AMINO COMPOUND

FIELD OF THE INVENTION

The present invention specifically relates to improved process for the preparation of optically chiral amino compound.

The present invention particularly relates to the improved process for the preparation of (S)-l-amino-2,3-dihydro-lH-indene-4-carbonitrile, an important intermediate for the synthesis of ozanimod.

The present invention more particularly relates to preparation of (S)-l-amino-

2,3-dihydro-lH-indene-4-carbonitrile using 4-cyano-l-indanone and a-methylbenzyl- amine derivatives as starting materials.

The present invention specifically relates to preparation of (S)-l-amino-2,3- dihydro-lH-indene-4-carbonitrile comprising diastereo selective chiral amine synthesis by protection with chiral auxiliary a-methylbenzylamine derivatives followed by reduction and debenzylation.

BACKGROUND OF THE INVENTION

Ozanimod (RPC-1063) is an investigational immunomodulatory drug in development for the potential treatment of relapsing multiple sclerosis (RMS), ulcerative colitis (UC) and Crohn's Disease. It acts as a sphingosine-l- phosphate (SlPl) receptor agonist that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. Ozanimod is chemically represented as 5- [3- [(IS)- 1 -(2- hydroxyethylamino)-2,3-dihydro-lH-inden-4-yl]-l,2,4-oxadiazo l-5-yl]-2-propan-2- yloxybenzonitrile. The chemical formula is C23H ₂₄ N ₄ O3, the molecular weight is 404.47 g/mol and the structural formula is: Formula 1

US 4,000,197 A discloses a process for the preparation of [R,R]-(+) or [S,S]-(-) Substituted N-(a-phenethyl)phenylisopropylamine hydrochloride, which is shown in the scheme given below:

Ar-CH ₂ CHCH ₃ +

[R,R]-(+) or [S,S]-

H?

Ar-CH ₂ CHNH ₂ -HCI CH ₃

R-(-) or S-(+)

EP 0 380 144 Bl discloses a process for the preparation of 2R,lR-2-methoxy- 5-[2-(l-methylbenzylamino)propyl]benzenesulfonamide hydrochloride, which is shown as given below:

.HCI

This patent also discloses preparation of (R)-(-)-5-(2-aminopropyl)-2-methoxy benzenesulfonamide hydrochloride, which is shown as given below:

US 5,932,749 A discloses the preparation of (R)-l-(benzo[d][l,3]dioxol-6- yl)butan-l -amine, which is shown as given below:

(R)-1 -(benzo[c ][1 ,3]dioxol-6-yl)butan-1 -amine

WO 2003/022785 A2 discloses asymmetric synthesis of (R)-(-)-8-Amino- 5,6,7,8-tetrahydroquinone, which is shown as given below:

NaBH ₄ ,EtOH, 0°C

93%

98% ee

WO 2006/030017 Al discloses synthesis of (2R)-4-phenyl-N-(R)-l -phenyl ethyl)butan-2-amine, which is shown as given below:

This application also discloses synthesis of (2R)-N-(R)-l-phenylethyl)octan-2-amine, which is shown as given below:

2-octanone Ra-Ni/H ₂ , 120 psi R,R S,R

room temperature (major)

This application also discloses the synthesis of (lR)-2,2-dimethyl-N-(R)-l-p ethyl)cyclopentanamine, which is shown as given below:

(major) Nature Protocols, 2(11), 2759-2765, 2007 discloses the preparation of (R,R)- bis(a-phenyleth l)amine, which is shown as given below:

ou ene _{( E} ,R)-i

1 . H ₂ , Pd/C 10%

65psi, EtOAc

2. HCI

3. NaOH

(R,R)-2

US 8,309,724 B2 discloses a process for preparing Sitagliptin, which is shown as given below:

WO 2013/126360 A2 discloses process for preparing aminosulfones, which is shown as given below:

In US 9,382,217 and WO 2016/164180 described the process for the preparation of Ozanimod from 4-bromo-2,3-dihydro- lH-inden-l-one (2), which is shown as iven below:

In view of the importance acquired by Ozanimod intermediate, there is a great need for developing an alternate process for synthesizing Ozanimod intermediate. All the prior art references shows the reactions of aliphatic ketones, cyclic ketones with a-methylbenzylamine derivatives. None of the prior art references discloses the reactions between 4-cyano-l-indanone and a-methylbenzylamine derivatives.

