DESC:Field of the Invention:
The present application relates to an improved process for the preparation of
Ozanimod, salts thereof. which is represented by the following structural formula-1.
5
Formula-1
Background of the Invention:
Ozanimod, has a chemical name (S)-5-(3-(1-((2-hydroxyethyl)amino)-2,3-10 dihydro-1H-inden-
4-yl)-1,2,4- oxadiazol-5-yl)-2-isopropoxybenzonitrile and is represented by the structure of
formula-1. Ozanimod is an investigational immunomodulatory drug developed by Receptos
for the treatment of relapsing multiple sclerosis (RMS) and ulcerative colitis.
The US patent No. 8481573 B2 (herein after designated as USf573) first reported racemic
15 Ozanimod, its synthetic process. The same process disclosed in Scheme-I.
The US patent No. 8362048B2 (herein after designated as US'048) covers process for
preparation of ozanimod (S) and (R) isomers and intermediates thereof. The process
involves asymmetric synthesis using chiral reagents such as S-tertiary butyl sulfinamide in
presence of titanium ethoxide.
20 The patent application WO2018215807A1 covers a process for preparation of Ozanimod by
chiral resolution method.
3
The patent application WO2019058290A1 covers a process for preparation of Ozanimod by
chiral resolution method using phenethylamine as chiral agent.
Scheme-I:
There are various processes reported for the preparation 5 of ozanimod and salts
thereof, using different solvents and reagents.
Based on draw backs in the prior art processes, there is a need for providing an
improved process for the preparation of Ozanimod and salts thereof, which involves simple
experimental procedures, well suited to industrial production, which avoids the use of
10 column chromatography purification, and which affords high pure Ozanimod and salts
thereof.
The present invention provides an improved process for preparation of Ozanimod and
salts thereof, which is efficient, industrially viable and cost effective.
Brief Description :
15 The first aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1.
The second aspect of the present invention is to provide a compound of formula-12.
The third aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1.
4
The fourth aspect of the present invention is to provide an improved process for the
preparation of the compound of formula-1.
Detailed Description:
As used herein the term gsuitable solventh used in the present invention refers to
ghydrocarbon solventsh such as n-hexane, n-heptane, cyclohexane, petether, 5 toluene, pentane,
cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; gether solventsh such as
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene
glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl
10 ether, 1,2-dimethoxy ethane and the like; gester solventsh such as methyl acetate, ethyl
acetate, isopropyl acetate, n-butyl acetate and the like; gpolar-aprotic solvents such as
dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), Nmethylpyrrolidone
(NMP) and the like; gchloro solventsh such as dichloromethane,
dichloroethane, chloroform, carbontetra chloride and the like; gketone solventsh such as
15 acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; gnitrile solventsh such as
acetonitrile, propionitrile, isobutyronitrile and the like; galcoholic solventsh such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-
fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2-methoxyethanol, l,2-ethoxyethanol,
diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol
20 monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; gpolar
solventsh such as water or mixtures thereof.
