DESC:Field of the Invention:
The present application relates to a process for the preparation of Ozanimod
Hydrochloride, and intermediates thereof. Ozanimod HCl is represented by the following
structural formula-1a.
5
Formula-1a
Background of the Invention:
Ozanimod, has a chemical name (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-1. Ozanimod is an immunomodulatory drug approved 10 by FDA on 25 March 2020
for the treatment of relapsing multiple sclerosis (RMS) .
The US patent No. 8481573 B2 (herein after designated as US’573) first reported racemic
Ozanimod, its synthetic process.
The US patent No. 8362048B2 (herein after designated as US'048) covers a process for
15 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 titaniumethoxide, which is an expensive reagent not suitable on commercial process.
The patent application WO2018215807A1 covers a process for preparation of Ozanimod by
chiral resolution method. The patent application WO2019058290A1 covers a process for
20 preparation of Ozanimod by chiral resolution method using phenethylamine as chiral agent.
There are various processes reported for the preparation of ozanimod and salts thereof,
using different solvents and reagents.
Based on drawbacks 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
25 experimental procedures, well suited to industrial production, which avoids the use of
3
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.
5 Brief Description :
The first aspect of the present invention is to provide a process for the preparation of
the compound of formula-1a.
The second aspect of the present invention is to provide a process for the preparation
of the compound of formula-1a.
10 The third aspect of the present invention is to provide purification process for the
preparation of the compound of formula-1.
The fourth aspect of the present invention is to provide a compound of formula-B.
Detailed Description of the drawings:
Figure1-1: Illustrates the PXRD pattern of crystalline form of Ozanimod hydrochloride
15 obtained from example-8
Figure-2: Illustrates the PXRD pattern of crystalline form of Ozanimod hydrochloride
obtained from example-12
Figure-3: Illustrates IR absorption of crystalline form of Ozanimod hydrochloride
Figure-4: Illustrates DSC thermogram of crystalline form of Ozanimod hydrochloride
20 Figure-5: Illustrates TGA thermogram of crystalline form of Ozanimod hydrochloride
Figure-6: Illustrates the PXRD pattern of crystalline form of Ozanimod obtained from
example-5.
Figure-7: Illustrates the PXRD pattern of crystalline form of compound of formula-B
obtained from example 23.
25 Detailed Description:
As used herein the term “suitable solvent” used in the present invention refers to
“hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petether, toluene, pentane,
cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; “ether solvents” such as
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene
30 glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,
4
diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl
ether, 1,2-dimethoxy ethane and the like; “ester solvents” such as methyl acetate, ethyl
acetate, isopropyl acetate, n-butyl acetate and the like; “polar-aprotic solvents such as
dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), Nmethyl
pyrrolidone (NMP) and the like; “chloro solvents” such 5 as dichloromethane,
dichloroethane, chloroform, carbontetra chloride and the like; “ketone solvents” such as
acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; “nitrile solvents” such as
acetonitrile, propionitrile, isobutyronitrile and the like; “alcoholic solvents” such as methanol,
ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-
10 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
monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; “polar
solvents” such as water or mixtures thereof.
As used herein the present invention the term “suitable base” refers to inorganic or
15 organic base. Inorganic base refers to “alkali metal carbonates” such as sodium carbonate,
potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” such as
sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as
sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal
alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium
20 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
like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like;
and organic bases such as like dimethylamine, diethylamine, diisopropyl amine, diisopropyl
ethylamine, diisobutylamine, triethylamine, pyridine, piperidine, 4-dimethyl amino pyridine
25 (DMAP), N-methyl morpholine (NMM), or mixtures thereof.
The term “reducing” agent used in the present invention refers suitable reducing
reagents are selected from Lithium aluminium hydride, Lithium tri-tert-butoxyaluminum
hydride, Lithium triethylborohydride, potassium triethylborohydride, Lithium borohydride,
potassium boro hydride, sodium borohydride, BF3 etherate solution, Pd/C, Ray-nickel;
5
The first aspect of the present invention provides a process for the preparation of
compound of formula-1a,
Formula-1a
5 comprising of:
a)reacting the compound of formula-2, with suitable reagent, suitable solvent to provide
compound of formula-3,
Formula-2 Formula-3
10 b)reducing the compound of formula-3 with a suitable reagent, solvent to provide compound
of formula-4,
Formula-4 Formula-5
c)reacting the compound obtained in step-b) with suitable reagent in presence of suitable
15 solvent, base to provide compound of formula-5,
d) reacting the compound obtained in step-c) with compound of formula-6, in presence of
suitable reagent, solvent to provide compound of formula-7,
6
Formula-6 Formula-7
e) reacting the compound obtained in step-d) with a suitable reagent, solvent to provide
compound of formula-8,
5
f) reacting the compound obtained in step-e) with a suitable reagent, solvent to provide
compound of formula-1 or 1a,
g) optionally purifying the compound of formula-1 with suitable reagent, solvent,
h) 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 suitable 10 solvent to get pure
compound of formula-1a.
