Field of the Invention
The present invention relates to a process for the preparation of vortioxetine or salts thereof. The present invention also relates to the process for the preparation of amino intermediate of vortioxetine.
Background of the Invention
Vortioxetine is chemically known as l-[2-(234-dimethyl-phenylsulfanyl)-phenyl]-piperazine and structurally represented as Formula-I. Vortioxetine hydrobromide is marketed under the trade name TRJNTELLIX by Takeda Pharmaceuticals U.S.A., Inc. and is indicated for the treatment of major depressive disorder (MDD).

Formula 1
Vortioxetine or a pharmaceutical^ acceptable acid addition salts thereof were first described in US7144884. The process described involves the use of resin base support as per below mentioned scheme 1 and crude product so obtained was purified by preparative LC-MS and subsequently by ion exchange chromatography as per scheme 1:
Scheme 1


WO2007144005Al describes manufacturing process for the preparation of vortioxetine, wherein the first step involves cross coupling reaction between 2,4- dimethylthiophenol and 2-bromoiodobenzene using Pd catalyst in presence of phosphine ligand and base, which furnishes l-(2-bromo-phenylsulfanyl)-2,4-dimethyl benzene, which was reacted with unprotected piperazine or protected to furnish respectively l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine or (4-[2-(2,4- dimethyl-phenylsulfanyl)- phenyl]-BOC-piperazine). Protected BOC group was removed by HC1 to produce vortioxetine. This patent further describes one pot process for the synthesis of vortioxetine.
WO2013102573 Al describes one pot process for the preparation of vortioxetine, which involves a coupling reaction between l-iodo-2,4-dimethylbenzene, 2- bromo thiophenol and piperazine in presence of Pd catalyst, phosphine ligand and base to yield l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine.
The processes for the preparation of vortioxetine and its intermediates described in the
aforementioned prior art suffer from disadvantages such as the use of resin base support,
Pd catalyst, phosphine ligand, use of tedious and cumbersome procedures like multiple
process steps, prolonged reaction time periods, purifications using preparative LC-MS
and ion-exchange chromatography, thus resulting in a poor product yield and quality.
Methods involving preparative LC-MS and ion-exchange chromatography purifications
are generally undesirable for large-scale operations, thereby making the process
commercially unfeasible. ' -
Many other patent publications have also been disclosed so far, which describes the process for the preparation of vortioxetine and salts thereof. Still there is a need to develop a simple, cost effective, high yielding and easy to implement on industrial scale process for the preparation of vortioxetine and salts thereof.
Object of the invention
The principal object of the present invention is to provide a process for the preparation of vortioxetine or salts thereof, which alleviates one or more drawbacks of prior art processes.

One object of the present invention is to provide an improved, efficient, - safe and convenient process for preparation of vortioxetine or salts thereof.
Another object of the present invention is to provide a process for preparation of amino intermediate of vortioxetine by using benzothiazole.
Yet another object of the present invention is to provide a process for preparation of, vortioxetine hydrobromide via vortioxetine hydrochloride.
Further yet another object of the present invention is a need to develop a simple, cost. effective and easy to implement process for the preparation of vortioxetine or salts thereof.
Summary of the Invention
In accordance with principal embodiment, the present invention provides a process for the preparation of vortioxetine or salts thereof, comprising the steps of: (a) reacting benzothiazole of Formula 2
L
Formula 2
with compound of Formula 3

Formula 3
wherein X is F, CI, Br, I
using suitable base in the presence of a suitable solvent, optionally in the presence of catalyst, to provide amino intermediate of Formula 4;


Formula 4
■ ■> ■ _
• •■"■**
(b) coupling the compound of Formula 4 with disubstituted amino compound of
Formula 5 or its salts thereof