It is therefore an object of the present invention to provide an improved process for the preparation of optically active chiral amine (S)-l-amino-2,3-dihydro-lH- indene-4-carbonitrile, an Ozanimod intermediate using 4-cyano-l-indanone and a- methylbenzylamine derivatives as starting materials.

OBJECTIVE OF INVENTION

The main objective of the present invention is to provide an improved process for the preparation of Ozanimod intermediate.

Another objective of the present invention is to provide improved process for the preparation of (S)-l-amino-2,3-dihydro-lH-indene-4-carbonitrile, an important intermediate for the preparation of Ozanimod.

Still another objective of the present invention is to provide synthesis of (S)-l- amino-2,3-dihydro-lH-indene-4-carbonitrile using 4-cyano-l-indanone and a- methylbenzylamine derivatives as starting materials.

Yet another objective of the present invention is to provide preparation of (S)- l-amino-2,3-dihydro-lH-indene-4-carbonitrile comprising diastereo selective chiral amine preparation by protection with chiral auxiliary a-methyl benzylamine derivatives followed by reduction and debenzylation.

SUMMARY OF INVENTION

Accordingly, the present invention provides a novel process for preparing Ozanimod intermediate of Formula 6

Formula 6

which comprises reacting compound of Formula 3 Formula 3

with compound of Formula 13 Formula 13

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups.

In a preferred aspect, the present invention provides an improved process for preparing compound of Formula 14

Formula 14

which comprises reacting compound of Formula 3

Formula 3

with compound of Formula 13 Formula 13

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, in the presence of suitable catalyst or water scavenging agent or without catalyst in organic solvents.

In a preferred aspect, the present invention provides an improved process for preparing compound of Formula 15

Formula 15 which comprises reduction of compound of Formula 14

Formula 14

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, using a reducing agent in suitable solvents followed by treatment with organic and inorganic acid.

In a preferred aspect, the present invention provides an improved process for preparing compound of Formula 16

rmula 16

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises treatment of compound of Formula 15

Formula 15

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, with suitable base.

In another preferred aspect, the present invention provides an improved process for preparing compound of Formula 6

Formula 6

which comprises debenzylation of Formula 16 rmula 16

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, in the presence of suitable catalyst in suitable solvents followed by treatment with organic and inorganic acid.

In another preferred aspect, the present invention provides an improved process for the preparation of (S)-l-amino-2,3-dihydro-lH-indene-4-carbonitrile hydrochloride of Formula 6

₂ Formula 6

a) reacting compound of 4-cyano-l-indanone of Formula 3 with (S)-a- methylbenzylamine of Formula 13 using suitable catalyst or water scavenging agent or without catalyst in an organic solvent to form a new compound of Formula 14,

b) reducing compound of Formula 14 using suitable reagent in suitable solvents followed by treatment with organic and inorganic acid to obtain compound of Formula 15,

Formula 15

c) treating compound of Formula 15 with suitable base to obtain compound of Formula 16, rmula 16

d) debenzylating of compound of Formula 16 using suitable catalyst in suitable solvents followed by treatment with organic and inorganic acid to obtain (S)-l- amino-2,3-dihydro-lH-indene-4-carbonitrile hydrochloride of Formula 6,

Formula 6

e) converting compound of Formula 6 to Ozanimod.

In another preferred aspect, the present invention provides novel intermediates of Formulae 14, 15 and 16.

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention provides an improved process for the preparation of optically active chiral amine (S)-l-amino-2,3-dihydro-lH-indene-4- carbonitrile, a key intermediate for the drug Ozanimod which is an agonist of the sphingosine- 1 -phosphate receptor.

In one embodiment, Formula 3 is reacted with Formula 13in the presence of suitable catalyst or water scavenging agent or without catalyst in an organic solvent to form a new compound of Formula 14.

In one embodiment, Formula 3 is preferably 4-cyano-l-indanone.

In one embodiment, R in (S)-a-methylbenzylamine derivatives of Formula 13 represents hydrogen, halogen, nitro, alkyl, alkoxy groups.

The term halogen as used herein includes fluorine, chlorine, bromine and iodine.

The term alkyl as used herein includes but not limited to C _\ -Ce alkyl such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and allyl. The term alkoxy as used herein includes but not limited to methoxy, ethoxy, propoxy, butoxy and acetoxy.

