DESC:The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present application relates to process for preparation of Siponimod its intermediates, hemifumarate salt and pharmaceutical compositions thereof.

BACKGROUND OF THE 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-carboxylic acid, and is represented by the structure of formula I.

Siponimod is an investigational selective sphingosine-1-phosphate receptor modulator drug currently in phase III clinical trials for the therapy of secondary progressive multiple sclerosis.
Siponimod base, 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).
The process described in US ‘519 is schematically represented below:

The US ‘536 describes crystalline forms of Siponimod hemifumarate salt and their pharmaceutical compositions.
There remains a need to provide commercially viable and advantageous processes for preparation of Siponimod, its salts and polymorphic forms of Siponimod hemifumarate.

SUMMARY OF THE INVENTION
The present application generally relates to process for preparation of Siponimod, its intermediates and pharmaceutically acceptable salts thereof.
In a first aspect the present application provides a compound of Formula V and its salts

wherein R1 and R2 each independently represents hydrogen, alkyl, halogen, nitro or R1 and R2 together form a 5 to 7 membered ring.
In a second aspect the present application provides a process for preparation of compound of formula V, comprising, reacting a compound of formula VI with a compound of formula VII in presence of a suitable base.

Where in X represents a hydrogen atom or a halogen atom; R1 and R2 each independently represents hydrogen, alkyl, halogen, nitro or R1 and R2 together form a 5 to 7 membered ring.
In a third aspect the present application provides use of compound of formula V or a salt thereof, prepared by the process described in the present application, for the preparation of Siponimod and its slats.
In a fourth aspect the present application provides a process for preparation of Siponimod of formula I, comprising:
a) reacting a compound of formula VI with a compound of formula VII in presence of a suitable base to get a compound of formula V

b) reacting the compound of formula V with a suitable amine to form a compound of formula IV

c) reacting the compound of formula IV with 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one of formula XII to form a compound of formula III

d) oxidizing the compound of formula III using a suitable oxidizing agent to form a compound of formula II

e) reacting the compound of formula II with azetidine-3-carboxylic acid to form Siponimod of formula I.

f) Optionally, converting Siponimod into its pharmaceutically acceptable salt.
In a fifth aspect the present application provides a process for preparation of compound of formula V-A, comprising:
a) Reacting a compound of formula VIII with cyclohexanone to form a compound of formula VII

b) Hydrogenating the compound of formula VII in presence of suitable catalyst to form a compound of formula VI

c) Reducing the compound of formula VI using a suitable reducing agent to form a compound of formula V

d) reacting the compound of formula V with a brominating agent to form a compound of formula V-A

e) reacting a compound of formula V-A with 2-hydroxyisoindoline-1,3-dione in presence of a suitable base to get a compound of formula IV

In a sixth aspect the present application provides a process for preparation of Siponimod hemifumarate salt.
In the seventh aspect, the present application provides amorphous form of Siponimod hemifumarate.
In the eighth aspect, the present application provides amorphous form of Siponimod hemifumarate characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figure 1.
In the ninth aspect, the present application provides a process for preparing amorphous form of Siponimod hemifumarate which comprises;
a) providing a solution of Siponimod hemifumarate in a solvent or a mixture of two or more solvents;
b) removing solvent from the solution of Siponimod hemifumarate obtained in step a); and
c) recovering amorphous form of Siponimod hemifumarate.
In the tenth aspect, the present application provides a process for preparing crystalline form A of Siponimod hemifumarate, comprising:
a) providing a solution of Siponimod hemifumarate in a solvent or a mixture of two or more solvents;
b) adding an anti-solvent the solution of Siponimod hemifumarate obtained in step a); and
c) isolating crystalline form A of Siponimod hemifumarate.
In the eleventh aspect, the present application provides pharmaceutical composition comprising amorphous Siponimod hemifumarate and one or more pharmaceutically acceptable excipients.
In the twelfth aspect, the present application provides pharmaceutical composition comprising Siponimod or its pharmaceutically acceptable salt prepared by the processes described in the present application and one or more pharmaceutically acceptable excipients.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is powder X-ray power diffraction ("PXRD") pattern of an amorphous form of Siponimod hemifumarate prepared according to Example 10.

DETAILED DESCRITPION
The present application generally relates process for preparation of Siponimod, its intermediates and pharmaceutically acceptable salts thereof.
In a first aspect the present application provides a compound of Formula V and its salts

wherein R1 and R2 each independently represents hydrogen, alkyl, halogen, nitro or R1 and R2 together form a 4 to 7 membered ring.
In a second aspect the present application provides a process for preparation of compound of formula V, comprising, reacting a compound of formula VI with a compound of formula VII in presence of a suitable base.