Formula 5
-wherein X is selected from F, CI, Br, I,
using suitable base in the presence of the suitable solvent, with or without use of an activating agent, to provide vortioxetine free base; and
(c) optionally, converting vortioxetine free base into its salts thereof.
In accordance with another embodiment, the present invention provides a process for the preparation of vortioxetine or salts thereof, comprising tBe steps of:
■.■■■' . . c ■ . ■
(a) reacting benzothiazole of Formula, 2
» - -
Formula 2
with compound of Formula 3 A
j-
Formula 3A

using aqueous tetrabutyl ammonium hydroxide solution, cuprous chloride" to provide amino intermediate of Formula 4;

Formula 4 ^
(b) coupling the compound of Formula 4 with 6/s(2-chloroethyl)amine hydrochloride of
Formula 5 or its salts thereof

Formula 5A
using potassium carbonate, potassium iodide in the presence of mixture of solvents sulfolane and toluene to provide vortioxetine free base; and
(c) optionally, converting vortioxetine free base into its salts thereof.
In accordance with the another embodiment, the present invention provides a process for
the preparation of vortioxetine hydrobromide wherein amino intermediate compound of
Formula 4 is prepared by the process comprising the steps of reacting benzothiazole of
Formula 2 ; .

Formula 2
f ...
with compound of Formula 3


Formula 3
wherein X is F, CI, Br, I,
suitable base in the presence of the suitable solvent, optionally in the presence of the catalyst, to provide amino intermediate of Formula 4.

Formula 4
In accordance with the further embodiment, the present invention provides a process for the preparation of vortioxetine hydrobromide wherein amino intermediate compound of Formula 4 is prepared by the process comprising the steps of reacting benzothiazole of Formula 2

Formula 2
with compound of Formula 3 A

Formula 3A
using aqueous tetrabutyl ammonium hydroxide solution, cuprous chloride to provide amino intermediate of Formula 4;


Formula 4
According to yet another embodiment of the present invention provides use . of benzothiazole of Formula 2 for the preparation of vortioxetine hydrobromide.
According to further yet another embodiment of the present invention provides a process for preparation of vortioxetine hydrobromide via vortioxetine hydrochloride comprising the steps of:
(a) reacting benzothiazole of Formula 2

Formula 2
with compound of Formula 3 A

Formula 3A
using suitable base, optionally using catalyst, in the presence of suitable solvent to provide amino intermediate of Formula 4;

Formula 4
(b) coupling the compound of Formula 4 with Z?zX2-chloroethyI)amine hydrochloride of Formula 5 or its salts thereof


Formula 5A
using suitable base, optionally using catalyst, in the presence of suitable solvents to provides to provide vortioxetine hydrochloride; and
(c) converting, vortioxetine hydrochloride into its hydrobromide salt thereof.
Detail description of the drawings:
Fig.l: Illustrates the X-ray powder diffraction (XRPD) pattern of Vortioxetine
hydrobromide obtained according to example 7
Fig.2: Illustrates the DSC of-Vortioxetine hydrobromide obtained according to example
7
Fig.3: Illustrates the XRPD of Vortioxetine hydrochloride monohydrate obtained
according to example 11
Fig.4: Illustrates the X-ray powder diffraction (XRPD) pattern of Vortioxetine free base
obtained according to example 16.
Detail description of the invention
The present invention provides an efficient and industrially advantageous process for the preparation of vortioxetine or salts thereof.
According to the principal embodiment, the present invention provides a process for the
preparation of vortioxetine or salts thereof comprising the steps of reacting
benzothiazole of Formula 2 with a compound of Formula 3 using suitable base in the
presence of the suitable solvent, optionally in the presence of catalyst, to provide amino
intermediate of Formula 4. The compound of formula 4 without isolation or after
isolation taken for next step, which involves coupling of the compound of Formula 4
with disubstituted amino of Formula 5 or its salts thereof using base, with or without use
of an activating agent, in the presence of the suitable solvent to provide vortioxetine free
base, •

Further, vortioxetine free base without isolation or after isolation is converted its salt thereof by treating with suitable source of acid known in the art using suitable solvent and rhethod known in the art.
According to one embodiment of the present invention provides a process for
preparation of vortioxetine hydrobromide via*vortioxetine>hydrochloride comprising the
steps of: r
(a) reacting benzothiazole of Formula 2

