DESC:IMPROVED PROCESS FOR THE PREPARATION OF SIPONIMOD CRYSTALLINE FORM S2
FIELD OF INVENTION
The present application relates to an improved process for the preparation of Siponimod crystalline Form S2.

BACKGROUND OF INVENTION
The drug compound having the adopted name Siponimod, has a chemical name (E)-1-(4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)-imino)ethyl)-2-ethylbenzyl)-azetidine-3-carboxy lic acid, and is represented by the structure of formula I.


Siponimod is a selective sphingosine-1-phosphate receptor modulator drug and is approved as Siponimod fumaric acid co-crystal for the treatment of secondary progressive multiple sclerosis.
Siponimod, its synthetic process and its pharmaceutical compositions are described in US patent No. 7,939,519 B2 (US ‘519). Siponimod hemifumarate salt and its pharmaceutical compositions are described in US patent application No. 20150175536 A1 (US ‘536).
US patent application No. 2020/0399213 A1 (US ‘213) describes various Siponimod solid forms such as Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, or Form I. However, synthesis of such solid forms entails prolonged times. For example, synthesis of Form I involves stirring the solution of Siponimod for about four days and evaporating the solution over a period of about 14 days.
Indian patent application No. 201941007652 (IN '652) describes Siponimod solid state forms such as Form S, Form S1 and Form S2. Synthesis of Form S2 involves multiple stages including Siponimod fumaric acid co-crystal preparation and then treating the said co-crystal with a base followed by isolation of Form S2.
There remains a need in the pharmaceutical industry to provide cost-effective, commercially viable and advantageous process for preparation of Siponimod crystalline Form S2.

SUMMARY OF INVENTION
First aspect of the present application provides a process for the preparation of Siponimod crystalline Form S2, comprising:
a) reacting (E)-4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethyl benzaldehyde and azetidine-3-carboxylic acid in presence of sodium borohydride and acetic acid,
b) crystallizing crude Siponimod in a mixture of acetone and acetonitrile.
Second aspect of the present application provides a process for preparation of crystalline form of Siponimod hemi-fumarate comprising reacting Siponimod with fumaric acid in presence of a mixture of water and a ketone solvent.

DETAILED DESCRIPTION OF INVENTION
First aspect of the present application provides a process for the preparation of Siponimod crystalline Form S2, comprising:
a) reacting (E)-4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethyl benzaldehyde and azetidine-3-carboxylic acid in presence of sodium borohydride and acetic acid,
b) crystallizing crude Siponimod in a mixture of acetone and acetonitrile.
One embodiment of the present application provides the reaction between (E)-4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethyl benzaldehyde and azetidine-3-carboxylic acid in presence of sodium borohydride and acetic acid.
Another embodiment of the present application provides crystallization of crude Siponimod using mixture of acetone & acetonitrile to prepare pure crystalline Form S2 of Siponimod. Crystallization may be carried out by a process comprising stirring a reaction mixture of Siponimod in a mixture of acetone & acetonitrile for about 1 hour to about 24 hours at a temperature of about 15°C to about boiling point of the mixture of the solvents. Specifically, the reaction mixture of step (b) may be stirred for about 18 hours at about 25°C. The ratio of acetone: acetonitrile in a mixture of acetone & acetonitrile may be from about 5:95 to about 95:5.
Yet another embodiment of the present application provides isolation of the precipitated material obtained in step-b) by using techniques known in the art e.g. evaporation, distillation, filtration of isolated solid and the like. The solid may be washed with water solvent. Suitable temperatures for isolation may be less than about 25°C, less than about 10 °C, or any other suitable temperatures. Filtration can be achieved by any means known in the art. The solid may optionally be dried. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80°C and more specifically less than about 60°C and most specifically at about 40°C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.
Second aspect of the present application provides a process for preparation of crystalline form of Siponimod hemi-fumarate comprising reacting Siponimod with fumaric acid in presence of a mixture of water and a ketone solvent.
One embodiment of the present application provides the ketone solvent may be selected from acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclopentanone and the like. Specifically, the ketone solvent is acetone.
Another embodiment of the present application provides isolation of crystalline form of Siponimod hemi-fumarate by using techniques known in the art e.g. evaporation, distillation, filtration of isolated solid and the like. Suitable temperatures for isolation may be about 25°C or any other suitable temperatures. Filtration can be achieved by any means known in the art. The solid may optionally be dried. The drying may be carried out at atmospheric pressure or above, or under reduced pressures, specifically at temperatures less than about 80°C and more specifically less than about 60°C and most specifically at about 40°C. The drying may be carried out for any time period required for obtaining a desired product quality, such as from about 5 minutes to about 24 hours, or longer.