Where in X represents a hydrogen or hydroxy or a halogen atom; R1 and R2 each independently represents hydrogen, alkyl, halogen, nitro or R1 and R2 together form a 5 to 7 membered ring.
The process involves reaction of compound of formula VI with a compound of formula VII in presence of a suitable base such as triethylamine or diisopropyl ethylamine, and a suitable solvent such as N,N-dimethylformamide or N,N-dimethylacetamide. The compound of formula VI can be prepared by the process described in this application or any of the processes described in the art.
The compound of formula VI, the solvent, the base and he compound of formula VII are mixed and the resulted mixture may be stirred for about 10 minutes to about 10 hours at a temperature of about 30 °C to about 100 °C.
After completion of the reaction the reaction mixture is added to water and the resultant suspension may be filtered or the mixture may be extracted with a suitable water immiscible solvent such as dichloromethane and the organic layer is concentrated to obtain the compound of formula V.
The obtained crude compound may be purified using known purification techniques such as slurrying and recrystallization using a suitable solvent to get pure compound of formula V.
In a third aspect the present application provides use of compound of formula V or a salt thereof, prepared by the process described in the present application, in the preparation of Siponimod and its slats.
In a fourth aspect the present application provides a process for preparation of Siponimod of formula I, comprising:
a) reacting a compound of formula VI with a compound of formula VII in presence of a suitable base to get a compound of formula V

b) reacting the compound of formula V with a suitable amine to form a compound of formula IV

c) reacting the compound of formula IV with 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one of formula XII to form a compound of formula III

d) oxidizing the compound of formula III using a suitable oxidizing agent to form a compound of formula II

e) reacting the compound of formula II with azetidine-3-carboxylic acid to form Siponimod of formula I.

f) optionally, converting Siponimod into its pharmaceutically acceptable salt.
The step (a) of the process involves reaction of compound of formula VI with a compound of formula VII in presence of a suitable base such as triethylamine or diisopropyl ethylamine, and a suitable solvent such as N,N-dimethylformamide or N,N-dimethylacetamide. The compound of formula VI can be prepared by the process described in this application or any of the processes described in the art.
The compound of formula VI, the solvent, the base and he compound of formula VII are mixed and the resulted mixture may be stirred for about 10 minutes to about 10 hours at a temperature of about 30 °C to about 100 °C.
After completion of the reaction the reaction mixture is added to water and the resultant suspension may be filtered or the mixture may be extracted with a suitable water immiscible solvent such as dichloromethane and the organic layer is concentrated to obtain the compound of formula V.
The obtained crude compound may be purified using known purification techniques such as slurrying and recrystallization using a suitable solvent to get pure compound of formula V.
The step (b) involves reaction of the compound of formula V with a suitable amine such as n-Butylamine, hydroxylamine and hydrazine in presence of a suitable solvent such as methanol, ethanol, isopropanol, acetone, THF and the like to form the compound of formula IV.
The compound of formula V, the solvent, and a suitable amine are mixed and the resulted mixture may be stirred for about 10 minutes to about 10 hours at a temperature of about 0 °C to about 50 °C.
After completion of the reaction the reaction mixture may be concentrated and the resulted crude may be purified using a suitable acid such as hydrochloric acid.
The step (c) of the process involves reaction of compound of formula IV with a compound of formula XII in presence of aa suitable solvent such as methanol, ethanol, isopropanol, THF and the like. The compound of formula XII can be prepared by the process described in this application or any of the processes described in the art.
The compound of formula IV, the solvent, and the compound of formula XII are mixed and the resulted mixture may be stirred for about 10 minutes to about 20 hours at a temperature of about 30 °C to about 100 °C.
After completion of the reaction the reaction mixture may be concentrated and the resulted crude compound of formula III may be purified using known purification techniques such as slurrying and/or recrystallization using a suitable solvent or using silica gel column chromatography.
The step (d) involves oxidation of the compound of formula III using a suitable oxidizing agent such as MnO2, CrO3, K2CrO7, TiO2 and KMnO4 and a suitable solvent such as heptane, n-hexane, toluene and the like to form a compound of formula II.
The compound of formula III, the solvent, and the oxidizing agent are mixed and the resulted mixture may be stirred for about 10 minutes to about 20 hours at a temperature of about 30 °C to about 120 °C.
After completion of the reaction the reaction mixture may be filtered to remove the oxidizing agent and other inorganic materials and the filtrate may be concentrated and the resulted crude compound of formula II may be purified using known purification techniques such as slurrying and/or recrystallization using a suitable solvent or using silica gel column chromatography.
The step (e) involves reaction of compound of formula II with azetidine-3-carboxylic acid using a suitable solvent such as methanol, ethanol, isopropanol and a suitable acid such as acetic acid and a suitable reducing agent such as Sodium cyano borohydride to form Siponimod of formula I.
The compound of formula II, the solvent, azetidine-3-carboxylic acid, acetic acid and Sodium cyano borohydride are mixed and the resulted mixture may be stirred for about 10 minutes to about 5 hours at a temperature of about 0 °C to about 50 °C.
After completion of the reaction the reaction mixture may be concentrated and the resulted crude is added to water and the mixture is extracted with a suitable solvent such as ethylacetate and the solvent layer may be concentrated to isolate the crude Siponimod of formula I. The crude Siponimod base may be purified using known purification techniques such as slurrying and/or recrystallization using a suitable solvent or using silica gel column chromatography.
The Siponimod base may be converted into a suitable acid addition salt such as Siponimod fumarate salt. The Siponimod base, a suitable solvent such as ethanol and fumaric acid are mixed and the resulted mixture may be stirred for about 10 minutes to about 3 hours at a temperature of about 0 °C to about 50 °C. The resulted mass may be filtered and the filtrate may be concentrated to obtain crude Siponimod fumarate salt. The crude salt may be purified by slurrying in a suitable solvent such as acetonitrile and acetone.
In a fifth aspect the present application provides a process for preparation of compound of formula V-A, comprising:
a) reacting a compound of formula XI with cyclohexanone to form a compound of formula VII

