The present invention relates to compounds of Formula X or pharmaceutically acceptable salts thereof,
.

Particularly, the present invention provides a process for the preparation of ozanimod or its pharmaceutically acceptable salts by using novel compounds of Formula X or pharmaceutically acceptable salts thereof.

Present invention further provides a stable amorphous form of ozanimod or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Ozanimod, is chemically defined as (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-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 for the treatment of ulcerative colitis and relapsing multiple sclerosis (RMS).

US patent No. 8,481,573 B2 discloses racemic ozanimod and its pharmaceutical compositions. US patent No. 8,481,573 B2 also describes a process for preparation of racemic ozanimod. The process is schematically represented in scheme I below:

.

US patent No. 8,362,048 discloses specific (S)-isomer of Ozanimod and process of preparation thereof. US’048 generically discloses the process of preparation of S-Ozanimod which is schematically represented in the scheme II as mentioned below:

Scheme II

Based on the process known from the prior published literature, the present invention is focused towards the development of a novel and cost effective process for the preparation of ozanimod using novel intermediates.

OBJECT OF THE INVENTION

The main object of the present invention is to develop a process for the preparation of ozanimod or its pharmaceutically acceptable salt.

Another object of the present invention is to prepare ozanimod or pharmaceutically acceptable salts thereof by using novel compounds of Formula X,
.

Another object of the present invention is to provide a stable amorphous form of ozanimod or its pharmaceutically acceptable salts, and process of preparation thereof.

SUMMARY OF THE INVENTION

The present invention provides novel compounds, their process of preparation and use in the preparation of ozanimod and/or pharmaceutically acceptable salts thereof.

Accordingly, in main aspect, the present invention novel compounds of Formula X,

wherein,
X is selected from any leaving group, , NH2 or protected amine;
Y is selected from O, N(OH);
Z is represented as:
,
wherein,
A is attached to the cyclic ring either by a single or double bond;
A represents –O, -N(R)2, R is independently selected from hydrogen, suitable nitrogen protecting group, substituted and unsubstituted alkyl, substituted and unsubstituted alkaryl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, sulphur containing moiety, silyl containing moiety, -COR1, R1 is selected from hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkaryl, and substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, or sulphur containing moiety.

In another aspect, the present invention provide compound of Formula X wherein wherein group ‘x’ is –NH2, and said compound is represented as compound of Formula II,
.

In another aspect, the present invention provide compound of Formula X, wherein group ‘X’ is represented as , with Y represents –O and Z is represented as , wherein A is O; and said compound is represented as compound of Formula III,
.

In another aspect, the present invention provides compound of Formula X wherein Y is O, A is =NR, and said compound is represented as compound of Formula IVa,
,
wherein R is any suitable nitrogen protecting group.

In another aspect, the present invention provide compound of Formula X wherein ‘Y’ is O and ‘A’ is =NR, wherein R is unsubstituted aralkyl, and said compound is represented as compound of Formula IV,
.

In another aspect, the present invention provide compound of Formula X wherein ‘Y’ is O and A is N(R)2, wherein atleast one R is nitrogen protecting group, and said compound is represented as compound of Formula Va,
,
wherein R is any suitable nitrogen protecting group.

In another aspect, the present invention provide compound of Formula X wherein ‘Y’ is O and ‘A’ is N(R)2, wherein atleast one R is unsubstituted aralkyl, and said compound is represented as compound of Formula V,
.
In another aspect, the present invention provide compound of Formula X wherein ‘Y’ is O and ‘A’ is N(R)2, wherein atleast one R is alkyl substituted with hydroxyl group, and said compound is represented as compound of Formula VIa,
,
wherein R is any suitable nitrogen protecting group.

In another aspect, the present invention provide compound of Formula X wherein, said compound is represented as compound of Formula VI,
.

In another aspect, the present invention provide compound of Formula X wherein ‘Y’ is O and ‘A’ is N(R)2, wherein atleast one R is hydrogen, and said compound is represented as compound of Formula VII,
.

In another aspect, the present invention provide compound of Formula X wherein ‘Y’ is N-OH and ‘A’ is N(R)2, wherein atleast one R is alkyl substituted with hydroxyl group, and said compound is represented as compound of Formula VIII,
.