Formula 2
with compound of Formula 3 A
*

Formula 3A
using suitable base, optionally using catalyst, in the presence of suitable solvent
to provide amino intermediate of Formula 4; ^
1 ' •
Formula 4
(b) coupling the compound of Formula 4 with 6/5(2-chloroethyl)amine hydrochloride of
Formula 5 or its salts thereof . '

~1
Formula 5A
using suitable base, optionally using catalyst, in the presence of suitable solvents to provides to provide vortioxetine hydrochloride; and
(c) converting vortioxetine hydrochloride into its hydrobrorhide salt thereof.
In accordance with the another embodiment, the present invention provides a process for the preparation of vortioxetine hydrobromide wherein amino intermediate compound of Formula 4 is prepared by the process comprising the steps of reacting benzothiazole of Formula 2 with compound of Formula 3 using suitable base in the presence of the suitable solvent, optionally in the presence of the catalyst, to provide amino intermediate of Formula 4.
In accordance with the another embodiment, the present invention provides a process for the preparation of vortioxetine hydrobromide wherein amino intermediate compound of Formula 4 is prepared by the process comprising the steps of reacting benzothiazole of Formula 2 with a compound of Formula 3 A using suitable base in the presence of the
suitable solvent, optionally in the presence of catalyst, to provide amino intermediate of
~> Formula 4.
The coupling of benzqthiazole of Formula 2 with compound of Formula 3 or 3 A using suitable base in the presence of the suitable solvent, optionally in the presence of catalyst, to provide amino intermediate of Formula 4 may be carried out at a 25°C to - reflux temperature for few minutes to few hours or till completion of reaction. Preferably reaction is conducted at a temperature of 60 to 80°C, more preferably reaction is conducted at a temperature of 70 to 75°C and it takes 4 to 8 hours for completion of the reaction. The reaction completion is monitored by suitable techniques such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), ultra performance liquid chromatography (UPLC) and like thereof.

: Suitable solvent used for preparation of amino intermediate of Formula 4 during the coupling of benzothiazole of Formula 2 with compound of Formula 3 or 3A includes but not limited to organic solvents selected from the group comprising of sulfoxide, amide, esters, ketone, nitrile, aliphatic or aromatic hydrocarbons, chloro solvents and water mixture thereof. Preferably, selected from water, dimethyl sulfoxide (DMSO), sulfolane, N,N-dimethylformamide (DMF), ethyl acetate, propyl acetate, butyl acetate, acetone, propanone, butanone, methyl isobutyl ketone, acetonitrile, toluene, xylenes, methylene dichloride (MDC), ethylene dichloride, chloroform and the like or mixture thereof, more preferably solvent used is water.
The suitable base used for the preparation of amino intermediate of Formula 4 during reaction of benzothiazole of Formula 2 with compound of Formula 3 or 3A may be selected from organic or inorganic base selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, alkoxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate, sodium tertiary butoxide, potassium tertiary butoxide, tripotassium phosphate (K3PO4), tetramethyl ammonium hydroxides(Me4NOH), tetraethylammonium hydroxide(Et4NOH), tetrabutyl ammonium hydroxide(Bu4NOH), tetrabutylphqsphonium hydroxide(Bu4POH), sodium with liquid ammonia, sodamide, diisopropyl ethyl amine, triethyl amine, tributyl amine, Af-methyl morpholine, and pyridine and like or mixture thereof; preferably base used is tetrabutyl ammonium hydroxide.
The catalyst used for the preparation of amino intermediate of Formula 4 during reaction of benzothiazole of Formula 2 with compound of Formula 3 or 3 A may be selected from Cul, CuCl, CuBr, Cul, Cu20, CuCh,- CuBr2, CuS04, FeCl3, Cu(OAc)2.H20, Cu(OAc)2.4H20, Ni(OAc)2.4H20, Pd(OAc)2, preferably base used is CuCl.
The coupling of the amino intermediate of Formula 4 with disubstituted amino compound or its salts thereof of formula 5 or ZuX2^chloroethyl)amine hydrochloride of formula 5A using suitable base in the presence, of the suitable solvent, with or without