Wherein in the suitable solvent is selected from hydrocarbon solvents, chloro solvents,
ether solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, polar
aprotic solvents, and water any mixture thereof; dimethyl formamide, dimethyl sulfoxide, N15
methyl-2-pyrrolidone; wherein step-a) the 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-CBSoxaborolidine,
BH3-DMS, (R)-2-methyl-CBS-oxaborolidine, ruthinium catalyst, R-RuBinap
([(R)-(+)-2,2'-bis(diphenyl phosphino)-1,1'- binaphthyl] ruthenium (II)), R-diphenylprolinol,
20 sodium borohydride, sodium triacetoxy borohydride, lithium aluminium hydride, lithium tritert-
butoxyaluminum hydride, lithium triethylboro hydride, 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; organic base such as triethylamine, diisopropyl ethylamine, diisopropyl amine,
7
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; organic base such as triethylamine, diisopropyl
ethyl amine, diisopropylamine, DMAP, 2,6-luitidine; Wherein in step-e) the suitable reagent
is selected from thionyl chloride, methanesulphonyl chloride, p-toluene 5 sulphonyl chloride,
p-nitro benzenesulphonyl chloride, ammonia, organic base such as triethylamine, diisopropyl
ethylamine, diisopropylamine, pyridine; Wherein in step-f) suitable reagent is ethanolamine
or ethanolamine salt; wherein in step-g) and h) the suitable solvent is selected from chloro
solvents, ether solvents, ketone solvents, ester solvents, alcohol solvents, polar aprotic
10 solvents, nitrile solvents or water any mixture thereof; suitable acid is HCl, HBr, HCl in ethyl
acetate, methanolic HCl, ethanolic HCl, IPA HCl, Dioxane HCl, tartaric acid, fumaric acid,
methane sulfonic acid, succinic acid, oxalic acid, p-toluene sulphonic acid, Di-p-toluoyl-Ltartaric
acid, Di-p-toluoyl-D-tartaric acid, citric acid, dibenzoyltartaric acid, aspartic acid,
camphorsulfonic acid, glutamic acid, malic acid, mandelic acid. Suitable base is selected
15 form inorganic base or organic base; suitable temperature 10-100°C.
The preferred embodiment of the present invention provides a process for the
preparation of compound of formula-1a,
Formula-1a
20 comprising of:
a)reacting the compound of formula-2 with copper cyanide, in presence of potassium iodide
in DMF to provide compound of formula-3,
Formula-2 Formula-3
8
b)reducing the compound of formula-3 with S-2-methyl-CBS, borane-DMS in MDC to
provide compound of formula-4,
Formula-4 Formula-5
c)reacting the compound obtained in step-b) with hydroxyamine HCl, 5 sodium bicarbonate in
methanol to provide compound of formula-5,
d) reacting the compound obtained in step-c) with compound of formula-6 in presence of
EDC, HOBt, triethylamine in DMF to provide compound of formula-7,
10 Formula-6 Formula-7 Formula-8a
e) reacting the compound obtained in step-d) with thionylchloride in MDC, DMF to provide
compound of formula-8a,
f) reacting the compound obtained in step-e) with ethanolamine to provide compound of
formula-1 or 1a,
15 g) purifying the compound of formula-1 with treating with di-para-toluoyl-L-tataric acid in
acetonitrile, methanol to provide Ozanimod DPTTA salt,
h) treating the compound obtained in step-g) with methanolic HCl in methanol to provide
Ozanimod HCl.
The present invention described as follows in a schematic representation:
20
9
The second aspect of the present invention is to provide a process for the preparation
of compound of formula-1a, described as follows in a schematic 5 representation :
The third aspect of the present invention is to provide purification process for
10 compound of formula-1.
a) stirring compound of formula-1 is suitable solvent at a suitable temperature,
b) isolating the pure compound of formula-1.
10
Other aspect of the present invention is to provide purification process for
compound of formula-1.
a) stirring compound of formula-1 is suitable solvent, suitable acid at a suitable temperature,
b) isolating the compound of formula-B,
c) optionally treating the compound obtained -b) with suitable 5 base and solvent,
d) treating the compound obtained is step-b) or c) with organic solvent in HCl and isolating
the pure compound of formula-1.
Other aspect of the present invention is to provide purification process for
compound of formula-1a.