As used herein the present invention the term gsuitable baseh refers to inorganic or
organic base. Inorganic base refers to galkali metal carbonatesh such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; galkali metal bicarbonatesh such as
25 sodium bicarbonate, potassium bicarbonate and the like; galkali metal hydroxidesh such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; galkali metal
alkoxidesh such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, sodium tert.butoxide, potassium tert-butoxide, lithium tert-butoxide and the like;
alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the
30 like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like;
5
and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl
ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine
(DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term greducingh agent used in the present invention refers suitable reducing reagents are
selected from Lithium aluminium hydride, Lithium tri-tert-butoxyaluminum 5 hydride, Lithium
triethylborohydride, potassium triethylborohydride, Lithium borohydride, potassium boro
hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
The term gprotectingh agent / group (PG) used in the present invention refers to a suitable
protecting reagents that are selected selected from di-tert-butyl dicarbonate, chlorobenzyl
10 formate, benzoylchloride, benzylbromide, benzylchloride, acetylchloride,
fluorenylmethyloxycarbonyl chloride; The term gphase transfer catalyst (PTC)h used in the
present invention refers are selected from triethylbenzyl ammonium chloride, tetrabutyl
ammoniumbromide, tetrabutyl ammonium chloride, tetrabutyl ammonium acetate, methyl
tributyl ammonium chloride, tetrabutyl ammonium hydroxide, tributylbenzylammonium
15 chloride;
The first aspect of the present invention provides an improved process for the
preparation of compound of formula-1,
20
Formula-1
comprising of:
a) Reacting the compound of formula-2
6
Formula-2
with suitable reagent, suitable solvent to provide compound of formula-3,
5
Formula-3
b) reducing the compound of formula-3 with a suitable reagent, solvent to provide compound
of formula-4,
10
Formula-4
c) reacting the compound obtained in step-b) with suitable reagent in presence of suitable
solvent, base to provide compound of formula -5,
15
Formula-5
7
d)reacting the compound obtained in step-c) with compound of formula -6
Formula-6
in presence of suitable reagent, solvent to provide 5 compound of formula-7,
Formula-7
e)reacting the compound obtained in step-d) with a suitable reagent, solvent to provide
10 compound of formula-1(S-isomer of Ozanimod) or its salt .
f)optionally purifying the compound of formula-1 with a suitable solvent,
g)converting the compound of formula-1 to a salt of ozanimod (compound of formula-1a) by
using a suitable acid, solvent and optionally purifying in a suitable solvent to get pure
compound of formula-1a.
15 Wherein in step-a) the suitable solvent is selected from chloro solvents, polar protic, polar
aprotic, polar or any mixture thereof; preferably dimethyl formamide, dimethyl sulfoxide, Nmethyl-
2-pyrrolidone; suitable reagents palladium catalyst, sodium cyanide, potassium
cyanide, copper cyanide, zinc cyanide, potassium iodide, sodium iodide and mixture thereof;
Wherein in step-b) the suitable solvent is selected from ether solvents, polar solvents,
20 alcohol solvents, polar aprotic solvents, polar protic solvents, toluene or any mixture thereof;
suitable reagents are (S)-2-methyl-CBS-oxaborolidine, BH3-DMS, (R)-2-methyl-CBSoxaborolidine,
BH3-DMS, ruthinium catalyst, R-RuBinap ([(R)-(+)-2,2Œ-bis(diphenyl
phosphino)-1,1Œ.binaphthyl] ruthenium (II)), S or R-diphenyl prolinol, sodium borohydride,
sodium triacetoxyborohydride, lithium aluminium hydride, lithium tri-tert-butoxyaluminum
8
hydride, lithium triethylborohydride, potassium triethylborohydride, lithium borohydride,
potassium borohydride, H2 (g) under Pd/C and mixture thereof; organic base;
Wherein in step-c) the suitable reagent is salt of hydroxylamine; such as hydrochloride,
sulphate; the suitable solvent is selected from chloro solvents, ether solvents, ester solvents,
polar solvents, alcohol solvents, polar aprotic solvents, polar protic 5 solvents or water any
mixture thereof; organic base such as triethylamine, diisopropyl ethylamine, diisopropyl
amine, inorganic base and mixture thereof.