b) hydrogenating the compound of formula VII in presence of suitable catalyst to form a compound of formula VI

c) reducing the compound of formula VI using a suitable reducing agent to form a compound of formula V

d) reacting the compound of formula V with a brominating agent to form a compound of formula V-A

e) reacting a compound of formula V-A with 2-hydroxyisoindoline-1,3-dione in presence of a suitable base to get a compound of formula IV

The step (a) of the process involves reaction of a compound of formula XI with cyclohexanone in presence of a suitable metal alkoxide such as sodium tert-butoxide or lithium tert-butoxide, a suitable catalyst such as tris-(dibenzylidene acetone)-dipalladium and X-Phos and a suitable solvent such as 1,4-dioxane to form a compound of formula X.
The compound of formula XI, Cyclohexanone, 1,4-dioxane and Tosyl hydrazide are mixed and the resulted mixture may be stirred for about 5 minutes to about 1 hour. Lithium tert.-butoxide, tris-(dibenzylidene acetone)-dipalladium and X-Phos are added to the reaction mixture and the resulted mixture may be stirred for about 30 minutes to about 20 hours at a temperature of about 30 °C to about 150 °C.
After completion of the reaction the mixture may be filtered and the filtrate may be concentrated. The residue may be added to a suitable solvent such as ethylacetate and the solvent layer may be washed to remove the impurities. The solvent layer may be concentrated to get the compound of formula X.
The step (b) process involves hydrogenation of the compound of formula X using hydrogen gas and a suitable catalyst such Palladium or Nickel and a suitable solvent such as methanol to form a compound of formula IX.
The compound of formula X, solvent and the catalyst are mixed in an autoclave. To the vessel hydrogen gas is filled upto about 100 psi and resulting mixture is hydrogenated at about 1 hour to about 20 hours at a temperature of about 0 °C to about 50 °C.
After completion of the reaction the mixture may be filtered and the filtrate containing the compound of formula IX may be concentrated or may be used directly in the next step.
The step (c) involves reduction of the compound of formula IX using a suitable reducing agent such as LiAlH4 or NaBH4 and a suitable solvent such as tetrahydrofuran to form a compound of formula VIII.
The compound of formula IX, solvent and the reducing agent are mixed and the resultant mixture is stirred for about 10 minutes to about 3 hours at a temperature of about 0 °C to about 50 °C.
After completion of the reaction the mixture may be quenched with water and the resultant solution may be extracted with a suitable solvent such as ethylacetate. The solvent layer may be concentrated to get crude compound of formula VIII. The crude may be purified using known purification techniques such as slurrying and/or recrystallization using a suitable solvent or using silica gel column chromatography.
The step (d) involves bromination of the compound of formula VIII using a suitable brominating agent such as PBr3 or POBr3 and a suitable solvent such as dichloromethane to form a compound f formula VI-A.
The compound of formula VIII, solvent and the brominating agent are mixed and the resultant mixture is stirred for about 10 minutes to about 5 hours at a temperature of about 0 °C to about 30 °C.
After completion of the reaction the mixture may be quenched with water and the resultant solution may be extracted with a suitable solvent such as dichloromethane. The solvent layer may be concentrated to get the compound of formula VI-A.
The step (e) process involves reaction of compound of formula VI-A with 2-hydroxyisoindoline-1,3-dione(compound of formula VII-A)in presence of a suitable base such as triethylamine or diisopropyl ethylamine, and a suitable solvent such as N,N-dimethylformamide or N,N-dimethylacetamide.
The compound of formula VI-A, the solvent, the base and the compound of formula VII-A are mixed and the resulted mixture may be stirred for about 10 minutes to about 10 hours at a temperature of about 30 °C to about 100 °C.
After completion of the reaction the reaction mixture is added to water and the resultant suspension may be filtered or the mixture may be extracted with a suitable water immiscible solvent such as dichloromethane and the organic layer is concentrated to obtain the compound of formula V-A.
In another aspect the present application provides use of compound of formula V-A, prepared by the process described in the present application, in the preparation of Siponimod and its slats.
In another aspect the present application provides a process for preparation of Siponimod hemifumarate. The Siponimod base may be converted into a suitable acid addition salt such as Siponimod hemifumarate salt. The Siponimod base, a suitable solvent such as ethanol and fumaric acid are mixed and the resulted mixture may be stirred for about 10 minutes to about 3 hours at a temperature of about 0 °C to about 50 °C. The resulted mass may be filtered and the filtrate may be concentrated to obtain crude Siponimod hemifumarate salt. The crude salt may be purified by slurrying in a suitable solvent such as acetonitrile or acetone.
In another aspect the present application provides an alternate process for preparation of compound of formula VIII as shown below:

In another aspect, the present application provides amorphous form of Siponimod hemifumarate.
In another aspect, the present application provides a process for preparing amorphous form of Siponimod hemifumarate which comprises;
a) providing a solution of Siponimod hemifumarate in a solvent or a mixture solvents;
b) removing solvent from the solution of Siponimod hemifumarate obtained in step a);
c) recovering amorphous form of Siponimod hemifumarate.
Siponimod hemifumarate used as the input in the process for preparation of amorphous form of the present application can be prepared by any process known in the art or the process described in this application.
Providing a solution of Siponimod hemifumarate in step a) includes direct use of a reaction mixture containing Siponimod hemifumarate that is obtained in the course of its synthesis; or dissolving Siponimod hemifumarate in a solvent.
Any physical form of Siponimod hemifumarate may be utilized for providing the solution of Siponimod hemifumarate in step a).
Suitable solvents which can be used for dissolving Siponimod hemifumarate include but are not limited to: alcoholic solvents such as methanol, ethanol, isopropyl alcohol, n-propanol, isoamyl alcohol and the like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride and the like; and any mixtures of two or more thereof.
After dissolution in step (a), the obtained solution may optionally be filtered to remove any insoluble particles. Suitable techniques to remove insoluble particles are filtration, centrifugation, decantation, and any other known techniques in the art. The solution can be filtered by passing through paper, glass fiber, or other membrane material, or a clarifying agent such as Celite. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature precipitation of solid.
Step (b) involves removing solvent from the solution of Siponimod hemifumarate.
Suitable techniques which can be used for the removal of solvent include but not limited to evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, agitated thin-film drying, Rotary vacuum paddle dryer, agitated nutsche filter drying, pressure nutsche filter drying, freeze-drying or any other suitable technique known in the art. The drying may be carried at normal pressure or under reduced pressure.
Step (c) involves recovering an amorphous form of Siponimod hemifumarate. The said recovery can be done by using the processes known in the art.
In an embodiment, the isolation of amorphous form of Siponimod hemifumarate may be carried out by employing any of the techniques known to a person skilled in art. Techniques for the isolation of amorphous form of Siponimod hemifumarate include, but not limited to: decantation, filtration by gravity or suction, centrifugation, and the like, and optionally washing with a solvent.
The resulting compound in step (c) may optionally be further dried. Drying can be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying can be carried out at temperatures of less than about 100°C, less than about 60°C, less than about 40°C, or any other suitable temperatures; at atmospheric pressure or under a reduced pressure; as long as the Siponimod hemifumarate is not degraded in its quality. The drying can be carried out for any desired times until the required product quality is achieved. Suitable time for drying can vary from few minutes to several hours for example from about 30 minutes to about 24 or more hours.
In another aspect, the present application provides amorphous form of Siponimod hemifumarate characterized by powder X-ray diffraction (PXRD) substantially as illustrated in Figure 1.
In another aspect, the present application provides pharmaceutical composition comprising amorphous Siponimod hemifumarate and one or more pharmaceutically acceptable excipients.
In another aspect, the present application provides pharmaceutical composition comprising Siponimod or its pharmaceutically acceptable salt thereof prepared by the processes described in the present application and one or more pharmaceutically acceptable excipients.
In another aspect, the present application provides Siponimod hemifumarate having particle sizes less than about 300 µm, or less than about 100 µm, or less than about 50 µm, or less than about 20 µm, or less than about 10 µm.
The present application provides Siponimod hemifumarate having a particle size distribution wherein the 10th volume percentile particle size (D10) is less than about 15 µm, the 50th volume percentile particle size (D50) is less than about 35 µm, and/or the 90th volume percentile particle size (D90) is less than about 60 µm.
The “10th volume percentile” as used herein, unless otherwise defined refers to the size of particles, below which 10% of the measured particle volume lies; “50th volume percentile” as used herein, unless otherwise defined refers to the size of particles, below which 50% of the measured particle volume lies, and “90th volume percentile” as used herein, unless otherwise defined refers to the size of particles, below which 90% of the measured particle volume lies.
Particle size distributions of Siponimod hemifumarate particles may be measured by any technique known in the art. For example, particle size distributions of Siponimod hemifumarate particles may be measured using light scattering equipment, such as, for example, a Malvern Master Sizer 2000 from Malvern Instruments Limited, Malvern, Worcestershire, United Kingdom (helium neon laser source, Siponimod hemifumarate suspended in light liquid paraffin, size range: 0.01 µm to 3000 µm).
In the third aspect, the present application provides a pharmaceutical composition comprising Siponimod hemifumarate prepared by the processes of the present application and one or more pharmaceutically acceptable excipient.
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. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
DEFINITIONS
The following definitions are used in connection with the present application 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.
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, “comprising” means 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 2-(trifluoromethyl)-2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-carboxylic acid (compound of formula X)