10 a) stirring compound of formula-1a in suitable solvent, suitable temperature,
b) isolating the compound of formula-1a.
Wherein in step-a,b,c and d) the suitable solvent is selected from chloro solvents,
ether solvents, ketone solvents, ester solvents, polar solvents, alcohol solvents, polar aprotic
15 solvents, nitrile solvents or water any mixture thereof; suitable acid is HCl, HBr, HCl in ethyl
acetate, methanolic HCl, ethanolic HCl, IPA HCl, Dioxane HCl, tartaric acid, fumaric acid,
methane sulfonic acid, succinic acid, oxalic acid, p-toluene sulphonic acid, Di-p-toluoyl-Ltartaric
acid, Di-p-toluoyl-D-tartaric acid, citric acid, dibenzoyltartaric acid, aspartic acid,
camphorsulfonic acid, glutamic acid, malic acid, mandelic acid, pyroglutamic acid and valine.
20 Suitable base is selected form inorganic base; suitable temperature 10-100°C.
Other preferred embodiment of the present invention is to provide purification
process for compound of formula-1a. comprising of ,
a) treating Ozanimod with dipara toluoyl L-tartaricacid in a mixture of acetonitrile, methanol,
b) isolating Ozanimod diparatoluoyltartrate salt,
25 c) treating the compound obtained step-b) with methanol HCl,
d) isolating Ozanimod hydrochloride as pure compound.
The Ozanimod used in the present invention purity may be >70 % or >80 % or >90 %
or > 95 % or > 99 % ; Chiral purity by HPLC may be ~50 % or >60% or >70 % or >80 % or
>90 % or >95 % or > 99.%.
30
11
The present invention described as follows in a schematic representation:
The fourth aspect of the present invention is to provide a compound of formula-B
(Ozanimod di-para-toluoyl-L-tartaric acid salt). The other aspect of the present invention is
to provide novel crystalline Form of compound of formula-B, herein 5 after designated as
crystalline Form-M, The crystalline Form-M of the present invention is characterized by its
powder X-Ray diffraction pattern having peaks at about 3.4, 4.6, 7.5, 9.3, 10.1, 11.3, 12.1,
13.2, 13.6, 15, 16.2, 16.7, 16.8, 17.9, 19.0, 22.9, 23.8 & 29 ± 0.2° 2?. The said crystalline
Form-M is further characterized by its powder X-Ray diffraction pattern substantially in
10 accordance with figure-7,
Formula-B
The process for the preparation of compound of formula-1a developed by the present
inventors produces highly pure compound of formula-1a with good yield. All the related
15 substances and residual solvents are controlled well within the limits as suggested by ICH
12
guidelines and most of the related substances are controlled in non-detectable levels.
The compound of formula-I produced by the process of the present invention is
having purity of greater than 99.5%, preferably greater than 99.7%, more preferably greater
than 99.9% by HPLC
Ozanimod hydrochloride produced by the present invention 5 can be further
micronized or milled to get the desired particle size to achieve desired solubility profile based
on different forms of pharmaceutical composition requirements. Techniques that may be used
for particle size reduction include, but not limited to ball, roller and hammer mills, and jet
mills. Milling or micronization may be performed before drying, or after the completion of
10 drying of the product.
PXRD analysis of Ozanimod hydrochloride was carried out using BRUKER D8
ADVANCED/ AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A°
and continuous scan speed of 0.03°/min. IR spectra were recorded on a Perkin-Elmer FT-IR
spectrometer.
15 The process described in the present invention demonstrated 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 compound of formula-3.
20 A round bottom flask was charged with compound of formula-2 ( 200 g ), CuCN (126.4 g)
and KI ( 236.0 g) in DMF ( 400 mL) at 25-30 °C, heated to 145-150°C and stirred for 24 hr.
Cooled the reaction mass to 25-35°C, charged with water ( 2.4 L) and ethyl acetate ( 1 L )
and stirred for 30 min. Filtered the solid waste and separated both layers. The aqueous layer
was extracted with ethyl acetate ( 1 L), the combined organic layer was washed with brine
25 solution (1 L) and evaporated the organic layer to get the crude compound. The compound
was charged with water (1 L) and stirred for 2 hr at 25-35°C, filtered the solid and washed
with water (100 mL), dried to get the title compound.
Yield: 100 g.
Example-2: Preparation of compound of formula-4.
13
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 -
10-20°C, charged a solution of compound of formula-3 (100 g) in dichloromethane (500 mL)
and stirred for 2 hr. The reaction mixture was quenched with methanol 5 (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
10 tert-butyl ether (500 mL), n-heptane (500 mL), filtered the obtained solid and dried to get the
title compound.