In another aspect, the present invention provides a process for the preparation of ozanimod or pharmaceutical acceptable salts thereof, wherein said process comprising the steps of;
a) reacting compound of Formula II or its salt either with 1-oxoindane-4-carbonyl chloride, or 1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid in presence of suitable reagent to give compound of Formula III or its salt,
;
b) converting compound of Formula III or its salt to ozanimod; and
c) optionally converting ozanimod to its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the preparation of ozanimod or pharmaceutical acceptable salts thereof, wherein said process comprising the steps of;
a) reacting compound of Formula III or its salts with (S)-(-)-1-phenylethylamine or its salt to give compound of Formula IV or its salt,
;
b) converting compound of Formula IV or its salt to ozanimod; and
c) optionally converting ozanimod to its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for preparing ozanimod or pharmaceutical acceptable salts thereof, wherein said process comprising the steps of;
a) reacting compound of Formula V or its salt with 2-haloethanol of Formula XII to give compound of Formula VI or its salt,
;
wherein X is any suitable leaving group;
b) deprotecting compound of Formula VI or its salt to give compound of Formula VII or its salt,
;
c) converting compound of Formula VII to ozanimod; and
d) optionally converting ozanimod to its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for preparing ozanimod or pharmaceutical acceptable salts thereof, wherein said process comprising the steps of;
a) converting compound of Formula VII or its salt to compound of Formula VIII or its salt,
;
b) cyclizing compound of Formula VIII or its salt to give ozanimod; and
c) optionally converting ozanimod to its pharmaceutically acceptable salt.

In another aspect, the present invention provides substantially pure ozanimod or pharmaceutically acceptable salt thereof, substantially free of compounds of Formula X, wherein said ozanimod or pharmaceutically acceptable salt thereof, is characterized by purity of 99.0% and above.

In another aspect, the present invention provides solid dispersion of ozanimod or pharmaceutically acceptable salt thereof together with at least one pharmaceutically acceptable carrier or polymer.

In another aspect, the present invention provides stable amorphous form of ozanimod or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable for atleast six months at 25oC to 40oC and 60% to 75% RH.

In another aspect, the present invention provides a process for the preparation of ozanimod of Formula I by employing novel compounds of Formula II, III, IV, V, Va, VI, VII and VIII, wherein said process comprising of reaction steps as mentioned in the scheme below:

DETAILED DESCRIPTION
Drawings:
Figure 1 represents XRPD peaks of amorphous solid dispersion of Ozanimod prepared as per example 9.
Figure 2 represents XRPD peaks of amorphous form of Ozanimod prepared as per example 10.
Definitions
“Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, valine, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like or, benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl)morpholine, dicyclohexyl amine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.

The term “substantially free” or “substantially pure” used in the context of the present invention means ozanimod having each impurity less than about 0.2% by area percentage of HPLC. In particular, less than about 0.15% by area percentage of HPLC. More particular, not in detectable amount by area percentage of HPLC.

The “suitable solvent” as used in the context of the present invention, is selected from the group comprising of, but not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, butanenitrile, water and mixture thereof.

The “Suitable nitrogen protecting group” or “protecting group” as used in the context of the present invention refers to compounds that has a purpose of temporarily masking the functionality of the site to which it is attached on a molecule. Prior to the use of the molecule in a subsequent analysis or application, the protecting group may or may not be removed.

In one embodiment, the present invention provide compounds of Formula X, salts, isomers, polymorphs thereof,

wherein,
X is selected from any leaving group, , -NH2, protected amine;
Y is selected from =O, =N(OH);
Z is represented as:
,
wherein,
A is attached to the cyclic ring either by a single or double bond,
A represents –O, N(R)2, R is independently selected from hydrogen, suitable nitrogen protecting group, substituted and unsubstituted alkyl, substituted and unsubstituted alkaryl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, sulphur containing moiety, silyl containing moiety, -COR1, R1 is selected from hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkaryl, and substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, sulphur containing moiety.

In another embodiment, the present invention provide compound of Formula X wherein said compound is represented as formulae as follows:
, , , , , , , ,
, and ;
wherein R is any suitable nitrogen protecting group.

In another embodiment, the present invention provides a process for the preparation of ozanimod or pharmaceutical acceptable salts thereof, wherein said process comprising the steps of;
a) reacting compound of Formula II or its salt either with 1-oxoindane-4-carbonyl chloride, or 1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid in presence of suitable reagent to give compound of Formula III or its salt,
;
b) converting compound of Formula III or its salt to ozanimod; and
c) optionally converting ozanimod to its pharmaceutically acceptable salt.