use of an activating agent to provide vortioxetine free base may be carried out at a temperature of 70°C to reflux temperature, for few minutes to few hours or till completion of reaction. Preferably reaction is conducted at a temperature of 90 to 120°C; more preferably reaction is conducted at a temperature of 110 to 115°C for 35 to 40 hours.
Further converting vortioxetine free base ih-situ or after isolation into its salt thereof by treating with suitable source of acid known in the art using suitable solvent and method known in the art.
Vortioxetine hydrochloride obtained can be anhydrous or hydrated such as hemihydrates, monohydrate, sesquihydrate, dihydrate, hemipentahydrate, trihydrate, pentahydrate and the like^
Vortioxetine hydrochloride without isolation or after isolation is converted to its hydrobromide salt using suitable solvent, base and hydrobromic acid.
The suitable solvent used during coupling in amino intermediate of Formula 4 with disubstituted amino compound or its salts thereof of formula 5 or bis(2-chloroethyl)amine hydrochloride of formula 5A may be selected from but not limited to organic solvents selected from ketone such as acetone, propanone, butanbhe- methyl isobutyl ketone and the like thereof; hydrocarbons are selected from aliphatic hydrocarbons or aromatic hydrocarbons, aliphatic hydrocarbons are selected from the group comprising of alkanes or cycloalkanes such as pentane, hexane, heptane, octane, cyclohexane, cyclopentane and the like, aromatic hydrocarbons are selected from the group comprising of toluene, xylene. Polar solvents are selected from the group comprising of amide such as N,N-dimethylformamide (DMF), N?N-dimethyl acetamide (DMAc), sulpholane, acetonitrile and the like thereof or mixture thereof. Preferably solvents used are sulpholane and toluene.
The base used during coupling of amino intermediate of Formula 4 with disubstituted amino compound or its salts thereof of formula 5 or 6/s(2-chloroethyl)amine hydrochloride of formula 5A may be selected from organic or inorganic base, wherein inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates,

bicarbonates selected from the group comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate; organic bases may be selected from diisopropyl ethyl amine, triethyl amine, tributyl amine, TV-methyl morpholine and pyridine or like thereof, preferably base used is potassium carbonate.
Activating agent used during coupling amino intermediate of Formula 4 with disubstituted amino compound or its salts thereof of formula 5 or bis(2-chloroethyl)amine hydrochloride of formula 5 A may be selected from such as sodium iodide (Nal), potassium iodide (KI), Cul, CuCl , phase transfer catalyst such as tetra butylammonium bromide (TBAB), tetrabutylammonium iodide (TBAI), tetrabutylammonium chloride (TBAI) and the like or mixture thereof, preferably the base used is potassium iodide (KI).
The reaction completion is monitored by suitable techniques such as thin layer chromatography (TLC), high performance liquid chromatography (HPLC), gas chromatography (GC), ultra performance liquid chromatography (UPLC) and like 'thereof.
The suitable solvent for conversion of vortioxetine hydrochloride to vortioxetine hydrobromide may be selected from group comprising of but not limited to water, organic solvents selected from the group comprising of sulfoxide, amide, esters, ketone., nitrile, aliphatic or aromatic hydrocarbons, chloro solvents and water mixture thereof. Preferably, selected from water, dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), ethyl acetate, propyl acetate, butyl acetate, acetone, propanone, butanone, methyl isobutyl ketone, acetonitrile, toluene, xylenes, methylene dichloride (MDC), ethylene dichloride, chloroform and the like or mixture thereof, preferably solvents used-are water and ethyl acetate.
The suitable base for conversion of vortioxetine hydrochloride to vortioxetine hydrobromide may be selected from group comprising of but not limited may be selected from organic or inorganic base, wherein inorganic base is selected from alkali or alkaline earth metal hydroxides, carbonates, bicarbonates selected from the group