Yield: 88 g.
Example-3: Preparation of compound of formula-5.
A round bottom flask was charged with compound of formula-4 (100 g), sodium bicarbonate
15 (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.
20 Yield: 100 g.
Example-4: 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'-ethylcarbodiimide hydrochloride (EDC) (104.4 g), hydroxybenzotriazole
(73.9 g), triethylamine (55.24 g) in dimethyl formamide (800 mL) at 25-35°C and stirred for
25 2 hr. A compound of formula-5 ( 100 g) charged in small portions to the reaction mixture and
stirred for 3 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 heated to 110-120°C, stirred
30 for 24 hr. Cooled the reaction mixture to 25-35°C, the obtained solid was filtered and washed
14
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-5: Preparation of compound of formula-1.
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 5 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
combined organic layer was washed with sodium bicarbonate solution (1 L) and dried the
10 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), to get the title compound. MC ~ 5 %, obtained PXRD depicted in figure-6.
15 Yield: 100 g ; HPLC: 85%: Chiral purity by HPLC: S-isomer > 85 % ; R-isomer : < 15 %.
Example-6: Preparation of compound of formula-B.
A round bottom flask was charged with compound of formula-1 (10 g; chiral purity: S-iosmer
85 % & R-isomer 15 %), di-para-toluoyl-L-tartaric acid (9.6 g) in a mixture of methanol :
acetonitrile (100 mL) at 25-35°C and stirred for 2 hr. The precipitated solid was slowly
20 heated to 60-70°C and stirred for 45 min. The reaction mixture was cooled 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 acetonitrile (10 mL) to get the di-para-toluoyl-L-tartaric acid salt of Ozanimod.
The obtained salt was suspended in a mixture of acetonitrile and methanol ( 100 mL), heated
to 65-70°C stirred for 2 hr. Filtered the obtained solid and washed with acetonitrile (10 mL)
25 to get the dptta salt of Ozanimod.
Yield: 10 g ; Chiral purity by HPLC: S-isomer 97.7 % ; R-isomer : 2.3 %
Example-7: Preparation of compound of formula-1a.
A round bottom flask was charged with compound of formula-B (100.0 g), water (1.6 L) and
10% potassium carbonate solution (400.0 mL) maintained pH 7.8 stirred for 4 hr. Filtered
30 the obtained solid and washed with water (100 mL), to get the wet crude compound. The
15
obtained compound was stirred in ethyl acetate (500.0 mL) and HCl in ethyl acetate (150.0
mL) for 2 hr. The precipitated solid was filtered, and washed with methyl tert-butyl ether
(200.0 mL) to obtain the crude compound of formula-1a.
The obtained compound was dissolved in methanol (1 L) and slowly heated to 65-75°C and
stirred for 1 hr. The reaction mixture was allowed to room temperature 5 and stirred for 3 hr,
filtered the obtained solid and washed with chilled methanol (100 mL) and dried to get the
title compound.
Yield: 40.0 g ; Purity by HPLC: 99.5 %; Chiral purity: 99.99 %.
Example-8: Preparation of compound of formula-1a.
10 A round bottom flask was charged with compound of formula-1 (100 g; chiral purity: Siosmer
85 % & R-isomer 15 %), di-para-toluoyl-L-tartaric acid (95.9 g) in 30 % methanol :
acetonitrile (1 L) 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,
further cooled to 0-5°C and stirred for 3 hr. Filtered the obtained solid and washed with
15 acetonitrile (100 mL) to get the dptta salt of Ozanimod. The obtained salt was suspended in a
mixture of acetonitrile and methanol ( 1 L), heated to 65-70°C stirred for 2 hr. Filtered the
obtained solid and washed with acetonitrile (100 mL) to get Ozanimod dptta salt.
The obtain salt was dissolved in water (1.6 L) adjusted the pH upto 7.8 using 10 % potassium
carbonate solution (400 mL) and stirred for 4 hr. Filtered the obtained solid, washed with
20 water (200 mL) to get the wet compound of formula-1. The crude compound was dissolved
in ethyl acetate (500 mL ) and HCl in ethyl acetate (150 mL) stirred for 30 min. filtered the
obtained solid, washed with methyl tert-butyl ether (200 mL ) to get the crude title compound.
The obtained compound was purified in methanol (500 mL) to get the title compound.
The PXRD depicted in figure-1.
25 Yield 45 g ; Chiral purity by HPLC: 99.99 %; HPLC purity: > 99.5 %
Example-9: Preparation of compound of formula-1a.