DEFINITIONS
The following definitions are used in connection with the present invention unless the context indicates otherwise.
The term "about" when used in the present application preceding a number and referring to it, is meant to designate any value which lies within the range of ±10%, preferably within a range of ±5%, more preferably within a range of ±2%, still more preferably within a range of ±1 % of its value. For example, "about 10" should be construed as meaning within the range of 9 to 11, preferably within the range of 9.5 to 10.5, more preferably within the range of 9.8 to 10.2, and still more preferably within the range of 9.9 to 10.1 at they modify as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Reasonable variations of the described procedures are intended to be within the scope of the present invention. While particular aspects of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.

EXAMPLES
Example 1: Preparation of Siponimod crystalline form S2

A solution of sodium borohydride (13.15 g) in dichloromethane (1 L). Acetic acid (84 g) was added to the above solution slowly over a period of 20 minutes. The reaction mass was stirred for 3-5 hours. Azetidine-3-carboxylic acid (46.9 grams) was added to the above solution. A solution of (E)-4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzaldehyde (100 grams) in methylene chloride (200 ml) was added to the above solution. The reaction mixture was stirred for about 9 hours. About half of the reaction mass was quenched with water (50 ml). The layers were separated and the organic layer was distilled off completely under reduced pressure. Water (500 ml) and ethyl acetate (750 ml) were added to the reaction mixture and stirred for 10-15 minutes. The layers were separated and the organic layer was washed with 3% aqueous sodium bicarbonate solution followed by 3% aqueous brine solution. The layers were separated and the organic layer was distilled off completely under reduced pressure. Acetone was added to the residue and distilled under reduced pressure. Acetone and acetonitrile in 1:1 ratio were added to the residue and stirred for 10 minutes. Crystalline form S2 of Siponimod seed material was added the reaction mass and stirred for about 18 hours. The precipitated solid was filtered, washed with water and then dried under vacuum to get the title compound.

Yield: 45 grams

Example 2: Preparation of crystalline form of Siponimod hemi-fumarate

Fumaric acid (1.123 grams) was added to a mixture of aqueous acetone (50 ml). Filtered the reaction mixture through buchner funnel and washed with aqueous acetone (10 ml). Crystalline form A seed material was added to the above reaction mixture. Siponimod (5 grams) was added to the mixture of acetone (75 ml) and water (1.5 ml). Filtered the reaction mass through buchner funnel and washed with aqueous acetone (10 ml). The obtained Siponimod solution was combined with above fumaric acid solution. The reaction mixture was cooled to 25-30°C and stirred for 6 hours. The precipitated solid was filtered, washed with acetone and then dried under vacuum to get the title compound.

Yield: 3.55 grams
,CLAIMS:1. A process for the preparation of Siponimod crystalline Form S2, comprising:
a) reacting (E)-4-(1-(((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethyl benzaldehyde and azetidine-3-carboxylic acid in presence of sodium borohydride and acetic acid,
b) crystallizing crude Siponimod in a mixture of acetone and acetonitrile.

2. The process as claimed in claim 1, wherein the ratio of acetone and acetonitrile is between 5:95 to 95:5.

3. The process as claimed in claim 1, wherein the ratio of acetone and acetonitrile is between 1:1.

4. A process for preparation of crystalline form of Siponimod hemi-fumarate comprising reacting Siponimod with fumaric acid in presence of a mixture of water and a ketone solvent.

5. The process as claimed in claim 4, wherein the ketone solvent is selected from a group consisting of acetone, methyl ethyl ketone, methyl isobutyl ketone and cyclopentanone.

6. The process as claimed in claim 5, wherein the ketone solvent is acetone.