In one embodiment, (S)-a-methylbenzylamine derivatives includes but not limited to (S)-a-methylbenzylamine, (S)-2-methoxy-a-methylbenzylamine, (S)-4- methoxy-a-methylbenzylamine, (S)-2-chloro-a-methyl-benzylamine, (S)-2-bromo-a- methylbenzylamine, (S)-4-chloro-a-methylbenzylamine, (S)-4-bromo-a- methyl benzylamine, (S)-2-nitro-a-methylbenzylamine, (S)-4-nitro-a-methylbenzyl amine, (S)-a,2-dimethylbenzylamine, (S)-a,4-dimethylbenzylamine, (S)-2-nitro-a-methyl- benzylamine, (S)-4-nitro-a-methylbenzylamine and more preferably (S)-4-methoxy- a-methyl-benzylamine.

In one embodiment, catalyst used in reacting Formula 3 with Formula 13 includes but not limited to p-toluenesulfonic acid, acetic acid, hydrochloric acid, sulfuric acid.

In one embodiment, water scavenger used in reacting Formula 3 with Formula 13 includes but not limited to titanium tetraethoxide, copper sulphate and triisopropyl borate and more preferably without any catalyst or scavenger.

In another embodiment, solvents used in reacting Formula 3 with Formula 13 includes but not limited to toluene, chloroform, dichloromethane, ethylene dichloride, carbon tetrachloride, methyl tert-butyl ether, heptane, hexane, o-xylene, cyclohexane, methanol, THF, and the like or mixtures thereof and more preferably the solvent is heptane.

In another embodiment, reaction conditions used for reacting Formula 3 with Formula 13 is the reaction temperature may range from 40 to 145°C and preferable temperature in the range of 100-105°C.

In yet another preferred embodiment, reduction of compound of Formula 14 is carried out using suitable reagent in suitable solvents followed by treatment with organic and inorganic acid to obtain compound of Formula 15.

In one embodiment, reagent used in reducing Formula 14 into Formula 15 includes but not limited to palladium on carbon, Raney nickel, platinum on carbon, palladium hydroxide on carbon, ruthenium on carbon, sodium borohydride, sodium cyanoborohydride, sodium triacetoxy borohydride, more preferable palladium on carbon under hydrogen gas.

In one embodiment, solvent used in reducing Formula 14 into Formula 15 includes but not limited to methanol, ethanol, isopropyl alcohol, ethyl acetate, isopropyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethoxyethane and the like or mixture thereof, more preferably ethyl acetate.

In one embodiment, hydrogen pressure used is about 1 kg/cm ² to 15 kg/cm ² , preferably 5 kg/cm ² to 6 kg/cm ² .

In another embodiment, reaction is carried out at a temperature in the range from about 25 to 100°C more preferably at 40-45°C.

In another embodiment, acid used for the purification is selected from organic and inorganic acids preferably p- toluenesulfonic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid and the like or mixture thereof, preferably p-toluenesulfonic acid.

Yet another embodiment, the compound of Formula 15 is treated with suitable base to obtain compound of Formula 16.

In one embodiment, base is selected from but not limited to inorganic or organic base such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, diisopropylethylamine and the like, more preferably sodium hydroxide.

In yet another preferred embodiment, debenzylation of compound of Formula 16 is carried out using suitable catalyst in suitable solvents followed by treatment with organic and inorganic acid to obtain (S)-l-amino-2,3-dihydro-lH-indene-4- carbonitrile of Formula 6.

In one embodiment, catalyst is selected from palladium on carbon and palladium hydroxide on carbon.

In one embodiment, solvent used is selected from methanol, ethanol, isopropyl alcohol, ethyl acetate, acetic acid, trifluoroacetic acid and the like or mixture thereof, more preferably trifluoroacetic acid without any catalyst. In one embodiment, reaction is carried out at a temperature in the range from about 25 to 100°C more preferably at 70-75°C.

In one embodiment, acid used for the making salt may be organic and inorganic acids selected from para toluenesulfonic acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, hydrochloric acid, hydrobromic acid, sulfuric acid trichloroacetic acid ,trifluoroacric acid and the like or mixture thereof preferably trifluoroacetic acid.

In another preferred embodiment, the compounds of Formula 3, 13, 14, 15, 16 or their salts used in the present invention may be isolated or not. Any of the above reactions may be carried out in- situ reactions to obtain Formula 6 or its pharmaceutically acceptable salts.

In another embodiment, the present invention provides an improved process for the preparation of Ozanimod compound of Formula 1 using chiral amine of Formula 6 prepared by the process of the present invention.