A round bottom flask was charged with compound of formula-1 (10 g; chiral purity: S-iosmer
85 % & R-isomer 15 %), in methanol : acetonitrile (100 mL; 2:8) at 25-35°C and stirred for
2 hr. The reaction mixture was charged with methanoilc HCl (40 mL) slowly, heated to 60-
30 70°C and stirred for 2 hr. Cooled the reaction mixture to 10-20°C and stirred for 3 hr, filtered
16
the precipitated solid and washed with methanol (15 mL) to get the wet compound of
formula-1a.The obtained compound was purified in methanol (50 mL), and dried to get the
title compound. The PXRD complies with figure-2
Yield: 7.6 g ; Chiral purity by HPLC: 99.99 %; HPLC purity: > 99.5 %
Example-10: Preparation of compound 5 of formula-1a.
A round bottom flask was charged with compound of formula-1 ( 50 g), di-para-toluoyl-Ltartaric
acid (48 g) in 30 % methanol : acetonitrile (500 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
10 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 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 %
15 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
dried over anhydrous sodium sulphate. The ethyl acetate layer (300 mL) was charged with
HCl in ethyl acetate (100 mL) and stirred for 30 min. Filtered the precipitated solid and dried
to get the title compound.
20 Yield: 35 g; The PXRD complies with figure-2
Example-11: Purification of compound of formula-1a.
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
25 washed with methanol (150 mL) and dried to get the title compound.
The obtained PXRD is similar to the figure-1.
Yield: 86.5 g ; Chiral purity by HPLC: 99.99 %
Example-12: Purification of compound of formula-1a
A round bottom flask was charged with compound of formula-1 ( 50 g), methanol (500 mL)
30 at 25-35°C, heated to 65-70°C and stirred for 1 hr. Cooled the reaction mixture to 25-35°C,
17
filtered the obtained solid and washed with methanol (50 mL ) and dried to get the title
compound. The obtained PXRD depicted in figure-2.
Yield: 43.5 g ; Chiral purity by HPLC: 99.99 %
Example-13: Purification of compound of formula-1a.
A round bottom flask was charged with compound of formula-1 ( 50 g), 5 isopropanol (500 mL)
at 25-35°C, heated to 70-80°C and stirred for 2 hr. Cooled the reaction mixture to 25-35°C,
filtered the obtained solid and washed with isopropanol (50 mL) and dried to get the title
compound.
Yield : 45 g; The PXRD complies with figure-2
10 Example-14: Preparation of 4-hydroxy-methylbenzoate.
A round bottom flask was charged with 4-hydroxybenzoic acid (500.0 g), methanol (1 L) and
H2SO4 (248.5 g) at 20-25°C, heated to 65-70°C stirred for 12 hr. The reaction mixture was
quenched with crushed ice (3000 g) and stirred at 20-25°C, filtered the precipitate solid and
washed with water (2 x500 mL) to get the title compound.
15 Yield: 503 g
Example-15: Preparation of methyl-4-hydroxy-3-iodobenzoate.
A round bottom flask was charged with methyl-4-hydroxy-benzoate (503.0 g), triflouro acetic
acid (6.0 vol) and N-Iodosuccinimide (916.0 g) 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 obtain solid,
20 washed with water (500 mL). The obtain compound was stirred in water (1.5 L ) for 20 min,
filtered and dried to get the title compound.
Yield: 860.0 g
Example-16: Preparation of methyl-3-iodo-4-isopropoxybenzoate.
A round bottom flask was charged with methyl-4-hydroxy-3-iodobenzoate (860.0 g), and
25 K2CO3 (1070.7 g), DMF (2580 mL), followed by addition of isopropyl bromide (474.7 g)
and heated to 65-70°C stirred for 7 hr. The reaction mixture was 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
30 obtain the title compound. Proceeded for next step without any purification.
18
Yield: 950.0 g
Example-17 : Preparation of methyl- 3-cyano-4-isopropoxybenzoate.
A round bottom flask was charged with methyl-3-iodo-4-isopropoxybenzoate (950.0 g),
CuCN (398.5 g), 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 5 at 25-35°C 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
10 Example-18: Preparation of Compound of formula-6.
A round bottom flask was charged with methyl-3-cyano-4-isopropoxybenzoate (864.0 g),
THF (2.59 L), water (864.0 mL ), NaOH (233.0 g) 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
x 2.59 L), stirred for 30 min. The organic layer was separated, the aqueous layer pH was
15 adjusted to 3.0-4.0 with 4N HCl (864.0 mL) and stirred for 2 hr. Filtered the obtained solid,
washed with water (864.0 ml) and dried to get the title compound.
Yield: 721.0 g.
Example-19: Preparation of Compound of formula-6.
