DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No.
IN 202041020866 filed on May 18, 2020.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of ozanimod.
BACKGROUND OF THE INVENTION
Ozanimod, 5-[3-[(1S)-2,3-dihydro-1-[(2-hydroxyethyl)amino]-1H-inden-4-yl]-1,2,4-oxadiazol-5-yl]-2-(1-
methylethoxy)benzonitrile, having the structure shown in below is an immunomodulatory drug.
Ozanimod is reported in US 8,796,318 and US 8,481,573.
OBJECT AND SUMMARY OF THE INVENTION
The principle object of the present invention is to provide an improved process for the preparation of
ozanimod.
Another object of the present invention is to provide a process for the preparation of (S)-1-hydroxy-2,3-
dihydro-1H-indene-4-carbonitrile of formula II, which is a key intermediate in the preparation of
Ozanimod.
In one aspect, the present invention provides a process for the preparation of (S)-1-hydroxy-2,3-dihydro-
1H-indene-4-carbonitrile of formula II comprising the steps of:
a) reacting 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile of formula I with DIP chloride; and
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b) isolating (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile of formula II.
DETAILED DECSRIPTION OF THE INVENTION
The principle object of the present invention is to provide an improved process for the preparation of
ozanimod.
Another object of the present invention is to provide a process for the preparation of (S)-1-hydroxy-2,3-
dihydro-1H-indene-4-carbonitrile of formula II, which is a key intermediate in the preparation of
Ozanimod.
The schematic representation of present invention and its further conversion into Ozanimod is depicted in
Scheme-1.
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In one aspect, the present invention provides a process for the preparation of (S)-1-hydroxy-2,3-dihydro-
1H-indene-4-carbonitrile of formula II comprising the steps of:
a) reacting 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile of formula I with DIP chloride; and
b) isolating (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile of formula II.
In one embodiment, 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile of formula I is reacted with DIP chloride
((-)-B-Chlorodiisopinocampheylborane) and isolated (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile
of formula II. The above reaction of formula I with DIP chloride is carried out in presence of a suitable
solvent includes, but not limited to ether solvents such as methyl tertiary butyl ether, diisopropyl ether, 1,4-
dioxane, ethyl tertiary butyl ether, tetrahydrofuran; alkane solvents such as toluene, heptane, hexane;
chlorinated solvents such as dichloromethane, dichloroethane; preferably tetrahydrofuran.
In an another embodiment, (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile of formula II may be
prepared by reacting 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile of formula I with the (R)-(+)-2-Methyl-
CBS-oxazaborolidine; RuCl(p-cymene) (R,R)-Ts-DPEN or RuCl(pcymene) (S,S)-Ts-DPEN.
Next, the isolation of the above resulting (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile of formula
II may be carried out by methods well known in the art, for example, by filtering the reaction mixture or by
distillation to obtain a solid. The solid may be further processed by drying to obtain (S)-1-hydroxy-2,3-
dihydro-1H-indene-4-carbonitrile of formula II.
According to the present invention, (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile of formula II
results into higher yield as there are less number of steps in the sequence of preparing (S)-isomer
intermediate, which certainly results into higher yield.
In one more embodiment, the resulting (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile intermediate
of formula II may further converted into Ozanimod as per the processes known in the art.
In another embodiment, the resulting (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile intermediate of
formula II may further converted into Ozanimod as per the process known US 9388147.
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In view of the above description and the examples below, one of the ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.
Examples:
Example: 1 To a stirred solution of 10 g ( 0.063 m) of 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile in 50 ml of tetrahydrofuran was added 51 g (1.5 m.eq, 60% in hexane) of (-)-DIP chloride at -20 to -25°C dropwise over a period of 60 minutes and further stirred for another 30 minutes at same temperature and then allowed to raise to ambient temperature (25 – 30°C) and stirred for 120 minutes. After completion of the reaction, the reaction was quenched with diethanolamine solution (10g in 100 ml water) at 25 – 35 °C. 50 ml of methylene chloride was charged to the reaction mixture, stirred for 30 minutes and separated the organic layer. The organic layer was washed with 30 ml of 10 % sodium chloride solution. Distilled the organic layer and 100 of hexane was added to the residue, stirred and filtered. The filtrate was concentrated and cooled and thus obtained solid was filtered to isolate 6.5 g (64.3%) of (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile as a off-white powder.
DIP Chloride: (-)-B-Chlorodiisopinocampheylborane (60% in Hexane)
Example: 2 To a stirred solution of 51 g of (1.5 m.eq, 60% in hexane) DIP chloride was added a solution of 10 g of (0.063 m) 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile in 50 ml of tetrahydrofuran at -20 to -25 °C dropwise over a period of 60 minutes and further stirred for another 30 minutes at same temperature and then allowed to raise to ambient temperature (25 – 30°C) and stirred for 120 minutes. After completion of the reaction, the reaction was quenched with diethanolamine solution (10g in 100 ml Water) at 25 – 35°C. 50 ml of methylene chloride was charged to the reaction mixture stirred for 30 minutes and separated the organic layer. The organic layer was washed with 30 ml of 10 % sodium chloride solution. Distilled the organic layer to give a residue. To the resulting residue was added 100 ml of hexane, stirred and filtered. The filtrate is concentrated and cooled, thus obtained solids was filtered to isolate 6.8 g(67.3%) of (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile as a off-white powder. ,CLAIMS:1. A process for the preparation of (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile of formula II
comprising the steps of:
a) reacting 1-oxo-2,3-dihydro-1H-indene-4-carbonitrile of formula I with DIP chloride; and
b) isolating (S)-1-hydroxy-2,3-dihydro-1H-indene-4-carbonitrile of formula II.
2. The process as claimed in claim 1, wherein the reaction is carried out in presence of a solvent.
3. The process as claimed in claim 2, wherein the solvent is selected from ether solvent and alkane
solvent.
4. The process as claimed in claim 3, wherein the ether solvent is selected from methyl tertiary butyl
ether, diisopropyl ether, 1,4-dioxane, ethyl tertiary butyl ether, tetrahydrofuran.
5. The process as claimed in claim 3, wherein the alkane solvent is selected from toluene, heptane,
hexane; chlorinated solvents such as dichloromethane, dichloroethane.
6. The process as claimed in claim 1, wherein the (S)-1-hydroxy-2,3-dihydro-1H-indene-4-
carbonitrile of formula II is further converted into Ozanimod.