The present invention provides an improved process for preparing (S)-l-amino-

2,3-dihydro-lH-indene-4-carbonitrile of Formula 6, an important intermediate for the synthesis of Ozanimod.

₂ Formula 6

which comprises reacting compound of Formula 3

Formula 3

with compound of Formula 13 Formula 13

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups. In a preferred embodiment, the present invention provides an improved process for preparing compound of Formula 14

Formula 14

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises reactingcompound of Formula 3

Formula 3

with compound of Formula 13

i Formula 13

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, in the presence of suitable catalyst or water scavenging agent or without catalyst in organic solvents.

In yet another preferred embodiment, the present invention provides an improved process for preparing compound of Formula 15

Formula 15

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises reduction of compound of Formula 14

Formula 14 wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, using a suitable reagent in suitable solvents followed by treatment with organic and inorganic acid.

In another preferred embodiment, the present invention provides an improved process for preparing compound of Formula 16

ormula 16

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, which comprises treatment of compound of Formula 15.

Formula 15

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, with suitable base.

In another preferred embodiment, the present invention provides an improved process for preparing compound of Formula 6

₂ Formula 6

which comprises debenzylation of Formula 16

ormula 16

wherein R is selected from hydrogen, halogen, nitro, alkyl, alkoxy groups, in the presence of suitable catalyst in suitable solvents followed by treatment with organic and inorganic acid. In yet another preferred embodiment, the present invention provides an improved process for the preparation of (S)-l-amino-2,3-dihydro-lH-indene-4- carbonitrile of Formula 6

a) reacting compound of 4-cyano-l-indanone of Formula 3 with (S)-a- methyl benzylamine of Formula 13 using of suitable catalyst or water scavenging agent or without catalyst in an organic solvent to form a new compound of Formula 14,

Formula 13 Formula 14

b) reducing compound of Formula 14 using suitable reagent in suitable solvents followed by treatment with organic and inorganic acid to obtain compound of Formula 15,

Formula 15

c) treating compound of Formula 15 with suitable base to obtain compound of Formula 16,

ormula 16

d) debenzylating of compound of Formula 16 using suitable acid catalyst in suitable solvents followed by treatment with organic and inorganic acid to obtain (S)-l- amino-2,3-dihydro-lH-indene-4-carbonitrile of Formula 6, ₂ Formula 6

e) converting compound of Formula 6 to Ozanimod.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. EXAMPLES

Example 1: Preparation of l-{[(lS)-l-(4-methoxyphenyl)ethyl]imino}-2,3 dihydro-lH-indene-4-carbonitrile, a compound of Formula 14:

To the stirred mixture of 50.0 gm of 4-cyano-l-indanone (Formula 3) (0.318 moles) and 500 ml of heptane, 60 gm of (S)-(-)-l-(4-methoxyphenyl)ethylamine (Formulal3) (0.398 moles, 1.25eq.) was added at ambient temperature. The resulting mixture was heated to 100-105°C and water was removed azeotropically. After 15.0 hrs, the reaction mass was cooled to 25-30°C and stirred for 1.0 hr. The product was filtered, washed with heptane and dried to obtain a light brown solid of compound of Formulal4(84.0 g, 90.93% yield) with HPLC purity 94.35% & SOR -72° (c=0.1 in CHC1 ₃ at 20°C).

MR: 130.4-132.1°C; IR (KBr, cm ^"1 ): 2226, 1661, 1611, 1513, 1245, 1030; 1H- NMR(CDC1 ₃ ): δ 8.11-8.09 (d, 1H, J=7.74Hz), 7.66-7.64 (d, 1H, J=7.47Hz),7.41-7.89 (m, 3H), 6.89-6.87 (d, 2H, J=8.50Hz), 4.66-4.61 (q, 1H, J=6.46, 12.96 Hz), 3.79 (s, 3H), 3.26-3.21 (m, 2H), 2.90-2.88 (m, 1H), 2.78-2.73 (m, 1H), 1.56-1.55 (d, 3H, J=6.49Hz); ¹³ C-NMR(CDCl ₃ ): 169.99, 158.48, 152.56, 141.66, 137.59, 134.28, 127.72, 127.66 (2C),127.15,117.12, 113.87(2C), 109.93, 61.56, 55.32, 27.85, 27.67, 24.77;MS (m/z): 291.1 [M+l] ⁺ . Example 2: Preparation of (lS)-l-{[(lS)-l-(4-methoxyphenyl)ethyl]amino}-2,3- dihydro-lH-indene-4-carbonitrile p-toluenesulfonic acid salt, a compound of Formula 15:

To the stirred mixture 80.0 gm of Imine (0.2756 moles) (Formula 14)and 1040 ml of ethyl acetate in autoclave vessel, 8.0 gm of 10% Pd/C (-50% wet)was added at ambient temperature. The autoclave was evacuated with nitrogen gas and 5.0 kg of hydrogen Gas was applied. The reaction mass was heated to 40-45°C and maintained for 8-10hrs. After completion, the reaction mass was cooled to 25-30°C and filtered to remove the Pd/C through celite. 46.0 gm of p-toluenesulfonic acid monohydrate was added to the filtrate at 25-30°C and stirred for 2.0hrs. The product was filtered, washed with ethyl acetate and dried to obtain a light brown solid of compound of Formula 15 (99.0 g, 77.34% yield) with HPLC purity 99.66%, Chiral HPLC Purity (SS) 99.67% & (RS) 0.13% & SOR -71° (c=0.1 in MeOH at 25°C).

MR: 190.4-192.1°C; IR (KBr, cm-1): 3077, 2227, 1611, 1514, 1249, 1227, 1171; 1H-NMR (DMSO-d6): δ 9.20-9.08 (brd, 2H), 7.95-7.93 (d, 1H, J=7.76Hz),7.85- 7.83 (d,lH, J=7.65Hz), 7.56-7.53 (d, 1H, J=8.56Hz), 7.52-7.47 (m, 3H),7.14-7.12 (d, 2H, J=7.87Hz), 7.03-7.01 (d, 2H, J=8.56Hz), 4.81(br, 1H), 4.57-4.55 (m, 1H), 3.78 (s, 3H), 3.26-3.18 (m, 1Η),3.05-2.97 (m, 1H), 2.46-2.36 (m, 1H), 2.30 (s, 3H), 2.24-2.18 (m,lH), 1.62-1.61 (d, 3H, J=6.65Hz); ¹³ C-NMR(CDC13): 160.16, 149.25, 145.90, 139.75, 138.27, 133.42, 131.33, 129.80 (2C), 129.48, 128.59 (2C), 128.37, 125.94 (2C), 117.64, 114.78 (2C), 108.78, 60.23, 56.02, 55.73, 30.04, 28.73, 21.25, 19.57; MS (m/z): 293.1 [M+l] ⁺ .

Example 3: Preparation of (lS)-l-{[(lS)-l-(4-methoxyphenyl)ethyl]amino}-2,3- dihydro-lH-indene-4-carbo-nitrile, a compound of Formula 16:

To the stirred mixture 90.0 gm of amine PTSA salt (0.1937 moles) (Formula 15) and 450 ml of water was added 50% sodium hydroxide solution to get pH~l 1. The product was extracted with ethyl acetate. The organic layers was combined, washed with brine solution and concentrated to obtain a light brown liquid on standing become solid of compound of Formula 16 (55.8 gm, 98.51% yield) with HPLC Purity 98.60%, Chiral HPLC Purity (SS)100.0% & SOR -123° (c=0.1 in MeOH at 25°C).

IR (KBr, cm ^"1 ): 2962, 2227, 1610, 1511, 1465, 1451, 1244; 1H NMR(CDC1 ₃ ): δ 7.58-7.56 (d, 1H, J=7.52Hz), 7.47-7.45 (d, 1H, J=7.64Hz),7.32-7.30 (d,lH, J=8.40Hz), 7.28-7.25 (m, 1H), 6.90-6.88 (d, 2H, J=8.52Hz), 4.19-4.16(t, 1H, J=6.70Hz), 4.01-3.97 (q, 1H, J=6.48, 12.92Hz), 3.80 (s, 3H), 3.16-3.09 (m, 1H), 2.92- 2.83 (m, 1H), 2.35-2.26 (m, 1H), 1.79-1.70 (m, 1H), 1.37-1.35 (d, 3H,J=6.48Hz); ¹³ C- NMR(CDC1 ₃ ): 158.71, 147.84, 147.70, 138.02, 130.77, 128.74, 127.72 (2C), 127.02, 117.87,113.94 (2C), 108.96, 60.95, 55.92, 55.31, 34.65, 29.94, 24.49; MS (m/z): 293.1 [M+l] ⁺ .