In another embodiment, the present invention provides a process for preparing ozanimod or pharmaceutical acceptable salts thereof, wherein said process comprising the steps of;
a) reacting compound of Formula III or its salts with (S)-(-)-1-Phenylethylamine or its salt to give compound of Formula IV or its salt,
;
b) converting compound of Formula IV or its salt to ozanimod; and
c) optionally converting ozanimod to its pharmaceutically acceptable salt.

In another embodiment, the present invention provides a process for preparing ozanimod or pharmaceutical acceptable salts thereof, wherein said process comprising the steps of;
a) reacting compound of Formula V or its salt with 2-haloethanol of Formula XII to give compound of Formula VI or its salt,

wherein;
X is any suitable leaving group;
b) deprotecting compound of Formula VI or its salt to give compound of Formula VII or its salt,
:
c) converting compound of Formula VII to ozanimod; and
d) optionally converting ozanimod to its pharmaceutically acceptable salt.

In another embodiment, the present invention provides a process for the preparation of ozanimod or pharmaceutical acceptable salts thereof, wherein said process comprising the steps of;
a) converting compound of Formula VII or its salt to compound of Formula VIII or its salt.
;
b) cyclizing compound of Formula VIII or its salt to give ozanimod; and
c) optionally converting ozanimod to its pharmaceutically acceptable salt.

In another embodiment, the present invention provides process for the preparation of ozanimod or pharmaceutically acceptable salt thereof, wherein said process involves isolation of intermediates which are optionally purified before proceeding to next step.

In another embodiment, the present invention provides process for the preparation of ozanimod or pharmaceutically acceptable salt thereof, wherein said process involves in-situ reaction steps wherein intermediates are not isolated and are used as such in the next reaction step.

In another embodiment, the present invention provides substantially pure ozanimod or pharmaceutically acceptable salt thereof, substantially free of compounds of Formula X, wherein said ozanimod or pharmaceutically acceptable salt thereof is characterized by purity of 99.0% and above.

In another embodiment, the ozanimod may optionally be prepared by resolution of racemic ozanimod and wherein said racemic ozanimod is prepared through intermediates of Formula X, which are proceeded as racemic compounds.

In an alternate embodiment, the present invention provides process for the purification of ozanimod or its pharmaceutically acceptable salt, comprising the steps of:
a) adding ozanimod or its pharmaceutically acceptable salt in a suitable solvent;
b) optionally heating at a temperature ranging from 30oC to boiling point of the solvent;
c) optionally adding antisolvent for precipitation; and
d) removing the solvent to get pure ozanimod or its pharmaceutically acceptable salt.

In another embodiment, the present invention provides stable amorphous form of ozanimod or pharmaceutically acceptable salt thereof, wherein said amorphous form is stable for for atleast six months at 25oC to 40oC and 60% to 75% RH.

In another embodiment, the present invention provides a process for the preparation of a stable amorphous form of ozanimod or a pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of ozanimod or a pharmaceutically acceptable salt thereof in one or more suitable solvent; and
b) isolating the stable amorphous form of ozanimod or a pharmaceutically acceptable salt thereof.

In another embodiment, the present invention provides an amorphous solid dispersion of ozanimod or pharmaceutically acceptable salt thereof, with at least one pharmaceutically acceptable carrier or polymer.

In another embodiment, the present invention provides a process for the preparation of an amorphous solid dispersion of ozanimod or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of ozanimod or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding atleast one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of ozanimod or a pharmaceutically acceptable salt thereof.

In another embodiment, pharmaceutically acceptable carrier used for preparing solid dispersion may include, but not limited to, an inorganic oxide such as SiO2, TiO2, ZnO2, ZnO, Al2O3 and zeolite; a water insoluble polymer is selected from the group consisting of cross-linked polyvinyl pyrrolidinone, cross-linked cellulose acetate phthalate, cross-linked hydroxypropyl methyl cellulose acetate succinate, microcrystalline cellulose, polyethylene glycol, polyethylene/polyvinyl alcohol copolymer, polyethylene/polyvinyl pyrrolidinone copolymer, cross-linked carboxymethyl cellulose, sodium starch glycolat, and cross-linked styrene divinyl benzene or any other carrier at any aspect of present application. In an embodiment, atleast one pharmaceutically acceptable carrier may be selected from the group consisting of polyvinyl pyrrolidone, povidone K-30, povidone K-60, Povidone K-90, polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene–polyoxypropylene copolymers (Poloxamer® 188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, poloxamer 188, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-RLPO), hydroxypropylmethyl cellulose phthalate, hydroxypropylmethyl cellulose acetate succinate (HPMC-AS), hydroxypropylmethyl cellulose, hydroxypropyl cellulose SSL(HPC-SSL), hydroxypropyl cellulose SL(HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, Soluplus® (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG)), gelucire 44/14, ethyl cellulose, D-alpha-tocopheryl polyethylene glycol 1000 succinate, cellulose acetate phthalate, carboxy methyl ethyl cellulose and the like; cyclodextrins, gelatins, hypromellose phthalates, sugars, polyhydric alcohols, and the like; water soluble sugar excipients, preferably having low hygroscopicity, which include, but are not limited to, mannitol, lactose, fructose, sorbitol, xylitol, maltodextrin, dextrates, dextrins, lactitol and the like; polyethylene oxides, polyoxyethylene derivatives, polyvinyl alcohols, propylene glycol derivatives and the like.