4-Bromo-3-(trifluoro methyl) benzoic acid (XI, 5.0 g), Cyclohexanone (3.85 mL), 1,4-dioxane (250 mL) and Tosyl hydrazide (6.92 g) were charged into a 1000 mL round bottom flask. The resulting reaction mixture was stirred for 10 min and degassed with nitrogen gas for 5 min. To the reaction mixture lithium tert.-butoxide (3.71 g), tris-(dibenzylidene acetone)-dipalladium (0) (Pd2(dba)3, 0.255 g) and X-Phos (0.531) added in one portion and the resulted mixture was degassed with nitrogen gas for 5 min. The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was cooled to 30 °C and 1N hydrochloric acid (10 mL) was added. The reaction mixture was filtered through celite pad and bed was washed with ethylacetate (20 mL). The filtrate was concentrated under reduced pressure at 45 °C and ethylacetate (100 mL) was added to the resultant residue. The organic layer was washed with 1N hydrochloric acid (10 mL) 10% NaCl solution (10 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure at 45 °C. The crude was purified with silica gel (60-120 mesh) column chromatography and compound was eluted in 10-15% EtOAc in Hexane. The organic layer was concentrated to yield 3.5 g of the compound of formula X as pale yellow solid. Purity: 81.69%.
Example-2: Preparation of 4-cyclohexyl-3-(trifluoromethyl)benzoic acid (compound of formula IX)

Compound of formula X (1.0 g) and methanol (10 mL) were charged into a 250 mL hydrogenation vessel and added 10% palladium on carbon at 28 °C. Applied H2-gas to the reaction mixture and evacuated the H2-gas from the vessel. The vessel was filled with hydrogen gas and maintained 80 Psi at 29 °C for 72 hours. The reaction mixture was filtered through celite pad and the pad was washed with methanol (10 mL). The filtrate was concentrated under reduced pressure at 45 °C. The crude compound of formula IX (0.87 g of pale yellow solid; HPLC purity: 93.23%) is used in the next step without any purification.
Example-3: Preparation of (4-cyclohexyl-3-(trifluoromethyl)phenyl)methanol (compound of formula VIII)

Compound of formula IX (0.87 g) and THF (50 mL) were charged into a 250 mL round bottom flask under N2-atmosphere. The mixture was cooled to 0 °C and Lithium Aluminum hydride solution (2M in THF, 1.6 mL) was added drop wise to the reaction mixture. The resulting reaction mixture was stirred at 20°C for 1 hour. The reaction mixture was cooled to 0 °C and quenched with cold water (1 mL) followed by 1N HCl (1 mL). The reaction mixture was diluted with ethylacetate (10 mL) and filtered through celite pad and the celite pad was washed with ethylacetate (5 mL). The organic layer was washed with brine solution (5 mL) and dried over sodium sulphate. The organic layer was concentrated under reduced pressure at 45 °C. The crude was purified by silica gel (60-120 mesh) column chromatography and compound was eluted in 15% EtOAc in Hexane. The fractions containing the compound of formula VIII were combined and concentrated under reduced pressure at 45 °C to yield 603 mg of compound of formula VIII as colorless oil. HPLC purity: 97.64%.
Example-4: Preparation of 4-(bromomethyl)-1-cyclohexyl-2-(trifluoromethyl)benzene (compound of formula VI-A)

Compound of formula VIII (0.60 g) and DCM (6 mL) were charged into a 50 mL round bottom flask under N2-atmosphere. The mixture was cooled to 0 °C and Phosphorous tribromide solution (1.0 M in DCM, 2.55 mL) was added drop wise to the reaction mixture. The resulting reaction mixture was stirred at 20 °C for 3 hours. The reaction mixture was quenched with cold saturated sodium bicarbonate solution (2.0 mL). Layers separated and the aqueous layer was extracted with DCM (10 mL). The organic layers were combined and washed with brine solution (5 mL) and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure at 45 °C to yield 688 mg of compound of formula VI-A as colorless oil. HPLC purity: 99.92%.
Example-5: Preparation of 2-((4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)-isoindoline-1,3-dione (compound of formula V-A)