A round bottom flask was charged with methyl-4-hydroxy-3-iodobenzoate (100.0 g), and
20 K2CO3 (74.44 g), DMF (300 mL), followed by addition of isopropyl bromide (53.09 g) and
heated to 55-65°C stirred for 6 hr. The reaction mixture was cooled to 20-30°C and charged
with copper cyanide (48.28 g) and heated to 100-110°C stirred for 10 hr. The reaction
mixture was cooled to 20-30°C, charged with water (1.2L, 12 v) and ethyl acetate ( 400 mL,
4.0 v), stirred for 30 min. Filtered the reaction mass and washed with ethyl acetate (400 mL),
25 separated the layers. The aqueous layer was extracted with ethyl acetate (400 mL), the
combined organic layer was washed with brine solution (250 mL). The organic layer was
distilled off completely to obtained the residue compound.
The residue compound was charged with methanol (300 mL), sodium hydroxide solution
(17.26 g in 170 mL) and stirred for 12 h at 20-30°C. The solvent was distilled off
30 completely below 45°C, cooled the reaction mixture and charged with water (500 mL), ethyl
19
acetate (250 mL). The organic layer was separated, aqueous layer was extracted with ethyl
acetate (250 mL). The aqueous layer was charged with carbon (5 g) filtered the mass, washed
with water (200 mL) and adjusted the pH to 1.5 with Con.HCl (75 mL) and stirred for 2 hr.
Filtered the precipitated compound and washed with water (200 mL) and dried. The wet
material was charged with toluene (300 mL) and stirred for 4 hr at 5 105-115°C to removal of
water by azeotropic method. The resulting toluene solution was cooled to 20-30°C, filtered
the solid compound and dried to get the title compound.
Yield: 52 g
Example-20: Preparation of 3-(2-bromophenyl)propanoic acid.
10 A round bottom flask was charged with triethylamine (392 mL) and formic acid (265 mL) at
10-20°C and stirred for 30 min at 20-30°C. A mixture of meldrum’s acid (84.2 g) and 2-
bromo benzaldehyde (100 g) were added slowly to the above reaction and heated to 95-
105°C, stirred for 6 hr. Cooled the reaction mixture to 10-20°C, charged with dil HCl (280
mL in 550 mL of water) and stirred for 3 hr. Filtered the precipitated solid, washed with
15 water (200 mL) and dried to get the title compound.
Yield: 84.5 g
Example-21: Preparation of Compound of formula-2.
A round bottom flask was charged with 3-(2-bromophenyl)propanoic acid (100 g), DMF (5
mL) and dichloromethane (1 L) and stirred for 30 min at 20-30°C. To the reaction mixture
20 thionyl chloride (78.7 mL) was added drop wise and stirred for 4 hr at reflux temperature.
The reaction mixture was cooled to 10-20°C, charged anhydrous aluminium chloride (75.6 g)
in portion wise and stirred at 20-30°C for 4 hr. The reaction mixture was cooled to 5-15°C,
charged with HCl (500 mL in 500 mL of water) drop wise and stirred for 15 min. Separated
the both layers, the aqueous layer was extracted with dichloromethane (2x250 mL) and the
25 combined organic layer was washed with sodium hydroxide solution (40 g in 400 mL ) and
brine solution. The organic layer was distilled off completely, and co distilled with methanol
(50 mL) to get the crude compound. The obtained compound was charged to water (300 mL)
and stirred for 30 min below to 60 °C, and stirred for 2 hr at 20-30°C. Filtered the obtained
compound and washed with water (100 mL), dried to get the title compound.
30 Yield: 80.5 g.
20
Example-22: Preparation of Compound of formula-7.
A round bottom flask was charged with compound of formula-2 (300 g), CuCN (191.9 g) and
KI ( 355.7 g) in DMF ( 600 mL) at 25-30°C, heated to 145-150°C and stirred for 24 hr.
Cooled the reaction mass to 20-30°C, charged with water ( 3 L) and ethyl acetate ( 1.4 L) and
stirred for 30 min. Filtered the solid and washed with ethyl acetate 5 (300 mL) and separated
the layers. The aqueous layer was extracted with ethyl acetate (2x600 mL), the combined
organic layer was washed with brine solution (1 L) and evaporated the organic layer, co
distilled with toluene (150 mL) to get the crude compound. An other round bottom flask was
charged with dichloromethane (750 mL), (S)-(-)-2-methyl -CBS-oxazaborolidine (92.9 g,
10 1M solution) at -5 to 5°C, followed by addition of borane-DMS complex (160 g, 10M) over
a period of 1 hr. The reaction mixture further cooled to -15 to -25°C, charged a solution of
the above crude compound in dichloromethane (750 mL) and stirred for 3 hr. The reaction
mixture was quenched with methanol (300 mL) at below 0°C, gradually allowed to 20-30°C
charged with water (1.5 L) and stirred for 30 min. Separated the organic layer, the aqueous
15 layer was extracted with dichlorometane (2x600 mL). The combined organic layer was dried
over anhydrous sodium sulphate, evaporated the organic layer to get the crude compound.
