DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 202141007085 filed on Feb 19, 2021.

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Ozanimod or its pharmaceutically acceptable salt.

BACKGROUND OF THE INVENTION
Ozanimod, 5-[3-[(1S)-2,3-dihydro-1-[(2-hydroxyethyl)amino]-1H-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-(1-methylethoxy)benzonitrile hydrochloride, having the structure shown in below is an immunomodulatory drug.

Ozanimod and its Hydrochloride salt is reported in US 8,796,318 and US 8,481,573.
Ozanimod is approved under the brand name of ZEPOSIA. ZEPOSIA is a sphingosine 1-phosphate receptor modulator indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

OBJECT AND SUMMARY OF THE INVENTION
The principle object of the present invention is to provide an improved process for the preparation of ozanimod or its pharmaceutically acceptable salt.

Another object of the present invention is to provide a process for the preparation of a (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V or its salt, which is a key intermediate in the preparation of Ozanimod.

In one object, the present invention provides a keto reductive amination process for the preparation of ((R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V comprising the steps of:
a) reacting a keto compound of formula II with a chiral reagent NH2-R to give imine compound of formula III ;

b) reducing the imine compound of formula III into a substituted amine compound of formula IV;

c) converting the substituted amine compound of formula IV into an amine compound of formula V; and

d) isolating an amine compound of formula V or its salt.

Wherein -R is selected from substituted alkyl, substituted aryl, -SOR1, R1 is alkyl.

In one more object, the present invention provides a process for the preparation of ((R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V or its salt comprising the steps of:
a) reacting a keto compound of formula II with (S)-t-butyl sulfinimide to give methoxy
imine compound of formula IIIa ;

b) reducing the methoxy imine compound of formula IIIa into methoxy amine compound of formula IVa;

c) converting the methoxy amine compound of formula IV into amine compound of formula V; and

d) isolating amine compound of formula V or its salt.

In one object, the present invention provides a process for the preparation of ((R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V comprising the steps of:
a) reacting a keto compound of formula II with (S)-4-methoxy phenyl ethylamine to give methoxy
imine compound of formula IIIb;

b) reducing the methoxy imine compound of formula IIIb into methoxy amine compound of formula IVb;

c) converting the methoxy amine compound of formula IVb into an amine compound of formula V; and

d) isolating amine compound of formula V or its salt.

Yet another object, the present invention provides a novel intermediate of formulas III, IIIa, IV and IVa.
DETAILED DECSRIPTION OF THE INVENTION
The principle object of the present invention is to provide an improved process for the preparation of ozanimod.

Another object of the present invention is to provide a process for the preparation of a (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V, which is a key intermediate in the preparation of Ozanimod.

In one embodiment, the compound of formula II may be prepared as per the processes known in the literature.
The schematic representation of the present invention is depicted in Scheme-1.

In one aspect, the present invention provides a keto reductive amination process for the preparation of ((R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V comprising the steps of:
a) reacting a keto compound of formula II with a chiral reagent to give imine compound of formula III ;

b) reducing the imine compound of formula III into a substituted amine compound of formula IV;

c) converting the substituted amine compound of formula IV into an amine compound of formula V; and

d) isolating an amine compound of formula V or its salt.

Wherein -R is selected from, substituted alkyl, substituted aryl, -SOR1. R1 is selected from alkyl.

According to the present invention, the compound of formula II is reacted with a chiral reagent NH2-R to give an imine compound of formula II. The compound of formula II is reduced to give a substituted amine compound of formula IV. The formula IV is converted into an amine of formula V and optionally isolated as its salts.

In a preferred embodiment, substituted aryl is (S)-4-methoxy phenyl ethylamine; and SOR1 is (S)-t-butyl sulfinimide.

In another aspect, the present invention provides a process for the preparation of ((R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V or its salt comprising the steps of:
a) reacting a keto compound of formula II with (S)-t-butyl sulfinimide to give methoxy
imine compound of formula IIIa.

b) reducing methoxy imine compound of formula IIIa into methoxy amine compound of formula IVa;

c) converting methoxy amine compound of formula IV into amine compound of formula V; and

d) isolating amine compound of formula V or its salt.

In one embodiment, keto compound of formula II is reacted with (S)-t-butyl sulfinimide to give methoxy imine compound of formula IIIa in presence of a suitable solvent. The suitable solvent is including, but not limited to alkanes such as toluene, xylene, heptane; nitriles such as acetonitrile and ethers such as tetrahydrofuran, 2- methyl tetrahydrofuran.

The resulting methoxy imine compound of formula IIIa is reduced to give methoxy amine compound of formula IVa. The reduction of formula III is carried out in presence of a suitable reducing agent and solvent. The suitable reducing agent includes, but not limited to sodium borohydride, lithium borohydride, potassium borohydride ; the suitable solvent includes, but not limited to ethers such as tetrahydrofuran, alcohols such as ethanol and alkanes such as toluene.

