (2.0 g) and dichloromethane (40 mL) were charged into a 250 mL round bottom flask and the mixture was cooled to 0 °C. Triethylamine (1.76 mL) and thionyl chloride (1.76 mL) were added to the reaction mixture. The reaction mixture temperature was allowed to rise to 28 °C and stirred for 5 hours at 28 °C. The reaction mixture was quenched with ice water (20 mL) and the resultant mixture was extracted with dichloromethane (3 ? 30 mL). The organic layer was washed with saturated sodium bicarbonate solution (50 mL) and brine solution (50 mL). The organic layer was dried over sodium sulphate and concentrated under vacuum at 40 °C to yield 2.1 g of the crude compound of formula V.

Example-1c: Preparation of 1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-indene-4-carbonitrile (compound of formula IVa)

Compound of formula V (2.1 g) and dimethylacetamide (21 mL) were charged into a 100 mL round bottom flask at 28 °C. Ethanolamine (2.1 mL) and DIPEA (6.3 mL) were added and the mixture was heated to 100 °C. The reaction mixture was stirred for 16 hours at 100 °C. The reaction mixture was quenched with water (50 mL) and the resultant aqueous mixture was extracted with ethylacetate (3 x50 mL). The organic layer was washed with cold water (3 x40 mL) and washed with brine solution (3x50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure at 40 °C to yield 2.0 g of the crude compound of formula IVa. LCMS Purity: 96.82%; Chiral HPLC purity: 49.02%, 50.97%.

Example 1d: Preparation of tert-butyl-(4-cyano-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate (compound of formula IVb)

Compound of formula IVa (1.8 g) and dichloromethane (20 mL) were charged into a 100 mL round bottom flask at 28 °C. Reaction mixture was cooled to 0 °C and triethylamine (1.87 mL) and di-tert-butyl dicarbonate (boc anhydride, 2.25 mL) were added dropwise at 0 °C. The resulting mixture was heated to 30 °C and stirred for 16 hours. The reaction mixture was quenched with water (50 mL) and the resultant aqueous mixture was extracted with dichloromethane (2 x50 mL). The organic layer was washed with brine solution (40 mL) and dried over sodium sulphate. The organic layer was concentrated under reduced pressure at 40 °C. The resultant crude compound purified using silica gel column chromatography (50% ethylacetate in hexane) to yield 2.2 g of the title compound as brown solid.

Example 1e: Preparation of tert-butyl-(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate (compound of formula IVc)

Compound of formula IVb (2.0 g), ethanol (20 mL), hydroxylamine hydrochloride (1.61 g) and triethylamine (3.2 mL) were charged into a 100 mL round bottom flask at 28 °C. The mixture was heated to 80 °C and stirred for 7 hours. The reaction mixture was concentrated under reduced pressure at 45 °C. Dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL) were added to the residue and the resultant mixture was stirred for 5 minutes. Layers separated and the aqueous layer was extracted with dichloromethane (2 x50 mL). The organic layer were combined and washed with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) and brine solution (50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure at 40 °C to yield 2.3 g of dark brown foamy solid.

Example 1f: Preparation of tert-butyl-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate (compound of formula III)

3-Cyano-4–isopropoxybenzoic acid (1.45 g) and dimethylformamide (18.7 mL) were charged into a 100 mL round bottom flask at 28 °C. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 1.5 g) and 1-hydroxybenzotriazole (HOBt, 1.43 g) were added to the reaction mixture at 28 °C and the resultant mixture was stirred for 1 hour. The compound of formula IVc (2.2 g) was dissolved in dimethylformamide (8.8 mL) and added to the reaction mixture at 28 °C and the reaction mixture was stirred for 2 hours. The reaction mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to 28 °C and quenched with saturated aqueous sodium bicarbonate solution (50 mL). The mixture was extracted with ethylacetate (3 x50 mL). The ethylacetate layers were combined and washed with water (3 x 50 mL) followed by brine solution (50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure at 40 °C to yield the title compound as brown color syrup. The crude compound purified using silica gel column chromatography (5% methanol in DCM) to yield 1.2 g of the title compound as brown color syrup. HPLC Purity: 94.85%