The crude compound was charged with methanol (1.2 L), sodium bicarbonate (144 g),
hydroxyl amine hydrochloride (119 g) at 20-30°C and stirred for 10 min, heated to 65-75°C
and stirred for 14 hr . Cooled the reaction mixture to 20-30°C, filtered the reaction mixture
20 washed with methanol (300 mL) and the filtrate was distilled off completely, co distilled with
toluene (2x150 mL) to remove traces of methanol to get the crude compound. An other round
bottom flask was charged with compound of formula-6 (117 g), dimethyl formamide (450
mL), hydroxybenzotriazole (92.6 g), triethylamine (69.17 g) and N-(3-dimethyl amino
propyl)-N'-ethylcarbodiimide hydrochloride (EDC) (130.8 g) at 25-35°C and stirred for 6 hr.
25 To the reaction mixture a solution of the above crude compound in dimethyl formamide (450
mL) was added and stirred for 6 hr. Cooled the reaction mixture to 15-25°C, charged sodium
bicarbonate solution (270 g in 4.5 L of water) and stirred for 4 hr at 20-30°C. Filtered the
obtained solid, washed with water (300 mL) and dried to get the crude compound. The
obtained compound was suspended in toluene (900 mL) and heated to 110-120°C, stirred for
30 14 hr. Cooled the reaction mixture to 25-35°C, charged n-heptane (900 mL) and sodium
21
hydroxide solution (36 g in 1.8 L of water) and stirred for 2 hr. Filtered the obtained solid,
washed with water (600 mL) and dried to get the title compound.
Yield: 161 g; Chiral purity by HPLC: S-isomer 99.8 %; R-isomer :< 0.2 %;
Example-23: Preparation of compound of formula-B.
A round bottom flask was charged with compound of formula-7 (100 5 g), dichloromethane (3
L) and DMF (10 mL) at 25-35°C and stirred for 10 min. Cooled the reaction mixture to -5 -
5°C, slowly added a solution of thionyl chloride (50 mL ) in dichloromethane (500 mL) and
stirred at 25-30°C for 4 hr. The reaction mixture was cooled to 0-10°C, quenched with 10%
sodium carbonate solution (200 g in 2 L of water) and separated the organic layer. The
10 aqueous layer was extracted with dichloromethane (2x500 mL) and the combined organic
layer was washed with sodium bicarbonate solution (100 g in 1 L of water) and dried the
organic layer. The organic layer was distilled off upto 80% of the reaction mass below 50°C,
charged with ethanolamine (500 mL) and the solution was heated to 55-65°C stirred for 8 hr.
The reaction mixture gradually cooled to 25-35°C, quenched with water (3 L) and stirred for
15 2 hr. Filtered the obtained solid, washed with water (300 mL) to obtain the wet Ozanimod
compound. A round bottom flask was charged with the wet Ozanimod compound, di-paratoluoyl-
L-tartaric acid (124 g) in a mixture of 10% methanol in acetonitrile (1 L) at 25-35°C
and stirred for 2 hr. Filtered the obtained solid and washed with acetonitrile (200 mL) to get
the di-para-toluoyl-L-tartaric acid salt of Ozanimod.
20 Yield: 155 g ; Chiral purity by HPLC: S-isomer > 99 %
Example-24: Preparation of compound of formula-1a.
A round bottom flask was charged with compound of formula-B (100.0 g), methanol (500
mL) and added slowly 2N methanol.HCl (500.0 mL) and stirred for 3 hr at 25-35°C. Filtered
the obtained solid and washed with MTBE (200 mL) to get the crude compound. The
25 obtained ozanimod hydrochloride was charged with methanol (750 mL) and heated to 65-75°
stirred for 1 hr. Charged carbon (5 g) and stirred for 30 min at same temperature, filtered
through hyflow and washed with methanol (100 mL). Methanol was distilled off half from
the filtrate solution under vacuum below 55°C and stirred for 2 hr at 25-35°C. Filtered the
obtained compound washed with MTBE (100 mL) and dried to get the title compound.
30 Yield: 182 g ; HPLC >99.5 %; Chiral purity> 99.9 %. The PXRD complies with figure-2. ,CLAIMS:1. A process for the preparation of Ozanimod hydrochloride and its pharmaceutiaclly
acceptable salt, the compound of formula-1a.