Example 4:Preparation of (S)-l-amino-2,3-dihydro-lH-indene-4-carbonitrile hydrochloride, a compound of Formula 6:

48.0 gm of amine (Formula 16) was added to 288.0 of trifluoroacetic acid at ambient temperature and heated the reaction mass to 70-75°C. The reaction mass was refluxed for 16.0 hr. After completion, TFA was distilled out under vacuum at 40- 50°C and cooled to 25-30°C. The residue was diluted with water and washed with 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 at 40-45°C to get crude amine. The amine was diluted with 240ml of ethyl acetate and stirred. 48 ml of IPA-HCl (-13%) was added and stirred for l.Ohr. The product was filtered, washed with ethyl acetate and dried to obtain off-white solid of compound of Formula 6 (26.0 gm, 81.35% yield) with HPLC Purity 98.27%, Chiral HPLC Purity (S) 100.0% & SOR -45° (c=l in Methanol at 25°C).

MR: Not melted up to 270°C; IR (KBr, cm-1): 2229, 1497, 1370, 1127; 1H- NMR (DMSO-d ₆ ): δ 8.91 (br, 3H), 8.07-8.05 (d, 1H, J=7.68Hz), 7.81-7.79 (d, 1H, J=7.63Hz), 7.51-7.47 (t, 1H, J=7.71Hz), 4.80-4.77 (t, 1H, J=6.27Hz), 3.24-3.20 (m, 1H), 3.07-3.01 (m, 1H), 2.56-2.53 (m, 1H), 2.16-2.12(m, 1H); ¹³ C-NMR (DMSO- d ₆ ): 148.59, 141.64, 132.96, 130.86, 128.36, 117.77, 108.53, 54.87, 39.96, 30.14; MS (m/z): 159.0 [M+l] ⁺ , 142.0 [M-NH ₂ ].

Example 5: Preparation of (S)-tert-butyl 4-cyano-2,3-dihydro-lH-inden-l- ylcarbamate, a compound of Formula 7:

To a stirred solution of 30.0 gm of amine.HCl (Formula 6) (0.154 moles) and 300.0 of dichloromethane, 31.2 gm of triethyl amine (0.308 moles, 2.0 eq.)was added at 5-15°C. 43.47 gm of Boc anhydride (85%) (0.169 moles, 1.1 eq.) was added and warmed to ambient temperature. The reaction mass was stirred for 2.0hrs. After completion, the reaction mass was washed with water and brine solution. The organic layer was concentrated, cooled and stirred with hexane. The product was filtered, washed with hexane and dried to obtain off-white solid of Formula 7(36.9 gm, 92.71% yield) with HPLC Purity 96.93% & SOR -122° (c=l in CHC1 ₃ at 25°C).

MR: 129.7-132.1°C; IR (KBr, cm ^"1 ): 3364, 2979, 2225, 1677, 1514, 1169; 1H- NMR(CDC1 ₃ ): δ 7.56-7.50 (m, 2H), 7.33-7.29 (t, 1H, J=7.64Hz), 5.25-5.23 (m, 1H), 4.76-4.74 (d, 1H, J=6.24Hz) , 3.20-3.14 (m, 1H), 2.99 (m, 1H), 2.68-2.64 (m, 1H), 1.89-1.83 (m, 1H), 1.49 (s, 9H); ¹³ C-NMR(CDC1 ₃ ): 155.55, 147.03, 145.44, 131.34, 128.72, 127.56, 117.50, 109.01, 79.84, 55.79, 33.51, 29.62, 28.37(3C); MS (m/z): 259.0 [M+l] ⁺ , 203.1 [M-C(CH ₃ ) ₃ ] ⁺ .

Example 6: Preparation of (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl-(4- cyano-2,3-dihydro-lH-inden-l-ylcarbamate, a compound of Formula 9:

To a stirred solution of 20.0 gm of Formula 7 (0.0774 moles) and 200.0 of DMF under nitrogen atmosphere at 0-10°C,11.6 gm of sodium hydride (60%) (0.232 moles, 3.0eq.)was added at below 10°C. The reaction mixture was stirred for 2.0 hrs at 0-10°C. 37.0 gm of (2-bromoethoxy)-tert-butyldimethylsilane (Formula 8) (0.155 moles, 2.0eq.) was added and stirred for 8.0 hrs at 0-10°C. After completion, the reaction was quenched by the addition of saturated NaHCO ₃ and the product was extracted with ethyl acetate. The organic layer was concentrated and purify through column chromatography by using ethyl acetate/hexane to obtain a light brown liquid of Formula 9 (24.2 gm, 75.01% yield) with HPLC Purity 99.95% & SOR -80.0° (c=0.1 in CHC1 ₃ at 25°C).