Example 1g: Preparation of5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (racemic Ozanimod)
Compound of formula III (1.0 g) and 1,4-dioxane (5 mL) were charged into a 100 mL round bottom flask at 28 °C. The mixture was cooled to 0 °C and 4M HCl in 1,4-dioxane (4.96 mL) was added dropwise to the reaction mixture. The reaction mixture was allowed to rise to 28 °C. The reaction mixture was heated to 50 °C and stirred for 1 hour. The reaction mixture was cooled to 28 °C and diethyl ether (5.1 mL) was added to the reaction mixture and the resulted mixture was stirred for 30 minutes. The precipitation was filtered and the solid was washed with diethyl ether and suck dried for 1 hour. The solid was added to dichloromethane containing 15% methanol (60 mL) and water (20 mL) was added to the resultant mixture. The mixture was cooled to 0 °C and pH was adjusted to 7-8 with aqueous sodium bicarbonate solution. Layers separated and the aqueous layer was extracted with dichloromethane containing 15% methanol (60 mL). Organic layers were combined and dried over sodium sulphate and concentrated under reduced pressure at 45 °C to yield 370 mg of racemic Ozanimod as white solid. HPLC purity: 99.18%; Chiral HPLC purity: 49.14%, 50.85%

Example-2: Preparation of Ozanimod-(R)-isomer
Example-2a: Preparation of 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile

1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (8.0 g) and methanol (160 mL) were charged into a 1000 mL round bottom flask. The mixture was cooled to -40 °C and sodium borohydride 2.3 g) was added portion wise to the reaction mixture. The reaction mixture allowed to rise to 0 °C and stirred for 2 hours at 0 °C. The reaction mixture was quenched with ice water (5 mL) and the resultant mixture was concentrated at 45 °C under reduced pressure. Saturated ammonium chloride solution (30 mL) was added to the crude reaction mixture and stirred for 10 minutes and the mixture was then extracted with ethylacetate. The organic layer was washed with brine solution (50 mL), dried over sodium sulphate and concentrated under reduced pressure at 45 °C to yield 8.1 g of title compound. HPLC purity: 91.74%; Chiral HPLC purity: 49.97%, 50.03%.

Example-2b: Preparation of 1-chloro-2,3-dihydro-1H-indene-4-carbonitrile (compound of formula V)

1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile (8.0 g) and dichloromethane (160 mL) were charged into a 1000 mL round bottom flask and the mixture was cooled to 0 °C. Triethylamine (7.2 mL) and thionyl chloride(7.4mL) were added to the reaction mixture. The reaction mixture temperature was allowed to rise to 28 °C and stirred for 5 hours at 28 °C. The reaction mixture was quenched with ice water (20 mL) and the resultant mixture was extracted with dichloromethane (3 x 70 mL). The organic layer was washed with saturated sodium bicarbonate solution (50 mL) and brine solution (50 mL). The organic layer was dried over sodium sulphate and concentrated under vacuum at 40 °C to yield 8.5 g of the crude compound of formula V.

Example-2c: Preparation of 1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-indene-4-carbonitrile (compound of formula IVa)

Compound of formula V (7.5 g) and dimethylacetamide (75 mL) were charged into a 250 mL round bottom flask at 28 °C. Ethanolamine (7.66 mL) and DIPEA (22.69 mL) were added and the mixture was heated to 100 °C. The reaction mixture was stirred for 16 hours at 100 °C. The reaction mixture was quenched with water (50 mL) and the resultant aqueous mixture was extracted with dichloromethane containing 5% methanol. The organic layer was washed with cold water (3 x 50 mL) and washed with brine solution (3 x 50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure at 40 °C. The crude product was purified using silica gel column chromatography (5% methanol in DCM) to yield 5.2 g of the racemic compound of formula IVa. HPLC Purity: 99.3%; Chiral HPLC purity: 49.69%, 50.30%.