Wherein in step-d) the suitable reagent is EDC HCl, HOBt , TBAB, HATU, TBTU, CDI,
DCC, Pivolylchloride, methylchloroformate, ethylchloroformate, phenylchloroformate;
10 organic base such as triethylamine, diisopropyl ethyl amine, diisopropylamine, DMAP, 2,6-
luitidine; suitable solvent is selected from chloro solvents, ether solvents, ketone solvents,
ester solvents, polar solvents, alcohol solvents, polar aprotic solvents, polar protic solvents or
any mixture thereof;
Wherein in step-e) the suitable reagent is selected from methanesulphonyl chloride, p15
toluene sulphonyl chloride, ammonia, ethanolamine hydrochloride or ethanolamine; organic
base such as triethylamine, diisopropyl ethyl amine, diisopropyl amine, pyridine; suitable
solvent is selected from chloro solvents, ether solvents, ketone solvents, ester solvents, polar
solvents, alcohol solvents, polar aprotic solvents, polar protic solvents or water any mixture
thereof;
20 Wherein in step-f), g) the suitable solvent is selected from chloro solvents, ether solvents,
ketone solvents, ester solvents, polar solvents, alcohol solvents, polar aprotic solvents, polar
protic solvents or water any mixture thereof; suitable acid is HCl, HBr, tartaric acid, fumaric
acid, methane sulfonic acid, succinic acid, oxalic acid, PTSA salt;
The preferred embodimate of the present invention provides a process for the
25 preparation of compound of formula-1a,
Formula-1a
9
comprising of:
a)Reacting the compound of formula-2
Formula-2
5
with CuCN in DMF to provide compound of formula-3,
Formula-3
b)reducing the compound obtained in step-a) with S-methyl CBS 10 , boran DMS in dichloro
methane to provide compound of formula-4,
Formula-4
c) reacting the compound obtained in step-b) with hydroxylamine hydrochloride, in presence
15 sodium carbonate in methanol to provide compound of formula -5,
Formula-5
10
d)reacting the compound obtained in step-c) with compound of formula -6
Formula-6
in presence of EDC.HCl, HOBt triethylamine in DMF solvent 5 to provide compound of
formula-7,
Formula-7
10 e)reacting the compound obtained in step-d) with thionylchloride in dichloromethane, the
the isolated obtained compound was reacted with ethanolamine to provide compound of
formula-1.
f) treating the compound-1 with di-paratoluoyl-L-tartaric acid, followed by HCl to obtained
the compound of formula-1a,
15 g) purifying the compound of formula-1a in methanol.
The present invention described as below in a schematic representation :
11
The second aspect of the present invention provides a compound of formula-12,
5
Formula-12 (PG: acetyl, benzoyl)
An improvised process for Ozanimod described in schematic representation:
12
The third aspect of the present invention provides an improved process for
compound of formula-1,
An improvised process for Ozanimod described in schematic 5 representation:
13
The present invention also provides an improved process for the preparation of the
compound of formula-15,
5 Formula-15
Comprising of:
a) Chiral resolution of compound of formula-15A using chiral resolving agents, in a suitable
solvents to get the title compound of formula-15 and salts thereof. Optionally isolated as salt
of compound of formula-15.
10 Wherein in step-a) The suitable chiral resolving acid is selected from the group tartaric acid,
dibenzoyl tartaric acid, di-p-toluoyltartaric acid, aspartic acid, camphorsulfonic acid,
glutamic acid, malic acid, mandelic acid, pyroglutamic acid and valine. The suitable solvent
14
is selected from the group comprising ethanol, methanol, isopropyl alcohol, acetone, dioxane,
ethyl acetate, tetrahydrofuran, acetonitrile, toluene and water or mixtures thereof.
suitable acid salt is selected from HCl, HBr, tartaric acid, fumaric acid, methane sulfonic acid,
succinic acid, oxalic acid, PTSA salt;
5
Alternative process for preparation of compound of formula-15
The fourth aspect of the present invention provides an improved process 10 for the preparation
of compound of formula-1,
Formula-1
comprising of:
15 a) Resolution of recemic ozanimod by using suitable chiral resolving agents to produce Risomer
of Ozanimod or S-isomer of Ozanimod.
15
b)optionally converting S-isomer of ozanimod into pharmaceutically acceptable salts.
Step-a) The suitable chiral resolving acid is selected from the group tartaric acid, dibenzoyl
tartaric 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, dioxane, 5 ethyl acetate,
tetrahydrofuran, acetonitrile, toluene and water or mixtures thereof.
Step-b): pharmaceutically acceptable salts are selected from HCl, HBr, fumaric acid, tartaric
acid, para toluene sulfonic acid, methane sulfonic acid, citric acid.