IR (Neat, cm-1): 2955, 2930, 2229, 1695, 1454, 1404, 1253, 1155, 1102, 837, 778; 1H-NMR(CDC1 ₃ ): δ 7.50-7.48 (d, 1H, J=7.53Hz), 7.41-7.34 (m, 1H), 7.29-7.25 (m, 1H), 5.72 (brs, 0.5H), 5.23 (brs, 0.5H) 3.81-3.44 (m, 3H), 3.24-3.18 (m, 2H), 3.01- 2.92 (m, 1.5H), 2.48 (brs, 1H), 2.35-2.19 (m, 1H), 1.50 (brs, 4.5Hz), 1.23 (brs, 4.5Hz), 0.85 (s, 9H), 0.03-0.01 (d, 6H); ¹³ C-NMR(CDC1 ₃ ): 155.86, 155.06, 147.23, 146.57, 145.51, 144.33, 131.18, 130.78, 128.40, 128.15, 127.24, 127.08, 117.59, 109.25, 108.97, 80.17, 79.90, 63.99, 61.91, 61.48, 60.36, 49.79, 46.82, 30.31, 29.73, 28.46, 28.15, 25.90, 18.28, 14.19, -5.36; MS (m/z): 417.3 [M+l] ⁺ , 361.1 [M-C(CH ₃ ) ₃ ] ⁺ , 317.2 [M-Boc] ⁺ .

Example 7: Preparation of (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl-(4- (N-hydroxy carbamimidoyl)-2,3-dihydro-lH-inden-l-ylcarbamate, a compound of Formula 10:

To a solution of 20.0 gm of Formula 9 (0.048 moles) and 200.0 of ethanol at ambient temperature, 10.0 gm of hydroxylamine hydrochloride (0.144 moles, 3.0eq.) and 14.6 gm of triethylamine (0.144 moles, 3.0eq.)was added. The reaction mass was heated to 80-85°C and stirred for 2.0hrs. After completion, the reaction mass was concentrated and diluted with dichloromethane. The organic layer was washed with water and brine. The organic layer was concentrated to obtain a brown liquid of compound of Formula 10 (21.5 gm, 99.63% yield) with SOR -45.0° (c=l in CHC1 ₃ at 25°C).

IR (KBr, cm ^"1 ): 2930, 1679, 758; 1H-NMR(CDC1 ₃ ): δ 7.40-7.38 (d, 1H, J=7.48Hz), 7.31-7.16 (m, 2H), 5.76 (brs, 0.5H), 5.35(brs, 0.5H), 4.88 (s, 2H), 3.80- 3.38 (m, 2H), 3.27-3.17 (m, 2H), 2.98-2.90 (m, 2H), 2.39-2.04 (m, 2H), 1.53 (brs, 4.5Hz), 1.33 (brs, 4.5H), 0.91 (brs,9H), 0.04-0.01 (brd, 6H); ¹³ C-NMR(CDC1 ₃ ): 156.26, 155.65, 144.69, 143.72, 141.81, 141.21, 129.49, 126.88, 126.52, 126.17, 125.18, 124.88, 79.96, 79.73, 63.27, 61.92, 61.62, 61.13, 48.36, 46.06, 36.69, 30.79, 30.29, 28.57, 28.31, 25.98, 24.72, 18.34, 1.05, -5.31; MS (m/z): 450.2 [M+l] ⁺ , 350.2 [M-Boc]. Example 8: Preparation (S)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl-(4-(5- (3-cyano-4-isopropoxy phenyl)-l,2,4-oxadiazol-3-yl)-2,3-dihydro-lH-inden-l- yl)carbamate (12a) and (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-l,2,4- oxadiazol-3-yl)-2,3-dihydro-lH-ind-en-l-yl)carbamate, a compound of Formula 12b:

To a solution of 9.6 gm of 3-cyano-4-(propan-2-yloxy)benzoic acid (Formula 11) (0.0467 moles) in 210.0ml of DMF,9.08 gm of Ι, Ι'-carbonyldiimidazole (0.056 moles, 1.2eq.) was added at ambient temperature. After 2.0hrs stirring, 21.0 gm of compound of Formula 10(0.0467 moles, l.Oeq.) was added and the reaction was stirred for 4.0 hrs. TLC showed the complete conversion of compound of Formula 11 to the intermediate. The reaction mass was heated gradually to 90-95°C and stirred for lO.Ohrs. After complete cyclization, the reaction mass was concentrated and diluted with dichloromethane. The organic layer was washed with water and brine. The layer was concentrated to obtain brown liquid of Formulas 12a&12b (27.1 gm).