Compound of formula VI-A (0.65 g), N-hydroxy Phthalimide (VII-A, 0.495 g) and DMF (6.5 mL) were charged into a 25 mL round bottom flask under N2-atmosphere. DIPEA (1.05 mL) was added to the mixture and the resultant mixture was heated to 70 °C and stirred for 1 hour. The reaction mixture was cooled to 28 °C and water (20 mL) was added to the mixture and stirred for 10 minutes. The precipitation was filtered and the solid was dried under vacuum to get 752 mg of compound of formula V-A as pale yellow solid. Purity: 99.70%.
Example-6: Preparation of (E)-1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one-O-(4-cyclohexyl-3-(trifluoromethyl)benzyl)-oxime (compound of formula III)

Compound of formula V-A (0.70 g) and Methanol (7 mL) were charged into a 25 mL round bottom flask under N2-atmosphere and n-Butylamine (0.173 mL) was added drop-wise and the mixture was stirred at 29 °C for 1 hour. The reaction mixture was cooled to 0 °C and ethanolic HCl (4.0 mL) was added and stirred at 29 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure at 45 °C. The resulting crude compound was washed with MTBE (10 mL), filtered and the solid was dried under vacuum to yield compound of formula IV (HCl salt).
The compound of formula IV (HCl salt) was dissolved in methanol and a compound of formula XII (0.163 g) was added and the mixture was stirred for 16 hours at 28 °C. The reaction mixture was concentrated under vacuum. The residue was purified by silica column chromatography and the compound was eluted in 15% EtOAc in Hexane. The fractions containing the compound of formula III were combined and concentrated under reduced pressure at 45 °C to yield 210 mg of the title compound as colorless oil. Purity: 94.54%.
Example-7: Preparation of (E)-4-(1-(4-cyclohexyl-3-(trifluoromethyl)benzyl)oxy)imino)ethyl)-2-ethylbenzaldehyde (compound of formula II)

Compound of formula III (0.20 g) and heptane (8 mL) were charged into a 25 mL round bottom flask under N2-atmosphere. Activated Manganese (IV) oxide (0.268 g) was added to the mixture and the resulted mixture was stirred for 3 hours at 60 °C. The reaction mixture was filtered through a celite bed and the celite bed was washed with heptane. The filtrate was concentrated under vacuum at 45 °C to yield 0.18 g of the compound of formula II as off-white solid. Purity: 96.80%.
Example-8: Preparation of Siponimod (compound of formula I)

Compound of formula II (0.15 g) and methanol (3 mL) were charged into a 25 mL round bottom flask under N2-atmosphere. 3-azetidine carboxylic acid (0.070 g) and acetic acid (0.18 mL) were added at 29 °C and the mixture was stirred for 30 minutes. Sodium Cyano borohydride (0.011 g) was dissolved in methanol (1.5 mL) and added to the reaction mixture at 25 °C and the reaction mixture was stirred for 1 hour at 28 °C. Methanol was distilled-off from the reaction mixture under vacuum at 45 °C. Water (10 mL) was added to the crude and extracted with ethylacetate (2 X 10 mL). The ethylacetate layer was washed with water (10 mL) and brine solution (10 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure at 45 °C. The residue was purified by silica gel (100-200 mesh) column chromatography and compound was eluded in 8-10% MeOH in DCM. The fractions containing Siponimod concentrated under vacuum at 45 °C to yield 86 mg of Siponimod. Purity: 98.84%.
Example-9: Preparation of Siponimod hemifumarate

Siponimod base (144 g) and ethanol (1440 mL) were charged into a 2 L round bottom flask at 28 °C. The mixture was heated to 40 °C and fumaric acid (12.95 g) was added and the mixture was for 30 minutes. The mixture was filtered through a celite bed and the bed was washed with ethanol (360 mL). The filtrate was concentrated under reduced pressure at 45 °C. To the crude material acetonitrile (1100 mL) was added and stirred for 6 hours at 28 °C. The precipitation was filtered and the solid was washed with acetonitrile (288 mL). The wet compound was dried in hot air oven at 35 °C for 4 hours to yield 110 g of crude Siponimod hemifumarate. The crude compound and acetone (1100 mL) were charged into a 2 L round bottom flask and the mixture was stirred at 56 °C for 30 minutes. The mixture was cooled to 29 °C and stirred for another 1 hour at 28 °C. The precipitation was filtered and washed with acetone in a hot air oven at 40 °C to provide 90.5 g of Siponimod hemifumarate as off-white solid. Purity: 99.32%.
Example-10: Preparation of amorphous Siponimod hemifumarate
Siponimod hemifumarate (1.0 g) and a mixture of methanol and DCM (40 mL; 4 mL of methanol in 36 mL of DCM) were charged into a 100 mL round bottom flask under N2-atmosphere. The mixture was stirred for 30 minutes at 28 °C. The clear solution was filtered through a celite bed and the bed was washed with a mixture of methanol and DCM (10 mL; 1 mL of methanol in 9 mL of DCM). The filtrate was concentrated under vacuum at 45 °C to yield 0.9 g of amorphous Siponimod hemifumarate. Purity: 98.57%. PXRD as shown in Figure 1.
Example-11: Preparation of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (compound of formula XII)
Example-11(a): Preparation of 1-(3-bromo-4-(hydroxymethyl)phenyl)ethan-1-one