In preferred embodiments, pharmaceutically acceptable carrier used for preparing solid dispersion is selected from the group comprising of polyvinyl pyrrolidine, povidone K-30, povidone K-60, PovidoneK-90,polyvinylpyrrolidone vinylacetate, co-povidone NF, polyvinyl acetate phthalate, polysorbate 80,polyoxyethylene–polyoxypropylene copolymers (Poloxamer®188), polyoxyethylene (40) stearate, polyethyene glycol monomethyl ether, polyethyene glycol, pluronic F-68, methylcellulose, methacrylic acid copolymer (Eudragit), hydroxypropylmethyl cellulose (HPMC), hydroxypropylmethyl cellulose phthalate (HPMC phthalate), hydroxypropylmethyl cellulose acetate succinate (HPMC AS), hydroxypropyl cellulose SL (HPC), hydroxy ethyl cellulose (HEC) and ethyl cellulose (EC).

In preferred embodiments, removal of solvent at any stage of preparation of ozanimod or pharmaceutically acceptable salt, its amorphous form/ solid dispersion thereof, may include, but not limited to, solvent evaporation under atmospheric pressure or reduced pressure / vacuum such as a rotational distillation using Büchi® Rotavapor®, flash evaporation, rotational dying, agitated nutsche filter drying, spray drying, freeze drying, thin film drying, agitated thin film drying, rotary vacuum paddle dryer (RVPD), lyophilisation, and the like. In preferred embodiment, the solvent may be removed under reduced pressures and at a temperature of less than about 100°C, less than about 60°C, less than about 40°C, less than about 20°C, less than about 0°C, less than about -20°C, less than about -40°C, less than about -60°C, less than about -80°C.

In another embodiment, the present invention provides a substantially pure amorphous form of ozanimod or pharmaceutically acceptable salt thereof, wherein said amorphous form is substantially free of any crystalline form.

In further embodiment, the present invention provides ozanimod or its pharmaceutically acceptable salt characterized by particle size distribution wherein, d90 is between 0.1µm to 200µm, specifically d90 is between 2.0 µm to 150µm.

In one another embodiment, the ozanimod and its pharmaceutically acceptable salt prepared as per the process of the present invention is characterized with purity above 99%, preferably above 99.5%, and more preferably above 99.9%.

In one another embodiment, the present invention further provides a composition comprising ozanimod or its pharmaceutically acceptable salt and one or more pharmaceutical acceptable excipients, wherein said ozanimod or its pharmaceutically acceptable salt is prepared as per the process of the present invention.

In another embodiment, the present invention provides a method for preparation of composition comprising ozanimod or pharmaceutically acceptable salt thereof, wherein said composition is prepared by combining either amorphous form of ozanimod or solid dispersion of ozanimod with atleast one pharmaceutically acceptable excipients.

The embodiments of the present invention are exemplified herein below:

EXAMPLES

Example 1: Preparation of 1-oxo-2,3-dihydro-1H-indene-4-carbonyl chloride:

To a stirred solution of 1-oxindole-4-carboxylic acid (5g, 0.028mole) in dichloromethane (50ml) was added oxalyl chloride (7.11g; 0.056mol) at 0oC followed by refluxing for 1-2.0 hr. ooled the reaction mass to room temperature and proceeded to next step as such.

Example 2: Preparation of N-(3-cyano-4-isopropoxybenzyl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide:

To a stirred solution of 5-(aminomethyl)-2-isopropoxybenzonitrile (6g, 0.0315mole) in 20 ml of dichloromethane at 0oC was added triethylamine (6.36g, 0.063mole) followed by 1-oxoindane-4-carbonyl chloride (5.44g, 0.028mole). The resultant reaction mixture was stirred at 25oC for 3-5 hr. After completion of reaction, reaction mixture was diluted with water (100 ml) and extracted the compound with dichloromethane (3x50ml). The resultant organic extract was concentrated under reduced pressure to get crude compound. Crude compound was purified using methanol and dichloromethane mixture.