10 The present invention also provides an improved process for the preparation of the
compound of formula-6
Formula-6
15 comprising of:
b) Esterification of compound of formula-A,
Formula-A
with alcohol in presence of sulfuric acid or thionylchloride to provide compound of formula-
20 B,
Formula-B
16
b)reacting the compound of formula-B with a suitable reagent to provide compound of
formula-C ,
Formula-C
5
c)reacting the compound obtained in step-b) with isopropyl bromide or isopropyl iodide in
presence of base, solvent to provide compound of formula -D,
Formula-D
d)reacting the compound obtained in step-c) with suitable reagent, 10 solvent to provide
compound of formula-E,
Formula-E
e) hydrolysing the compound of formula-E with a suitable reagent to provide compound of
15 formula-6.
wherein in step-a, b, c, d, e, f) the suitable solvent is selected from chloro solvents, ether
solvents, ketone solvents, acetonitrile solvent, ester solvents, polar solvents, alcohol solvents,
polar aprotic solvents, polar protic solvents or water any mixture thereof;
step-b) suitable reagent in n-iodosuccinimide, N-bromosuccinamide, bromine, trifluoroacetic
20 acid;
step-c) suitable base potassium carbonate, sodium carbonate, organic base; step-d) suitable
reagent is sodium cyanide, potassium cyanide, zinc cyanide, copper cyanide; step-e) suitable
reagent is HCl, sodium hydroxide, potassium hydroxide, lithium hydroxide.
17
Schematic representation for the preparation of compound of formula-6:
The process described in the present invention was demonstrated 5 in examples
illustrated below. These examples are provided as illustration only and therefore should not
be construed as limitation of the scope of the invention.
Examples:
Example-1: Preparation of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile.
10 A round bottom flask was charged with compound of formula-2 (300.0 g), CuCN (191.0 g)
and KI ( 354.0 g, 1.5 eq) in DMF (1500 ml; 5v) at 25-30 ‹C. The reaction mixture was
heated to 145-150‹C and stirred for 24 hr. The reaction mass was cooled to 25-35‹C,
charged with water (6.0 L ) and ethyl acetate (1.5 L ) and stirred for 30 min. Filtered the solid
waste, separated both layers. The aqueous layer was extracted with ethyl acetate (1.5 L ), the
15 combined organic layer was washed with brine solution (1.5 L ) and evaporated the organic
layer to get the crude compound. The crude compound was purified in water (1.5 L) and
dried at 55-60‹C to get the title compound.
Yield: 160 g.
Example-2: Preparation of 4-hydroxy-methylbenzoate.
20 A round bottom flask was charged with 4-hydroxybenzoic acid (500.0 g, 1.0 eq), methanol
(2.0 vol) and H2SO4 (248.5 g, 0.7eq) at 20-25‹C, heated to 65-70‹C stirred for 12 hr. The
18
reaction mixture was quenched with crushed ice (3000 g) and stirred at 20-25‹C, filtered the
solid and washed with water (500 ml x2) to get the title compound.
Yield: 503 g
Example-3: Preparation of methyl-4-hydroxy-3-iodobenzoate
A round bottom flask was charged with methyl- 4-hydroxy-benzoate (503 5 g, 1.0 eq), triflouro
acetic acid (6.0 vol) and N-Iodosuccinimide (916.0 g, 1.05 eq) at 0-5‹C, stirred at 25-30‹C
for 14 hr. The reaction mixture was quenched with crushed ice, stirred for 2 hr. Filtered the
obtained solid, washed with water (500 ml). The obtained compound was stirred in water
(1500 ml ) for 20 min, filtered and dried to get the title compound.
10 Yield: 860.0 g
Example-4: Preparation of methyl-3-iodo-4-isopropoxybenzoate
A round bottom flask was charged with methyl-4-hydroxy-3-iodobenzoate (860.0 g, 1.0 eq),
and K2CO3 (1070.7 g, 2.5 eq), DMF (2580 ml, 3.0 v), followed by addition of isopropyl
bromide (474.7 g, 1.1 eq) and heated to 65-70‹C stirred for 7 hr. The reaction mixture was
15 charged with water (8.6 L, 10.0 v) and ethyl acetate ( 3.4 L, 4.0 v), stirred at 25-35‹C for 30
min. Separated the layers, aqueous layer was extracted with ethyl acetate (3.4 L, 4.0 v), the
combined organic layer was washed with brine solution (3.4 L, 4.0 v). The organic layer was
distilled off completely to obtain the title compound. Proceeded for next step without any
purification.