In another embodiment, the formula IVa of the above embodiment is converted into formula V or optionally its salt by treating with an acid in presence of a solvent. The suitable acid for the reaction includes, but not limited to trifluoro acetic acid, 1,4-Dioxane HCl, alcoholic HCl such as methanolic HCl, IPA-HCl; and the solvent includes, but not limited to methanol, isopropyl alcohol and 1,4-Dioxane.
In one embodiment, the formula V optionally isolated as suitable salt selected from hydrochloride, hydrobromide.
Yet another aspect, the present invention provides a process for the preparation of ((R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V or its salt comprising the steps of:
a) reacting a keto compound of formula II with (S)-4-methoxy phenyl ethylamine to give methoxy
imine compound of formula IIIb;

b) reducing the methoxy imine compound of formula IIIb into methoxy amine compound of formula IVb;

c) converting the methoxy amine compound of formula IVb into an amine compound of formula V; and

d) isolating amine compound of formula V or its salt.

In one embodiment, keto compound of formula II is reacted with (S)-4-methoxy phenyl ethylamine to give methoxy imine compound of formula IIIb in presence of a suitable solvent. The suitable solvent includes but not limited to alkanes such as toluene, xylene, heptane; and ethers such as tetrahydrofuran.

The resulting methoxy imine compound of formula IIIb is reduced to give methoxy amine compound of formula IVb. The reduction of formula IIIb is carried out in presence of a suitable reducing agent and solvent. The suitable reducing agent includes, but not limited to sodium borohydride, lithium borohydride, potassium borohydride; the suitable solvent includes, but not limited to alcohols such as methanol, ethanol and ethers such as tetrahydrofuran.

In another embodiment, the formula IVb of the above embodiment is converted into formula V or optionally its salt by treating with an acid in presence of a solvent. The suitable acid for the reaction includes, but not limited to trifluoro acetic acid, and in presence of suitable metal catalyst such as Palladium on Charcoal; the solvent includes, but not limited to ethylacetate, methanol and ethanol.
In one embodiment, the formula V optionally isolated as suitable salt selected from hydrochloride, hydrobromide.

Yet another object, the present invention provides a novel intermediate of formulas III, IIIa, IIIb, IV, IVa and IVb.

In one more embodiment, the resulting amine compound of formula V or its salt may further converted into ozanimod as per the processes known in the art.

In another embodiment, the resulting amine compound of formula V or its salt may further converted into ozanimod as per the process known in US 9388147 for example by treating Formula V with 2-halo ethanol.

In view of the above description and the examples below, one of the ordinary skills in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

Examples:
Example-1: Preparation of 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile:

To a suspension of 10 g of 4-cyano indanone in 100 ml of ethanol was added 1.2 g of sodium borohydride in lots at 0-5°C and stirring was continued for 30 minutes. Thereafter, the reaction mass temperature was raised to 25–30°C and stirred for 120 minutes. After completion of reaction, the reaction mass was concentrated and diluted with 100 ml of ethyl acetate. The obtained solution was washed with 100 ml of water and 40 ml of 10% NaCl solution sequentially. Thereafter, the organic layer was concentrated and crystallized with 30 ml of hexane to afford the 1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile as an off-white powder (9.9g, 97.8% yield).

Example-2: Preparation of 1- 5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile, a compound of formula IIa:

6.6g of Hydroxylamine hydrochloride and 1g of sodium carbonate were added sequentially to a suspension of 10 g of 4-cyanoindanol in 100 ml of ethanol at ambient temperature and contents were stirred at 80-85°C and continued stirring for 16 hours. After completion of the reaction, the reaction mixture was cooled and inorganic salts were removed by filtration and the obtained filtrate was concentrated to afford N-1-dihydroxy-2,3-dihydro-1H-indene-4-carboximidamide (Oxime Intermediate formula-VI) as a residue. Separately, 12.9 g of 3-cyano-4-isopropoxybenzoic acid, 12.7 g of 1-Hydroxy benzotriazole, 18.1 g of EDCA .HCl were stirred in 100 ml of dimethyl formamide at 25 – 30 °C for 2 hours. After completion of the reaction, solution of oxime intermediate in 20 ml of dimethyl formamide was added at 25 -30°C in ~60 minutes and stirred for 2-3 hours Thereafter, the temperature was raised to 85-90°C and stirring was continued for 16 hrs. After completion of the reaction, the reaction mass was cooled to 25– 30°C and diluted with 300 ml of water and stirred for 30-60 minutes. The product was filtered; dissolved in 150 ml of ethyl acetate and washed with 10%w/v potassium carbonate solution (2x 60 ml) and 10%w/v 30 ml of sodium chloride sequentially. The obtained organic layer was concentrated and recrystallized in a mixture of 20 ml ethyl acetate and 20 ml of hexanes to yield light brown solid of 1- 5-(3-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile, a compound of formula IIa 8.0g.