Example 3: Preparation of (S,E)-N-(3-cyano-4-isopropoxybenzyl)-1-((1-phenylethyl)imino)-2,3-dihydro-1H-indene-4-carboxamide:

N-(3-cyano-4-isopropoxybenzyl)-1-oxo-2,3-dihydro-1H-indene-4-carboxamide (5g, 0.01435mole) in toluene was stirred at 20-25oC and added (S)-(-)-1-Phenylethylamine (2.08g, 0.0172mole) followed by heating at 110-120oC for 14 hr. After completion of reaction, cooled the reaction mixture at 20-25oC and poured on ice. Extracted the compound with ethyl acetate (3x100ml) and the combined organic layer was dried over sodium sulphate. Concentrated the organic layer to get the desired product, which was purified using column chromatography with ethyl acetate and hexane solvents.

Example 4: Preparation of (S)-N-(3-cyano-4-isopropoxybenzyl)-1-(((S)-1-phenylethyl)amino)-2,3-dihydro-1H-indene-4-carboxamide:

To a stirred solution of (S,E)-N-(3-cyano-4-isopropoxybenzyl)-1-((1-phenylethyl)imino)-2,3-dihydro-1H-indene-4-carboxamide (4g 0.0088mole) in methanol at 0oC was added sodium borohydride (0.665g, 0.0176mole). The resultant reaction mixture was stirred for 4-6hr at 20-25oC, and progress was monitored by TLC. After completion of reaction, diluted with 150ml water and extracted the compound with ethyl acetate (3x100ml). The combined organic layer was dried over sodium sulphate and concentrated to get the desired crude compound.

Example 5: Preparation of (S)-N-(3-cyano-4-isopropoxybenzyl)-1-((2-hydroxyethyl)((S)-1-phenylethyl)amino)-2,3-dihydro-1H-indene-4-carboxamide:

To a stirred solution of (S)-N-(3-cyano-4-isopropoxybenzyl)-1-(((S)-1-phenylethyl)amino)-2,3-dihydro-1H-indene-4-carboxamide (2g, 0.0044mole) in DMF(20ml) was added potassium carbonate (2.45g; 0.0178mole) and bromoethanol (2.224g; 0.0178mole). The resultant reaction mixture was stirred at 100oC for 24 hr. After completion of reaction, resulting mixture was poured on ice and extracted the compound with ethyl acetate (2x100ml). The combined organic layer was dried over sodium sulphate and concentrated to get the desired product.

Example 6: Preparation of (S)-N-(3-cyano-4-isopropoxybenzyl)-1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-indene-4-carboxamide:

To a stirred solution of (S)-N-(3-cyano-4-isopropoxybenzyl)-1-((2-hydroxyethyl)((S)-1-phenylethyl)amino)-2,3-dihydro-1H-indene-4-carboxamide (2g, 0.004mole) in methanol (20 ml) was added 200mg of Pd/C. The resultant reaction mixture was stirred under hydrogen atmosphere at 20 psi for 5-8 hr to get compound desired compound.

Example 7: Preparation of (S)-N-(3-cyano-4-isopropoxybenzyl)-N'-hydroxy-1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-indene-4-carboximidamide:

To a solution of iodine (1.5eq) and triphenylphosphine (1.5eq) in dry dichiloromethane (10ml), was added (S)-N-(3-cyano-4-isopropoxybenzyl)-1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-indene-4-carboxamide (1.0eq). Cooled the reaction mixture to 0oC and added trietylamine (3.33eq) followed by hydroxyl amine hydrochloride (1.5eq). Raised the temperature to 20-30OC, and stirred for 2-4hr. After completion of reaction, concentrated the reaction mass and proceeded to next step as such.

Example 8: Preparation of Ozanimod:

To a stirred solution of (S)-N-(3-cyano-4-isopropoxybenzyl)-N'-hydroxy-1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-indene-4-carboximidamide (0.5mmol) in DMF (5ml), was added potassium phosphate (3eq) and the resultant reaction was stirred at 60oC for 6-8 hr under oxygen atmosphere. After completion of reaction, the reaction mixture was cooled to room temperature, poured on ice water and extracted with ethyl acetate (3x50ml). The combined organic layer was concentrated under reduced pressure and re-crystalized in methanol to get desired product.