Example-2d: Preparation of (R)-1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-indene-4-carbonitrile(compound of formula IVa (R)-isomer)

Compound of formula IVa (racemic) (5.1 g) and acetonitrile (102 mL) were charged into a 250 mL round bottom flask at 28 °C. Di-p-Toluyl- L-tartaric acid (4.87 g) was dissolved in acetonitrile (10 mL) and this solution was added dropwise to the reaction mixture at 28 °C. The resultant mixture was stirred for 3 hours at 28 °C. The precipitation was filtered and the solid was washed with acetonitrile (5 mL). The filtrate was evaporated and the residue was dissolved in dichloromethane containing 5% methanol (150 mL) and the organic layer was washed with sodium bicarbonate solution. The aqueous layer was washed with dichloromethane containing 5% methanol (3 x 100 mL). The organic layers were combined and dried over sodium sulphate and the organic layer was concentrated under reduced pressure at 40 °C to yield 1.1 g of the title compound. Chiral HPLC: 89.62%.

Example 2e: Preparation of tert-butyl (R)-(4-cyano-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate (compound of formula IVb (R)-isomer)

Compound of formula IVa (R-isomer) (700 mg) and dichloromethane (7 mL) were charged into a 100 mL round bottom flask at 28 °C. Reaction mixture was cooled to 0 °C and triethylamine (0.75 mL) and di-tert-butyl dicarbonate (boc anhydride, 0.875 mL) were added dropwise at 0 °C. The resulting mixture was heated to 30 °C and stirred for 16 hours. The reaction mixture was quenched with water (50 mL) and the resultant aqueous mixture was extracted with dichloromethane (3 x50 mL). The organic layer was washed with brine solution (40 mL) and dried over sodium sulphate. The organic layer was concentrated under reduced pressure at 40 °C. The resultant crude compound purified using silica gel column chromatography (50% ethylacetate in hexane) to yield 505 mg of the title compound. HPLC purity: 94.72%.

Example 2f: Preparation of tert-butyl (R)-(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate (compound of formula IVc (R)-isomer)

Compound of formula IVb (R-isomer) (490 mg) and hydroxylamine hydrochloride (394 mg) and triethylamine (0.8 mL) were charged into a 100 mL round bottom flask at 28 °C. The mixture was heated to 80 °C and stirred for 7 hours. The reaction mixture was concentrated under reduced pressure at 45 °C. Dichloromethane (50 mL) and saturated aqueous sodium bicarbonate solution (50 mL) were added to the residue and the resultant mixture was stirred for 5 minutes. Layers separated and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The organic layer were combined and washed with saturated aqueous sodium bicarbonate solution (50 mL), water (50 mL) and brine solution (50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure at 40 °C to yield 545 mg of dark brown foamy solid.

Example 2g: Preparation of tert-butyl (R)-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)(2-hydroxyethyl)carbamate (compound of formula II (R)-isomer)

3-Cyano-4–isopropoxy benzoic acid (352 mg) and dimethylformamide (4.59 mL) were charged into a 100 mL round bottom flask at 28 °C. 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl, 369 mg) and 1-hydroxybenzotriazole (HOBt, 353 mg) were added to the reaction mixture at 28 °C and the resultant mixture was stirred for 1 hour. The compound of formula IVc (R-isomer) (540 mg) was dissolved in dimethylformamide (2.16 mL) and aded to the reaction mixture at 28 °C and the reaction mixture was stirred for 2 hours. The reaction mixture was heated to 80 °C and stirred for 16 hours. The reaction mixture was cooled to 28 °C and quenched with saturated aqueous sodium bicarbonate solution (50 mL). The mixture was extracted with ethylacetate (3 x 35 mL). The ethylacetate layers were combined and washed with water (3 x 50 mL) followed by brine solution (50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure at 40 °C to yield the title compound as brown color syrup. The crude compound purified using silica gel column chromatography (5% methanol in DCM) to yield 510 mg of the title compound as brown color syrup.