Example-3: Preparation of 2-Isopropoxy-5-(3-(1-oxo-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl) benzonitrile, a compound of formula II:

To a suspension of 10 g of formula-IIa, 10 g of silica gel, 10 g of hyflo in 120 ml of dichloromethane was added 4.0 g of pyridinium chlorochromate at 0-5°C over a period of 30-60 minutes. Thereafter, the reaction temperature was raised and stirred at 25-30 °C for 3 hours. After completion of the reaction, reaction mass was filtered on Hyflo bed and the filtrate was washed with citric acid solution (2X 80 ml). Obtained organic layer was concentrated and crystallized with 60 ml of ethyl acetate. Filtered to afford the 2-Isopropoxy-5-(3-(1-oxo-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl) benzonitrile of Formula II as off-white solid 8.8 g.

Example-4: Preparation of (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride of formula V:

To the solution of 10 g of 2-Isopropoxy-5-(3-(1-oxo-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl) benzonitrile in 100 ml of toluene, added 5.1 g of (S)-2-methyl propane-2- sulfinimide and 15.8 g of titanium isopropoxide and the resulting mixture was stirred for 16 hours at 110°C. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 100 ml of tetrahydrofuran and further cooled to -78 °C. Thereafter, 2.63 g of sodium borohydride was added in portion wise over 30-60 minutes maintaining same temperature. After stirring at -78°C for 2-3 hours, the temperature was raised and stirred at ambient temperature for 180 minutes. Thereafter, the reaction mass was cooled and was quenched with 50 ml of 10% sodium chloride solution and 50 ml of saturated sodium potassium tartrate solution sequentially and diluted with 100 ml of ethyl acetate. After stirring at room temperature for 5-6 hrs, organic layer was separated and washed successively with 70 ml of water and 70 ml of 20% sodium chloride solution. The organic layer was concentrated under vacuum to afford 7.8 g residue of formula-IVa. The obtained residue was dissolved in 35 ml of methanol and cooled to 0-5°C. Further added 22 ml of 1,4-dioxane HCl. The reaction mass temperature was raised to ambient temperature and stirred for 2 hours. After completion of the reaction, the reaction mass was concentrated and resulting residue was crystallized in 30 ml of acetonitrile to afford (S)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride of Formula-V as light brown color solid. 4.6 g Purity: 99.0% by HPLC.

Example-5: Preparation of Ozanimod Hydrochloride:

To 5 g of Formula V in 50 ml of dimethyl sulfoxide, 15.3 g triethylamine and 4.1 g of 2-chloro ethanol were added at ambient temperature. The reaction mixture was stirred at 80-85°C for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with 100 ml of water before filtration of resulting solids. After drying, the solids were taken in methanolic HCl and stirred at room temperature for 60 – 90 minutes. Reaction mass was concentrated and crystallized with acetonitrile to yield crude ozanimod hydrochloride which is further purified in methanol to afford pure Ozanimod Hydrochloride as a white solid 3.0 g. Purity: 99.65% by HPLC.

Example-6: Preparation of Ozanimod Hydrochloride:

To 5 g of Formula V in 50 ml of dimethyl sulfoxide, 15.3 g of triethylamine and 6.3 g of 2-bromo ethanol were added at ambient temperature. The reaction mixture was stirred at 80-85 °C for 20 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with 100 ml of water before filtration of resulting solids. After drying, the solids were taken in methanolic HCl and stirred at room temperature for 60 – 90 minutes. The reaction mass was concentrated and crystallized with acetonitrile to yield crude ozanimod hydrochloride which further purified in methanol to afford pure Ozanimod Hydrochloride as a white solid 3.0 g.

Example-7: Preparation of Ozanimod Hydrochloride:

To 1g of Formula V in 10 ml of dimethyl sulfoxide, 1.5 g of triethylamine and 1.5 g of 2-(bromo ethoxy) tert-butyl dimethyl silane were added at ambient temperature. The reaction mixture was stirred at 100-102 °C for 6 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and quenched with 100 ml of water before filtration of resulting solids. After drying, the solids were taken in 3 ml of methanolic HCl and 3 ml of methanol and stirred at room temperature for 60 – 90 minutes. The reaction mass was concentrated and crystallized with acetonitrile to yield crude ozanimod hydrochloride which is further purified in methanol to afford pure Ozanimod Hydrochloride as a white solid 200 mg.