Example 9: Preparation of Ozanimod or (S)-5-(3-(2-(2-hydroxyethylamino)-2,3- dihydro-lH-inden-4-yl)-l,2,4-oxadiazol-5-yl)-2-isopropxybenz onitrile, a compound of Formula 1:

To a solution of 27.0 gm of compound of Formulas 12a & 12b and 130 ml of dioxane, 130 ml of dioxane-HCl (4N) was added at ambient temperature and stirred for 3.0 hrs. After completion, the product was diluted with 130 ml of ether and stirred. The product was filtered, washed with ether and dried to obtain 11.4 gm of crude hydrochloride salt. The crude hydrochloride salt was recrystallized from methanol to obtain hydrochloride salt of Formula 1(11.2 gm, 52.91% (Overall from 9) with HPLC Purity 99.75% , Chiral HPLC Purity (S) 100% & SOR -30.0°(c=0.1 in MeOH at 25°C).

MR: 236.4-240.3°C; IR (KBr, cm ^"1 ): 3265, 2947, 2733, 2229, 1620, 1286; 1H- NMR(DMSO-d6): δ 9.29 (brs, 2H), 8.53-8.52 (d, 1H, J=1.86Hz), 8.43-8.40 (dd, 1H, J=8.9, 2.0Hz), 8.17-8.16 (d, 1H, J=7.67Hz), 7.99-7.97 (d, 1H, J=7.61Hz), 7.59-7.56 (m, 2H), 5.30-5.28 (t, 1H, J=5.0Hz), 5.00-4.97 (m, 1H), 4.91 (brs, 1H), 3.74-3.70 (q, 2H, J=5.0Hz), 3.49-3.37 (m, 1H), 3.31-3.25 (m, 1H), 3.06-3.00 (m, 2H), 2.55-2.53(m, 1H), 2.33-2.30 (m, 1H), 1.39-1.38 (d, 6H, J=6.0Hz); ¹³ C-NMR(CDC1 ₃ ): 173.73, 168.42, 163.01, 145.07, 139.75, 135.05, 134.26, 129.78, 129.61, 127.93, 23.31, 116.33, 115.71, 115.38, 102.94, 73.03, 61.56, 57.09, 47.04, 32.17, 28.22, 21.95 (2C); MS (m/z): 405.2 [M+l] ⁺ .

To a slurry solution of 2.0 gm of Formula 1 hydrochloride salt and 20 ml of water, 4M sodium hydroxide solution was added to get pH~8-9. The product was extracted with dichloromethane. The organic layer was washed with water and concentrated. The product was isolated in heptane and dried to obtain off-white solid of Formula 1 (1.8 gm, 98.36% yield) with HPLC Purity 99.85%, Chiral HPLC Purity (S) 100% & SOR -31.0° (c=0.1 in MeOH at 25°C)

MR: 134.2-135.9°C; IR (KBr, cm-1): 3291, 2926, 2230, 1616, 1284, 1101, 1045, 763; 1H-NMR(DMSO-d6): δ 8.51-8.50 (d, 1H, J=2.0Hz), 8.42-8.39 (dd, 1H, J=8.9, 2.0Hz), 7.99-7.97 (d, 1H, J=7.6Hz), 7.57-7.54 (m, 1H), 7.44-7.40 (t, 1H, J=7.6Hz), 5.00-4.95 (m, 1H), 4.51-4.49 (t, 1H, J=5.3Hz, D ₂ O exchangeable), 4.25- 4.22 (t, 1H, J=6.6Hz), 3.52-3.47 (q, 2H, J=5.6Hz), 3.32-3.29 (m,lH), 3.09-3.05 (m, 1H), 2.70-2.66 (m, 2H), 2.39-2.35 (m, 1H), 1.85-1.81 (m, 1H), 1.40-1.38 (d, 6H, J=6.0Hz); ¹³ C-NMR(CDCl ₃ ): 173.44, 168.81, 162.90, 147.94, 143.45, 134.45, 134.15, 127.67 (2C), 127.78, 116.45, 115.72, 115.28, 102.89, 72.98, 62.86, 61.36, 49.59, 33.10, 31.90, 21.94 (2C); MS (m/z): 405.1 [M+l] ⁺ .