comprising of sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, cesium hydroxide, sodium carbonate, potassium carbonate, calcium . carbonate, magnesium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, magnesium bicarbonate, cesium bicarbonate; organic bases may be selected from diisopropyl ethyl amine, triethyl amine, tributyl amine, TV-methyl morpholine and pyridine or like thereof, preferably base used is sodium hydroxide.
According to yet another object of the present invention provide use of benzothiazole of Formula 2 for the preparation of vortioxetine hydrobromide.
Accordingly, vortioxetine hydrobromide obtained according to the instant invention possess the relative particle size distribution, wherein the 10th volume percentile particle size D (0.1) is less than about 100pm, the 50th volume percentile particle size D(0.5) is less than about 200|xm, or thb 90th volume percentile particle size D(0.9) is less than about 400pm, or any combination thereof.
In general, the particle size measurement is determined by Malvern light scattering, laser light scattering technique etc. In particular the particle size measurement is measured using a Malvern particle size analyzer.
In another aspect there is provided a pharmaceutical composition that includes a therapeutically effective amount of vortioxetine hydrobromide according to the process of the present invention and'one or more pharmaceutical^ acceptable carriers, excipients
or diluents. ■ ' J ' '
Major advantages realized in the present invention are that process can be easily and conveniently scaled-up for industrial large scale production. The process is simple economic with high throughput, operationally efficient and environment friendly. Further the advantages of the instant invention are reiterated as given below:
1) Single step process for the preparation of compound of formula 4, instead of two stage process. Also, the prior art process demands the additional purification.
2) The instant invention bypasses" the stage of catalytic hydrogenatipn with elevated temperature for preparation of compound of formula 4.

3) The instant invention follows green chemistry using aq. reaction media for
preparation of compound of formula 4.
4) Also, for preparation of compound of formula 4, the instant invention avoids the use
of highly pyrophoric catalyst (R-Nickel) and avoids the use of highly toxic & foul-
smelling starting material viz. 2,4-dimethyl thiophenol.
Although the following examples illustrate the present invention in more detail but the
examples are not intended in any way to limit the scope of the present invention. It will
thus be readily apparent to the one skilled in the art that varying substitutions and
modifications may be made to the invention disclosed herein without departing from the
scope and spirit of the invention. Thus, it should be understood that although the present
invention has been specifically disclosed by preferred embodiments and optional
features, modifications and variation of the concepts herein disclosed may be resorted to
by those skilled in the art and that such modifications and variations are considered to be
falling within the scope of the invention. -
Example!
Process for the preparation of [2-((2,4-dimethyIphenyI)thio)aniline] : A mixture of 224 g of 50 % aq. tetrabutylammonium hydroxide solution, 20 g of benzothiazole, 35 g of l-iodo-2,4-dimethylbenzene and 0.8 g of cuprous chloride were stirred at 70-75 °C for 6 hours. After completion of the reaction, the reaction mass was ^cooled to 25 to 30 °C, toluene (200 ml) and 15-20 % cone. HC1 (34 ml) were added. Further, separated the layers and pH of the organic layer adjusted to 12.5 to 13.5 using sodium hydroxide solution. The reaction mass was stirred at 20 to 30° (^filtered and washed with toluene (40 ml). Then, separated the layers, washed the organic layer with aq. solution of EDTA disodiurri (20 ml) and DM water (40 ml). The organic layer was concentrated under vacuum to obtain the title compound as oil. (Yield: 33.3 g) Example 2
Process for the preparation of Vortioxetine free base >
A mixture of 2-((2,4-dimethylphenyl)thio)aniline (15 g), 6zs(2-chloroethyl)amine hydrochloride (27 g), potassium carbonate (21 g), potassium iodide (1 g), sulfolane (22 ml) and toluene (22 ml) were stirred at 110 to 115 °C for 40 hours. After completion of the reaction, the reaction mass was cooled to room temperature, toluene (60" ml), DM water (60 ml) were added and adjusted pH 12 to 13 by using sodium hydroxide solution.