Example 9: Preparation of amorphous solid dispersion of Ozanimod with PVP K-90:

Ozanimod (1 g) was dissolved in ethanol (50 mL) at 25°C to make a solution. To this was added and PVP K-90 (0.8 g) with stirring and filtered the solution to make it particle free. The solvent was evaporated in rotavapour under reduced pressure at 55°C to obtain the title compound.

Example 10: Preparation of stable amorphous form of Ozanimod:

Added Ozanimod (10 gm) to ethyl acetate (150 ml), stirred for 30 minutes at 40oC. The solution was cooled and filtered on hyflo bed, followed by washing with ethyl acetate to obtain a solid mass. To the solid mas was added heptane (100 ml), distilled off the solvent and solid was collected. The solid was taken in heptane (100 ml), stirred for 2 hours at room temperature, filtered, washed the solid with heptane and dried the solid to obtain an amorphous form.

CLAIMS:We Claim:

1. A compounds of Formula X,

wherein,
X is selected from any leaving group, , NH2 or protected amine;
Y is selected from =O, =N(OH);
Z is represented as:
,
wherein,
A is attached to the cyclic ring either by a single or double bond;
A represents –O, -N(R)2, R is independently selected from hydrogen, suitable nitrogen protecting group, substituted and unsubstituted alkyl, substituted and unsubstituted alkaryl, substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl, sulphur containing moiety, silyl containing moiety, -COR1, R1 is selected from hydrogen, substituted and unsubstituted alkyl, substituted and unsubstituted alkaryl, and substituted and unsubstituted aryl, substituted and unsubstituted heteroaryl.

2. The compound as claimed in claim 1, wherein said compound is represented by formula selected from:
, , , , , , , , , and ;
wherein R is a suitable nitrogen protecting group.

3. A process for the preparation of ozanimod or pharmaceutically acceptable salts thereof, comprising the steps of:
a) reacting compound of Formula II or its salt either with 1-oxoindane-4-carbonyl chloride, or 1-oxo-2,3-dihydro-1H-indene-4-carboxylic acid in presence of suitable reagent to give compound of Formula III or its salt,
;
b) converting compound of Formula III or its salt to ozanimod; and
c) optionally converting ozanimod to its pharmaceutically acceptable salt.

4. The process as claimed in claim 3, wherein said process further comprises the steps of:
a) reacting compound of Formula III or its salts with (S)-(-)-1-Phenylethylamine or its salt to give compound of Formula IV or its salt;
b) reacting compound of Formula V or its salt with 2-haloethanol of Formula XII to give compound of Formula VI or its salt;
c) deprotecting compound of Formula VI or its salt to give compound of Formula VII or its salt;
d) converting compound of Formula VII or its salt to compound of Formula VIII or its salt;
e) cyclizing compound of Formula VIII or its salt to give ozanimod; and
c) optionally converting ozanimod to its pharmaceutically acceptable salt;

.

5. The process as claimed in claims 3 and 4, wherein said pharmaceutically acceptable salt of ozanimod is selected from hydrochloride, besylate, citrate, L-malate, dihydrogen phosphate, hydrogen sulfate, hemisulfate, L-tartrate, hemifumarate, hydrobromide, or methanesulfonate salt.

6. Substantially pure ozanimod of formula I or pharmaceutically acceptable salt, wherein said ozanimod is substantially free from compounds of Formula X or salt thereof.

7. Amorphous form of ozanimod or pharmaceutically acceptable salt wherein said amorphous form is stable for atleast six months at 25oC to 40oC and 60% to 75% RH and/or possess purity of 99.0% and above.

8. A process for the preparation of stable amorphous form of ozanimod or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of ozanimod or pharmaceutically acceptable salt thereof in one or more suitable solvent; and
b) isolating the amorphous form of cenobamate or pharmaceutically acceptable salt thereof.

9. A process for the preparation of an amorphous solid dispersion of ozanimod or pharmaceutically acceptable salt thereof, comprising the steps of:
a) providing a solution of ozanimod or pharmaceutically acceptable salt thereof in a suitable solvent;
b) adding at least one pharmaceutically acceptable carrier to the solution obtained in step a); and
c) isolating to get amorphous solid dispersion of ozanimod or a pharmaceutically acceptable salt thereof.

10. A method for preparation of composition comprising ozanimod or pharmaceutically acceptable salt thereof, wherein said composition is prepared by combining either amorphous form of ozanimod or solid dispersion of ozanimod with atleast one pharmaceutically acceptable excipients.