20 Yield: 950.0 g
Example-5 : Preparation of methyl- 3-cyano-4-isopropoxybenzoate
A round bottom flask was charged with methyl-3-iodo-4-isopropoxybenzoate (950.0 g, 1.0
eq ), CuCN (398.5 g, 1.5 eq), DMF (2.85 L) and heated to 145-150‹C, stirred for 12 hr. The
reaction mixture was charged with water (9.5 L) and ethyl acetate (2.85 L), stirred at 25-35‹C
25 for 30 min and separated both layers. The aqueous layer was extracted with ethyl acetate
(2.85 L), the combined organic layer was washed with brine solution (2.85 L) and evaporated
the organic layer to get the title compound.
Yield: 864.0 g
Example-6 : Preparation of 3-cyano-4-isopropoxybenzoic acid
30 A round bottom flask was charged with methyl-3-cyano-4-isopropoxybenzoate (864.0 g, 1.0
19
eq), THF (2.59 L), water (864.0 ml ), NaOH (233.0 g, 1.5 eq) and heated to 55-60 ‹C stirred
for 12 hr. The reaction mixture was cooled to 20-25‹C, charged with water (4.3 L) and ethyl
acetate (2.59 Lx2), stirred for 30 min. The organic layer was separated, the aqueous layer
pH was adjusted to 3.0-4.0 with 4NHCl (864.0 ml) and stirred for 2 hr. Filter the obtained
solid, washed with water (864.0 ml) and dried to 5 get the title compound.
Yield: 721.0 g
Example-7 : Preparation of 2-(2-bromoethoxy)tetrahydro-2H-pyran.
A round bottom flask was charged with bromo ethanol (200.0 g, 1.0 eq), slowly added
Dihydropyran (147.9 g, 1.1 eq ) at 0-5‹C, stirred for 6 hr. The reaction mixture was charge
10 with n-heptane (2.0 L, 10.0 v), washed with 10% methanol/ water(1000 ml x 3). The nheptane
layer was distilled off under vacuum to get the title compound.
Yield: 300.0 g
Example-8 : Preparation of (R)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile.
A round bottom flask was charged with (+) R-2-methyl-CBS-oxazaborolidine (1.6 mL, 1M
15 solution in toluene) and borane-dimethylsulfide (150 uL) under N2. A solution of compound
of formula-3 (100 g) in dichloromethane (500.0 ml) was added dropwise over 20 min while
maintaining the reaction temperature at -20 } 5‹C stirred for 2 h. The reaction mixture was
quenched by the dropwise addition of methanol (10 mL). The reaction mixture was further
diluted with methanol (200 mL) and the solvent distilled off completely to get the title
20 compound.
Yield: 92.0 g
Example-9 : Preparation of (R)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile.
A round bottom flask was charged with Sodium borohydride (20.0 g, 0.9 eq) in 1,2-di
methoxyethane (300 ml, 3.0v) and N-phenyldiethylamine hydrochloride (147.8 g, 1.2 eq) and
25 R- (+) Diphenylprolinol (193.7 g, 1.2 eq) under N2. A solution of compound of formula-3
(100.0 g, 1.0 eq) in 1,2-dimethoxy ethane (500 ml) was added drop wise over 20 min while
maintaining the reaction temperature at -20 } 5‹C stirred for 2 h. The reaction mixture was
quenched by the dropwise addition of ammoniumchloride solution (500 mL) and ethyl
acetate (2.59 Lx2), stirred for 30 min. The organic layer was separated and evaporated the
30 solvent to get the title compound.
20
Yield: 92.0 g
Example-10 : Preparation of (R)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile.
A round bottom flask was charged with R-RuBinap (0.4 mol% ) and TEA (1.5 eq) in
methanol (1000 ml, 10.0 v) under N2. A solution of compound of formula-3 (100.0 g) in
methanol (200 ml, 2.0 v) was added drop wise over 20 min and applied 5 H2 gas (60 Psi) while
maintaining the reaction temperature at 60 } 5‹C stirred for 6 h. The reaction mixture was
filtered through hyflow bed and washed with methanol (30 ml), the filtrate solvent was
distilled off completely to get the title compound.