The layers were separated and washed the organic layer with DM water (60 ml).
. Organic layer concentrated under vacuum to obtain the title compound as oily mass.
Example 3 -
Process for the preparation of Vortioxetine free base
To the oily mass obtained from example 2 was added acetone (45 ml). The reaction mass was stirred at room temperature for 3 hours and further cooled to 5 to 10° C for and stirred for 3 hours, Filtered, washed with acetone and dried under vacuum to obtain the title compound as solid. Example 4
Process for the preparation of Vortioxetine free base
To the oily mass obtained from example 2 was added acetonitrile (45 ml). The reaction mass was stirred at room temperature for 3 hours and further cooled to 5 to 10° C for and stirred for 3 hours. Filtered, washed with acetonitrile and dried under vacuum to obtain the title compound as solid. Example 5
Process for the preparation of Vortioxetine free base
To the oily mass obtained from example 2 was added ethyl acetate (45 ml). The reaction mass was stirred at room temperature for 3 hours and further cooled to 5 to 10° C for and stirred for 3 hours. Filtered, washed with ethyl acetate and dried under vacuum to obtain the title compound as solid. Example 6
Process for the preparation of Vortioxetine free base
To the oily mass obtained from example 2 was added toluene (45 ml). The reaction mass was stirred at room temperature for 3 hours and further cooled to 5 to 10° C for and stirred for 3 hours. Filtered, washed with, toluene and dried under vacuum to obtain the title compound as solid. Example 7
Process for the preparation of Vortioxetine hydrobromide
A mixture of vortioxetine free base (10 g) in ethyl acetate (100 ml) was.stirred at 25 to 30° C and 6 g of-48 % aq. hydrobromic acid was added. Stirred the reaction mass at 70 to 80° C for 1 hour and then added DM water (3 ml). The reaction mass was stirred at 70 to 80 °C for 1 to 2 hours, cooled to 20 to 30 °C and stirred at 20 to 30 °C for 12 to 15 hours. Filtered, washed with ethyl acetate and dried under vacuum to obtain the title compound. (Yield: 11.5 g)

Example 8
Process for the preparation of Vortioxetine hydrobromide without isolating free
base
A mixture of 2-((2,4-dimethylphenyl)thio)aniline (15 g), 6/5'(2-chloroethyl)amine hydrochloride (27 g), potassium carbonate (21 g), potassium iodide (1 g), sulfolane (22 ml) and toluene (22 ml) were stirred at 110 to 115 °C for 40 hours. After completion of the reaction, the reaction mass was cooled to 25 to 30 °C , toluene (60 ml), DM water (60 ml) were added and adjusted pH 12"to 13 by using sodium hydroxide solution. The layers were separated and washed the organic layer with DM water (60 ml). To the organic layer 48 % aq. hydrobromic acid (11.5 g) was added and stirred at 25 to 30 °C for 10 hours. Filtered, washed with toluene and dried under vacuum to obtain the title compound. (Yield: 15 g) Example 9
Process for the preparation of Vortioxetine free base
A mixture of 2-((2,4-dimethylphenyl)thio)aniline (15 g), Z?/X2-chloroethyl)amine hydrochloride (27 g), potassium carbonate (21 g), Potassium iodide (1 g), Sulfolane (22 ml) and toluene (22 ml) were stirred at 110 to 115 °C for 40 hours. After completion of the reaction, the reaction mass was cooled to 40 to 50°C and toluene (150 ml) was added. The reaction mass was stirred at 25 to 3Q. °C for 2 hours, then cooled to 0 to 5°C and stirred for 2 hours. Filtered, washed with chilled toluene to obtain the wet material (~60 g). To the wet material DM water (300 ml), ethyl acetate (225 ml) was added and adjusted pH 9 to 10 by using ammonia solution. The layers were separated and organic layer washed with DM water (150 ml). The organic layer was concentrated under vacuum to obtain the title compound. Example 10
A process for the preparation of [2-((2,4-dimethylphenyI)thio)aniline] : A mixture of 224 g of 50 % aq. tetrabutylammonium hydroxide solution, 20 g of. benzothiazole, 35 g of l-iodo-2s4-dimethylbenzene and 0.8 g of cuprous chloride were stirred at 70-75° C for 6 hours. After completion of the reaction, the reaction mass was cooled to 25 to 30 °C, filtered and washed with toluene (80 ml). Further, separated the layers and aqueous layer extracted with toluene (2 x 160 ml). The organic layer was washed with EDTA disodium solution (20 ml), DM water (40 ml) and distilled out the solvent to obtained oily mass. (Yield: 33g) Example 11