Example-8: Preparation of (S)-2-Isopropoxy-5-(3-(1-((1-(4-methoxyphenyl)ethyl)imino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, a compound of formula IIIb:

To the solution of 20 g of 2-isopropoxy-5-(3-(1-oxo-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl) benzonitrile in 200 ml of toluene was added 21.1 g of (S)-1-(4-methoxyphenyl) ethan-1-amine and 10.6 g p-toluene sulfonic acid monohydrate and the resulting mixture was stirred for 18 hours at 110 °C. After completion of the reaction, the reaction mixture was cooled to room temperature, diluted with 100 ml of ethyl acetate and 100 ml of water and separated the layers. The organic layer was concentrated under vacuum to afford residue. The obtained residue was crystallized from 40 ml of ethyl acetate and 80 ml of hexanes to afford (S)-2-isopropoxy-5-(3-(1-((1-(4-methoxyphenyl)ethyl)imino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile of Formula-IIIb as a brown color solid 23 g.

Example-9: Preparation of 2-Isopropoxy-5-(3-((S)-1-(((S)-1-(4-methoxyphenyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile, a compound of formula IVb.

To the solution of 30 g of 2-Isopropoxy-5-(3-((S)-1-(((S)-1-(4-methoxyphenyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile in 300 ml of THF and 300 ml of MeOH was added 6.9 g of sodium borohydride slowly at -30 °C. Slowly raised the reaction mixture temperature to 25 °C and continued stirring for 1 h. After completion of the reaction, it was cooled to 5-10 °C and quenched with 300 ml of water and diluted with 300 ml of methylene chloride. Stirred the contents for 30 min and separated the layers and washed the organic layer again with water (300 ml) and the separated organic layer was concentrated under vacuum to afford residue. The obtained residue was crystallized from 300 ml of methanol to afford 2-Isopropoxy-5-(3-((S)-1-(((S)-1-(4-methoxyphenyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile of Formula-IVb as a light brown color solid 24 g.

Example-10: Preparation of (S)-5-(3-(1-Amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile, a compound of formula V.

10 g of Formula-IVb was added to 150 ml of trifluoroacetic acid at ambient temperature and then raised to 70-75 °C. The reaction mixture was refluxed for 20-24 h, after completion of the reaction, the solvent was distilled under vacuum and cooled the reaction mixture to 25-30 °C. The obtained residue was diluted with 100 ml of water and washed with 100 ml of toluene, the aqueous layer was basified with sodium hydroxide solution and the product was extracted with ethyl acetate. The organic layer was washed with brine and concentrated under vacuum to get crude amine. The crude amine diluted with 20 ml of ethyl acetate and added 20 ml of IPA-HCl and stirred the contents for 2 hrs. The obtained solids were filtered and washed with ethyl acetate and dried to obtain (S)-5-(3-(1-Amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzo nitrile Formula-V as a light brown solid 6.0 g.

,CLAIMS:We Claim:
1. A keto reductive amination process for the preparation of ((R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V comprising the steps of:
a) reacting a keto compound of formula II with a chiral reagent to give imine compound of formula III;

b) reducing the imine compound of formula III into a substituted amine compound of formula IV;

c) converting the substituted amine compound of formula IV into an amine compound of formula V; and

d) isolating an amine compound of formula V or its salt.
Wherein -R is selected from, substituted alkyl, substituted aryl, -SOR1. R1 is selected from alkyl.

2. The process as claimed in claim 1, wherein the step a) is carried out in presence of a solvent selected from alkanes.

3. The process as claimed in claim 1, wherein the reducing agent for the reduction of step b) is selected from sodium borohydride, lithium borohydride and potassium borohydride.

4. The process as claimed in claim 1, wherein the conversion of step c) is carried out by treating Formula IV with an alcoholic HCl and trifluoroacetic acid.

5. A process for the preparation of ((R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V or its salt comprising the steps of:
a) reacting a keto compound of formula II with (S)-t-butyl sulfinimide to give methoxy
imine compound of formula IIIa ;

b) reducing methoxy imine compound of formula IIIa into methoxy amine compound of formula IVa;

c) converting methoxy amine compound of formula IV into amine compound of formula V; and

d) isolating amine compound of formula V or its salt.

6. A process for the preparation of ((R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile of formula V or its salt comprising the steps of:
a) reacting a keto compound of formula II with (S)-4-methoxy phenyl ethylamine to give methoxy imine compound of formula IIIb ;

b) reducing the methoxy imine compound of formula IIIb into methoxy amine compound of formula IVb;

c) converting the methoxy amine compound of formula IVb into an amine compound of formula V; and

d) isolating amine compound of formula V or its salt.

7. The process as claimed in proceeding claims, may further converted into Ozanimod or its pharmaceutically acceptable salts by treating Formula V or its salt with 2-halo ethanol.

8. The compounds of Formula III, IIIa, IIIb, IV, IVa and IVb.