3-bromo-4-methyl-acetophenone (200 g), N-bromo succinimide (167 g), azo-bis-isobutyronitrile (30.8 g) and 1, 2-dichloro ethane (2 L) were charged in a 3L RBF equipped with reflux condenser and guard tube at 28 °C. The reaction mixture was heated to 80 °C and stirred for 16 hours. The reaction was cooled to 30 °C and filtered through a celite bed and the celite bed was washed with DCM (200 mL). The filtrate was concentrated under reduced pressure at 50 °C. To the crude 1,4-dioxane (1400 mL), water (1400 mL) and calcium carbonate (281.59 g) were charged and the reaction mixture was stirred for 16 hours at 100 °C. The reaction mixture was cooled to 29 °C and filtered through a celite bed and the celite bed was washed with ethylacetate (500 mL). The filtrate was extracted with ethylacetate (3 X 500mL). The organic layers were combined and washed with water (300 mL) and brine (300 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum at 45 °C. The crude compound was purified using silica gel chromatography and the compound was eluted in 15-25% EtOAc/Hexane. The fractions containing the compound were combined and concentrated under reduced pressure at 45 °C to yield 126.2 g of the title compound as off-white solid. Purity: 98.32%.
Example-11(b): Preparation of 1-(4-(hydroxymethyl)-3-vinylphenyl)ethan-1-one

1-(3-bromo-4-(hydroxymethyl)phenyl)ethan-1-one (100 g) and THF (3 L) were charged in clean and dry RBF equipped with reflux condenser and guard tube at 28 °C. Dibutyl vinyl borate (144.64 g) and 2M aqueous sodium carbonate solution (323.87 g) were added. The reaction mass was purged with nitrogen gas for 30 minutes. PdCl2(PPh3)2 (15.32 g) was added to the reaction mass at 29 °C. The reaction mixture was heated to 80 °C and stirred for 10 hours. The reaction mass was cooled to 28 °C and extracted with ethylacetate (3 X 500 mL). Organic layer was washed with water (500 mL) and brine (800 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure at 45 °C to yield 120 g of pale colored syrup. Purity: 75.95%.
Example-11(c): Preparation of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (compound of formula XII)

Crude 1-(4-(hydroxymethyl)-3-vinylphenyl)ethan-1-one (126 g) and methanol (1512 mL) were charged into a hydrogenation vessel at 29 °C. 5% Pd/C (50% wet, 50.4 g) was added and hydrogen gas applied. The hydrogen gas was maintained at 15 psi for 4 hours at 28 °C. The reaction mixture was filtered through a celite bed and the bed was washed with methanol (500 mL). The filtrate was concentrated under reduced pressure at 45 °C and the resulting crude compound was purified by silica gel (60-120 mesh) column chromatography and compound was eluted in 15-20% EtOAc/Hexane. The fractions containing the compound were combined and concentrated under reduced pressure at 45 °C to yield 82.8 g of the compound of formula XII as light yellow syrup. Purity: 90.67%.
Example-12: Alternate method for preparation of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (compound of formula XII)
Example-12(a): Preparation of 1-(3-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)ethan-1-one

1-(3-bromo-4-(hydroxymethyl)phenyl)ethan-1-one (5 g) and DCM (50 mL) were charged into a 100 mL RBF equipped with nitrogen gas at room temperature and the mixture was cooled to 7°C. Imidazole (2.98 g) and TBDMSCl (5.14 g) were added to the reaction mixture. The resulting reaction mixture was stirred for 2 hours at 28 °C. Water (50 mL) was added to the reaction mass and stirred for 10 minutes. Layers separated and the organic layer was further washed with water (2 X 50 mL) and brine (50 mL) solution. The organic layer was dried over sodium sulphate and concentrated under reduced pressure below 50 °C to yield 6.5 g of title compound as light brown color syrup. Purity: 67.99%
Example-12(b): Preparation of 1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-vinylphenyl)ethan-1-one