Example 2h: Preparation of(R)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile (Ozanimod (R)-isomer)

Compound of formula II (R-isomer) (510 mg) and 1,4-dioxane (2.55 mL) were charged into a 100 mL round bottom flask at 28 °C. The mixture was cooled to 0 °C and 4M HCl in 1,4-dioxane (2.52 mL) was added dropwise to the reaction mixture. The reaction mixture was allowed to rise to 28 °C. The reaction mixture was heated to 50 °C and stirred for 1 hour. The reaction mixture was cooled to 28 °C and diethyl ether (5.1 mL) was added to the reaction mixture and the resulted mixture was stirred for 30 minutes. The precipitation was filtered and the solid was washed with diethyl ether and suck dried for 1 hour. The solid was added to dichloromethane containing 15% methanol (60 mL) and water (20 mL) was added to the resultant mixture. The mixture was cooled to 0 °C and pH was adjusted to 7-8 with aqueous sodium bicarbonate solution. Layers separated and the aqueous layer was extracted with dichloromethane containing 15% methanol (60 mL). Organic layers were combined and dried over sodium sulphate and concentrated under reduced pressure at 45 °C to yield 150 mg of Ozanimod (R)-isomer as white solid. Chiral HPLC purity: 99.63%.
,CLAIMS:We claim
1. A compound of formula IV or its acid addition salts or its isomers thereof.

wherein P1 and P2 are independently hydrogen or a protecting group selected from tert-butyloxycarbonyl (BOC group), benzyloxy carbonyl, trimethylsilyl or tert-butyl dimethylsilyl.
2. The process for the preparation of (S) or (R) isomers compound of formula IV according to claim 1, the process comprising resolution of racemic mixture of compound of formula IV using a chiral acid.

3. The process according to claim 2, wherein the chiral acid is selected from di-p-toluoyltartaric acid, tartaric acid, dibenzoyltartaric acid, aspartic acid, camphorsulfonic acid, glutamic acid, malic acid, mandelic acid, pyroglutamic acid or valine.
4. A process for the preparation of Ozanimod (R)-isomer, the process comprising the steps of:
a) reacting a compound of formula V with ethanolamine in presence of a base to obtain racemic mixture of compound of formula IV, and optionally protecting the racemic mixture of compound of formula IV with one or more protecting groups

b) treating the racemic mixture of compound of formula IV with a chiral acid to obtain the (R)-isomer of compound of formula IV

c) reacting the (R)-isomer of compound of formula IV with hydroxylamine in presence of a base to obtain the compound of formula III

d) reacting the compound of formula III with a compound of formula IX to obtain the compound of formula II

e) optionally deprotecting the compound of formula II to obtain Ozanimod (R)-isomer of formula I

5. The process according to claim 4, wherein the base is selected from N,N-Diisopropylethylamine, triethylamine or diethyl isopropyl amine.
6. The process according to claim 4, wherein the protecting group is selected from tert-butyloxycarbonyl (BOC group), benzyloxy carbonyl, trimethylsilyl or tert-butyl dimethylsilyl.
7. The process according to claim 4, wherein the chiral acid is selected from di-p-toluoyltartaric acid, tartaric acid, dibenzoyltartaric acid, aspartic acid, camphorsulfonic acid, glutamic acid, malic acid, mandelic acid, pyroglutamic acid or valine.
8. Compounds of formula V, formula IVa, formula IVb, formula IVc or isomers thereof.

9. A pharmaceutical composition comprising Ozanimod and one or more pharmaceutically acceptable excipient.