Yield: 92.0 g
10 Example-11: Preparation of compound of formula-4.
A round bottom flask was charged with (S)-(.)-2-Methyl-CBS-oxazaborolidine (98 mL), di
chloromethane (500 mL), followed by addition of borane-DMS complex (178.3 mL, 10M)
over a period of 30 min and stirred for 10 min at 25-35‹C. Cooled the reaction mixture to -
20‹C, charged a solution of compound of formula-3 (100 g) in dichloromethane (500 mL)
15 and stirred for 2 hr. The reaction mixture was quenched with methanol (300 mL) at -20‹C,
gradually allowed to 25-35‹C charged with water (1.2 L) and stirred for 30 min. Separated
the organic layer, the aqueous layer was extracted with dichlorometane (500 mL). The
combined organic layer was dried over anhydrous sodium sulphate, evaporated the organic
layer to get the crude compound. The obtained compound was stirred in a mixture of methyl
20 tert-butyl ether (500 mL), n-heptane (500 mL), filtered the obtained solid and dried to get the
title compound.
Yield: 88 g
Example-12: Preparation of compound of formula-5.
A round bottom flask was charged with compound of formula-4 (100 g), sodium bicarbonate
25 (105.7 g) in methanol (1 L) at 25-35‹C and stirred for 10 min. Hydroxylamine hydrochloride
(86.16 g) was charged slowly to the reaction mixture, heated to 65-75‹C and stirred for 14 hr .
Cooled the reaction mixture and evaporated the solvent, the obtained residue was charged
with ethylacetate (200 mL) and stirred for 1 hr. Filtered the compound obtained, washed with
ethyl acetate (30 mL) and dried to get the title compound.
30 Yield: 100 g
21
Example-13: Preparation of compound of formula-7.
A round bottom flask was charged with compound of formula-6 (101.4 g) , N-(3-Dimethyl
amino propyl)-NŒ-ethylcarbodiimide hydrochloride (EDC.HCl) (104.4 g), hydroxy
benzotriazole (73.9 g), triethylamine (55.24 g) in dimethyl formamide (800 mL) at 25-35‹C
and stirred for 2 hr. A compound of formula-5 ( 100 g) charged 5 in small portions to the
reaction mixture and stirred for 3 hr and heated to 110-120‹C, stirred for 24 hr. The reaction
mixture was quenched with 6 % sodium bicarbonate solution(2.4 L ) and stirred for 1 hr, the
obtained solid was filtered and washed with water (100 mL ) and dried to get the
intermediate compound. The obtained compound was suspended in toluene (500 mL) and
10 cooled the reaction mixture to 25-35‹C, the obtained solid was filtered and washed with
toluene (100 mL) and dried to get the title compound.
Yield: 131 g
Chiral purity by HPLC: S-isomer 99.8 %; R-isomer : 0.2 %;
Example-14: Preparation of compound of formula-1.
15 A round bottom flask was charged with compound of formula-7 (100 g), dichloromethane ( 2
L) and DMF (10 mL) at 25-35‹C and stirred for 10 min. Cooled the reaction mixture to 10‹C,
slowly added thionyl chloride (50 mL ) and stirred at 25-30‹C for 4 hr. The reaction mixture
was cooled to 25-35‹C, quenched with ice cold water (100 mL) and stirred for 15 min. The
both layers were separated, and aqueous layer was extracted with dichloromethane (1 L). The
20 combined organic layer was washed with sodium bicarbonate solution (1 L) and dried the
organic layer, evaporated to get the crude compound-8. The crude compound-8 and
ethanolamine (500 mL) were suspended in DMF (200 mL), heated to 75-80‹C and stirred for
6 hr. The reaction mixture gradually cooled to 25-35‹C, quenched with water (3 L) and
stirred for 15 min. Filtered the obtained solid, washed with water (50 mL) and dried to get
25 the title compound.
Yield: 100 g
Chiral purity by HPLC: S-isomer > 85 % ; R-isomer : < 15 %
Example-15: Preparation of compound of formula-1a.