1-(3-bromo-4-(((tert-butyldimethylsilyl)oxy)methyl)phenyl)ethan-1-one (6 g) and THF (180 mL) were charged into a 500 mL clean and dry RBF equipped with reflux condenser and guard tube at 28 °C. Dibutyl vinyl borate (5.78 g) and 2.0M aqueous sodium carbonate solution (12.96 g) were added. The reaction mass was purged with nitrogen gas for 30 minutes. PdCl2(PPh3)2 (0.613 g) was added to the reaction mass at 29 °C. The reaction mixture was heated to 80 °C and stirred for 9 hours. The reaction mass was cooled to 28 °C and extracted with ethylacetate (2 X 30 mL). Organic layer was washed with water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure at 45 °C to yield 5.3 g of light brown colored syrup. Purity: 59.27%.
Example-12(c): Preparation of 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one (compound of formula XII)

1-(4-(((tert-butyldimethylsilyl)oxy)methyl)-3-vinylphenyl)ethan-1-one (5.0 g) and methanol 25 mL) were charged into a 250 mL hydrogenation vessel at room temperature at 29 °C. 5% Pd/C (50% wet, 1.0 g) was added and hydrogen gas applied. The hydrogen gas was maintained at 20 psi for 3 hours at 28 °C. The reaction mixture was filtered through a celite bed and the bed was washed with methanol (20 mL). The filtrate was concentrated under reduced pressure at 45 °C and the resulting crude compound was diluted with methanol (25 mL) and 1N HCl (10 mL) at 28 °C. The mixture was stirred at 28 °C for 20 minutes. The reaction mixture was concentrated under reduced pressure at 45 °C. The resulting crude compound was purified by silica gel (60-120 mesh) column chromatography and compound was eluted in 20-25% EtOAc/Hexane. The fractions containing the compound were combined and concentrated under reduced pressure below 50 °C to yield 1.4 g of the compound of formula XII as light yellow syrup. Purity: 83.51%.
Example-13: Preparation of amorphous Siponimod hemifumarate
Siponimod hemifumarate (6.0 g) and methanol (350 mL) were charged into a 1000 mL rotavapor flask. The mixture was heated to 45 °C under rotation, and the clear solution was filtered under vacuum. The clear solution was concentrated under vacuum at 46 °C and the solid obtained was dried under vacuum to yield 5.2 g of amorphous Siponimod hemifumarate. PXRD as shown in Figure 1.
,CLAIMS:CLAIMS
We claim
1. Amorphous form of Siponimod hemifumarate.
2. A process for preparing amorphous form of Siponimod hemifumarate, comprising:
(a) providing a solution of Siponimod hemifumarate in a solvent or a mixture of two or more solvents;
(b) removing solvent from the solution of Siponimod hemifumarate obtained in step a); and
(c) recovering amorphous form of Siponimod hemifumarate.
3. The process according to claim 2, wherein the solvent used in step (a) is methanol.
4. The process according to claim 2, wherein the solvent used in step (a) is a mixture of methanol and dichloromethane.
5. A pharmaceutical composition comprising amorphous Siponimod hemifumarate and one or more pharmaceutically acceptable excipients.
6. Compound of Formula V or a salt thereof

wherein, R1 and R2 each independently represents hydrogen, alkyl, halogen, nitro or R1 and R2 together form a 4 to 7 membered ring.
7. The compound of Formula V according to claim 6 is a compound of formula V-A

8. A process for preparation of compound of formula V, comprising, reacting a compound of formula VI with a compound of formula VII in presence of a suitable base.

wherein, X represents a hydrogen atom or a halogen atom;
R1 and R2 each independently represents hydrogen, alkyl, halogen, nitro or R1 and R2 together form a 4 to 7 membered ring.
9. A process for preparation of compound of formula V-A, comprising:
f) Reacting a compound of formula XI with cyclohexanone to form a compound of formula X

g) Hydrogenating the compound of formula X in presence of suitable catalyst to form a compound of formula IX

h) Reducing the compound of formula IX using a suitable reducing agent to form a compound of formula VIII

i) reacting the compound of formula VIII with a brominating agent to form a compound of formula VI-A

j) reacting a compound of formula VI-A with 2-hydroxyisoindoline-1,3-dione in presence of a suitable base to get a compound of formula V-A

10. A process for preparation of Siponimod of formula I or a pharmaceutically acceptable salt thereof, comprising:
(a) reacting a compound of formula VI with a compound of formula VII in presence of a suitable base to get a compound of formula V

(b) reacting the compound of formula V with a suitable amine to form a compound of formula IV

(c) reacting the compound of formula IV with 1-(3-ethyl-4-(hydroxymethyl)phenyl)ethan-1-one of formula XII to form a compound of formula III

(d) oxidizing the compound of formula III using a suitable oxidizing agent to form a compound of formula II

(e) reacting the compound of formula II with azetidine-3-carboxylic acid to form Siponimod of formula I.

(f) optionally, converting Siponimod into its pharmaceutically acceptable salt.
11. The process according to claim 10, the pharmaceutically acceptable salt of siponimod is siponimod hemifumarate.
12. A pharmaceutical composition comprising Siponimod or any salt thereof prepared by the process described in the present application, and at least one pharmaceutically acceptable excipient.