5 Formula-1a
comprising of: a)reacting the compound of formula-2 with suitable reagent, suitable solvent
to provide compound of formula-3,
Formula-2 Formula-3
10 b)reducing the compound of formula-3 with a suitable reagent, solvent to provide compound
of formula-4,
Formula-4 Formula-5
c)reacting the compound obtained in step-b) with suitable reagent in presence of suitable
15 solvent, base to provide compound of formula-5,
d)reacting the compound obtained in step-c) with compound of formula -6
Formula-6
23
in presence of suitable reagent, solvent to provide compound of formula-7,
Formula-7
e)reacting the compound obtained in step-d) with a suitable reagent, solvent to provide
compound of formula-1(S-isomer of 5 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.
10 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,
chlorinated, water, alcohol and mixture thereof; 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-
15 CBS-oxaborolidine, BH3-DMS, (R)-2-methyl-CBS-oxaborolidine, BH3-DMS, ruthinium
catalyst, R-RuBinap, R-diphenyl prolinol, sodium boro hydride, sodium triacetoxyboro
hydride, LAH, lithium tri-tert-butoxy aluminum hydride, lithium triethylborohydride,
potassium triethylborohydride, lithium borohydride, potassium borohydride, H2 (g) under
Pd/C and mixture thereof; organic base;
20 Wherein in step-c) the suitable reagent is salt of hydroxylamine; such as hydrochloride,
sulphate; organic base, inorganic base; Wherein in step-d) the suitable reagent is EDC HCl,
HOBt , TBAB, HATU, TBTU, CDI, DCC, Pivolylchloride, methylchloroformate,
ethylchloroformate, phenylchloroformate; organic base, inorganic base; Wherein in step-e)
the suitable reagent is selected from methanesulphonyl chloride, p-toluene sulphonyl chloride,
25 ammonia, ethanolamine hydrochloride or ethanolamine; organic base such as triethylamine,
diisopropyl ethyl amine, diisopropyl amine, pyridine; wherein in step-f) to g) The suitable
acid is selected from HCl, HBr, tartaric acid, dipara toluoyl tartaric acid, fumaric acid,
24
methane sulfonic acid, succinic acid, oxalic acid, PTSA salt; HCl in alcohol solvents, HCl in
ether solvent, HCl in ethyl acetate;
3.A process for the preparation of Ozanimod hydrochloride of compound of formula-1a,
comprising of:
a)reacting the compound of formula-2 with CuCN in DMF to provide 5 compound of formula-
3,
Formula-2 Formula-3 Formula-4
b) reducing the compound obtained in step-a) with S-methyl-CBS, boran-DMS in dichloro
10 methane to provide compound of 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,
Formula-5 Formula-6 Formula-7
15 d) reacting the compound obtained in step-c) with compound of formula-6,
in presence of EDC.HCl, HOBt triethylamine in DMF solvent to provide compound of
formula-7,
e) reacting the compound obtained in step-d) with thionylchloride in dichloromethane, the
isolated compound further reacting with ethanolamine to provide Ozanimod,
20 f) treating the wet Ozanimod obtained in step-e) with di-paratoluoyl-L-tartaric acid in a
mixture of acetonitrile, methanol to get ozanimod di paratoluoyl L-tartaric acid salt,
g)treating the compound obtained in step-f) with methanolic HCl to obtained the compound
of formula-1a,
25
h) purifying the compound of formula-1a in methanol.
4. A compound of formula-B (ozanimod di-para-toluoyl-L-tartaric acid).
Formula-B
5.A process for preparation of Ozanimod hydrochloride 5 comprising of ,
a)treating Ozanimod with dipara toluoyl -L- tartaric acid in acetonitrile, methanol,
b)isolating Ozanimod diparatoluoyltartrate salt,
c)treating the compound obtained step-b) with methanol HCl,
d)isolating Ozanimod hydrochloride as pure compound .
10 6.A process for the purification of Ozanimod hydrochloride comprising of
a) suspending Ozanimod hydrochloride in methanol,
b) stirring the solution at 65-75°C for 1 hr,
c) isolating the ozanimod hydrochloride as pure compound.
7.The ozanimod hydrochloride obtained according to any of preceding claims having purity
15 > 95%, preferably > 99.9 % by HPLC.
8. The ozanimod hydrochloride obtained according to any of preceding claims having purity
> 95%, preferably > 99.9 % by chiral HPLC.
9. The ozanimod hydrochloride compound of formula-1a obtained according to any
preceding claims having particle size of D(0.9) < 200 ìm , preferably D(0.9) < 150 ìm.