A round bottom flask was charged with compound of formula-1 ( 50 g S-isomer > 85 % ; R30
isomer : < 15 %), di-para-toluoyl-Ltartaric acid (48 g) in 30 % methanol : acetonitrile (500
22
mL) at 25-35‹C, and stirred for 2 hr. The precipitate solid was slowly heated to 60-70‹C and
stirred for 45 min. The reaction mixture was cooled to 25-35‹C, stirred for 3 hr. Filtered the
obtained solid and washed with acetonitrile (10 mL) to get the di-para-toluoyl tartaric acid
salt of Ozanimod. The obtain salt was suspended in a mixture of acetonitrile and methanol
(500 mL), heated to 65-70‹C stirred for 2 hr. Filtered the obtain 5 solid and washed with
acetonitrile (100 mL) to get dptta salt of Ozanimod.
The obtained salt was dissolved in water (900 mL) adjusted the PH upto 7.8 using 10 %
potassium carbonate solution (200 mL) and stirred for 4 hr. The aqueous layer was extracted
with ethyl acetate (200 mL), the combined organic layer was washed with brine solution and
10 dried over anhydrous sodium sulphate. The ethyl acetate layer (300 mL) was charged with 20
HCl in ethyl acetate (100 mL) and stirred for 30 min. Filtered the precipitated solid and dried
to get the title compound.
Yield: 35 g
Example-16: Purification of compound of formula-1a.
15 A round bottom flask was charged with compound of formula-1a (100 g), methanol ( 1 L) at
25-35‹C, heated to 65-70‹C and stirred for 1 hr. Cooled the reaction mixture to 25-35‹C
stirred for 3 hr, further cooled to 0-5‹C, and stirred for 3 hr. Filtered the obtained solid and
washed with methanol (150 mL) and dried to get the title compound.
Yield: 86.5 g
20 Chiral purity by HPLC: 99.99 %
Example-17: Purification of compound of formula-1a.
A round bottom flask was charged with compound of formula-1a (10 g), isopropanol ( 100
mL) at 25-35‹C, heated to 65-70‹C and stirred for 1 hr. Cooled the reaction mixture to 25-
35‹C stirred for 3 hr, further cooled to 0-5‹C, and stirred for 3 hr. Filtered the obtained solid
25 and washed with isopropanol (50 mL) and dried to get the title compound.
Yield: 9.2 g
Chiral purity by HPLC: 99.99 % ,CLAIMS:1. A process for the preparation of ozanimod and its pharmaceutiaclly acceptable salt, the
compound of formula-1a.
5 Formula-1a
comprising of:
a) Reacting the compound of formula-2
Formula-2
10 with suitable reagent, suitable solvent to provide compound of formula-3,
Formula-3
b) reducing the compound of formula-3 with a suitable reagent, solvent to provide compound
of formula-4,
15
Formula-4
24
c)reacting the compound obtained in step-b) with suitable reagent in presence of suitable
solvent, base to provide compound of formula-5,
Formula-5
d)reacting the compound obtained in step-c) with 5 compound of formula -6
Formula-6
in presence of suitable reagent, solvent to provide compound of formula-7,
10 Formula-7
e)reacting the compound obtained in step-d) with a suitable reagent, solvent to provide
compound of formula-1(S-isomer of Ozanimod) or its salt,
f)optionally purifying the compound of formula-1 with a suitable solvent,
g)converting the compound of formula-1 to a salt of ozanimod (compound of formula-1a) by
15 using a suitable acid, solvent and optionally purifying in a suitable solvent to get pure
compound of formula-1a.
2. A process for the preparation of ozanimod according to claim-1 wherein in the suitable
solvent is selected from hydrocarbon, polar aprotic, polar protic, ether, nitrile, ketone, ester,
20 chlorinated, water, alcohol and mixture thereof;
25
3.A process for the preparation of ozanimod according to claim-1 wherein step-a) suitable
reagents palladium catalyst, sodium cyanide, potassium cyanide, copper cyanide, zinc
cyanide, potassium iodide, sodium iodide and mixture thereof;
Wherein in step-b) suitable reagents are (S)-2-methyl-CBS-oxaborolidine, BH3-DMS, (R)-2-
methyl-CBS-oxaborolidine, BH3-DMS, ruthinium catalyst, R-RuBinap 5 ([(R)-(+)-2,2Œ-
bis(diphenyl phosphino)-1,1Œ.binaphthyl] ruthenium (II)), R-diphenyl prolinol, sodium
borohydride, sodium triacetoxyborohydride, lithium aluminium hydride, lithium tri-tertbutoxyaluminum
hydride, lithium triethylborohydride, potassium triethylborohydride,
lithium borohydride, potassium borohydride, H2 (g) under Pd/C and mixture thereof; organic
10 base;
Wherein in step-c) the suitable reagent is salt of hydroxylamine; such as hydrochloride,
sulphate; organic base such as triethylamine, diisopropyl ethylamine, diisopropyl amine,
inorganic base and mixture thereof.
Wherein in step-d) the suitable reagent is EDC HCl, HOBt , TBAB, HATU, TBTU, CDI,
15 DCC, Pivolylchloride, methylchloroformate, ethylchloroformate, phenylchloroformate;
organic base such as triethylamine, diisopropyl ethyl amine, diisopropylamine, DMAP, 2,6-
luitidine;
Wherein in step-e) the suitable reagent is selected from methanesulphonyl chloride, ptoluene
sulphonyl chloride, ammonia, ethanolamine hydrochloride or ethanolamine; organic
20 base such as triethylamine, diisopropyl ethyl amine, diisopropyl amine, pyridine;
Wherein in step-f), g) The suitable acid is selected from HCl, HBr, tartaric acid, fumaric acid,
methane sulfonic acid, succinic acid, oxalic acid, PTSA salt;
4.A process for the preparation of ozanimod and ozanimod hydrochloride of compound of
25 formula-1a,
Formula-1a
26
comprising of:
a)Reacting the compound of formula-2
Formula-2
with CuCN in DMF to provide 5 compound of formula-3,
Formula-3
b)reducing the compound obtained in step-a) with S-methyl CBS , boran DMS in dichloro
methane to provide compound of formula-4,
10
Formula-4
c) reacting the compound obtained in step-b) with hydroxylamine hydrochloride, in presence
sodium carbonate in methanol to provide compound of formula -5,
15
Formula-5
d) reacting the compound obtained in step-c) with compound of formula-6,
27
Formula-6
in presence of EDC.HCl, HOBt triethylamine in DMF solvent to provide compound of
formula-7,
5
Formula-7
e) reacting the compound obtained in step-d) with thionylchloride in dichloromethane, the
the isolated obtained compound was reacting with ethanolamine to provide compound of
10 formula-1,
f) treating the compound-1 with di-paratoluoyl-L-tartaric acid, followed by HCl to obtained
the compound of formula-1a,
g) purifying the compound of formula-1a in methanol.
15 5.A process for the purification of Ozanimod hydrochloride comprising of
a) Suspending ozanimod hydrochloride in suitable solvent,
b) stirring and isolating the ozanimod hydrochloride as pure compound.
6. A process for the preparation of ozanimod according to claim-5, wherein in the suitable
20 solvent is selected from hydrocarbon, polar aprotic, polar protic, ether, nitrile, ketone, ester,
chlorinated, water, alcohol and mixture thereof;
7.A process for the purification of Ozanimod hydrochloride comprising of
a) Suspending ozanimod hydrochloride in isopropanol,
25 b) stirring the solution at 65-75‹C for 1 hr,
28
c) isolating the ozanimod hydrochloride as pure compound.
8. The ozanimod hydrochloride obtained according to any of preceding claims having purity
> 95%, preferably > 99.9 % by HPLC.
5
9. The ozanimod hydrochloride obtained according to any of preceding claims having purity
> 95%, preferably > 99.9 % by chiral HPLC.
10. The ozanimod hydrochloride compound of formula-1a obtained according to any
preceding claims having particle size of D(0.9) < 200 ƒÊm , preferably 10 D(0.9) < 150 ƒÊm.