Process for the preparation of Vortioxetine hydrochloride monohydrate
The mixture of 2-((2,4-dimethyIphenyl)thio)aniline (15 (g), to(2-chloroethyl)amine hydrochloride (27 g), potassium carbonate (21 g), potassium iodide (1 g), sulfolane (22 ... ml) and toluene (22 ml) were stirred at 110 to 115 °C for 40 hours. After completion of the reaction, the reaction mass was cooled to 25 to 30°C, toluene (60 ml), 13% sodium chloride aqueous solution (105 ml) were added and stirred the reaction mass for 2-3 hours. Filtered, washed with toluene (15 ml), DM water (60 ml) and dried under vacuum to obtain the title compound. (Yield : 13.5 g) Example 12
Process for the preparation of Vortioxetine hydrobromide
The mixture vortioxetine hydrochloride (13 g), ethyl acetate (104 ml) and DM water (45 ml) were stirred at 25 to 30 °C for 10 to 15 minutes. After that, pH of the reaction mixture was adjusted to 9.5 to 10.5 using aq. sodium hydroxide solution. The layers were separated and aqueous layer, extracted with ethyl acetate (26 ml). Combined organic layer washed with DM water (26 ml). To the organic layer 48 % aq. HBr solution (11.2 g) was added slowly at 25 to 30°C. The reaction mass was stirred at 20 to 30 °C for 12 to 15 hours. Filtered, washed with ethyl acetate and dried under vacuum to obtain the title" compound. (Yield: 15g) Example 13
Process for the preparation of Vortioxetine hydrobromide
The mixture of 2-((2,4-dimethylphenyl)thio)aniline (15 g)5 6/X2-chloroethyl)amine
hydrochloride (27 g), potassium carbonate (21 g), potassium iodide (1 g), sulfolane (22
ml) and toluene (22 ml) were stirred at 110 to 115 °C for 40 hours. After completion of
the reaction, the reaction mass was cooled to 25 to 30°C, toluene (60 nil), 13% sodium
chloride aqueous solution (105 ml) was added and stirred the reaction mass for 2-3
hours. Filtered, washed with toluene (15 ml) and DM water (60 ml). To the obtained wet
cake ethyl acetate (120 ml), DM water (45 ml) were added, stirred at 25 to 30°C for 10
to 15 minutes and adjusted pH of reaction mixture to 9.5 to 10.5 using aq. sodium
hydroxide solution. The layers were separated; aqueous layer was extracted with ethyl
acetate (30 ml). The combined organic layer was washed with DM water (30 ml).
Further, to the organic layer was added 48 % aq. HBr (1 Ig) at 20 to 30°C and stirred for
12 to 15 hours. Filtered, washed with ethyl acetate and dried under vacuum to obtain the
title compound. (Yield: 15 g) •

Example 14
Process for the preparation of Vortioxetine hydrobromide;
A mixture of vortioxetine free base (10 g) in acetone (100 ml) was stirred in 25 to 30° C
and 48 % aq. hydrobromic acid (6 g) was added. The reaction mass was stirred at 70 to
80° C for 1 hour and then added DM water (3 ml). The reaction mass was stirred at 70.
to 80 °C for 1 to 2 hours, cooled to 20 to 30 °C and stirred at 20 to 30 °C for 12 to 15
hours. Filtered, washed with acetone and dried under vacuum to obtain the title
compound. (Yield: 11.5 g).
Example 15 ^
Process for the purification of Vortioxetine hydrobromide
The mixture of vortioxetine hydrobromide (10 g) in acetone 100 ml was stirred at 25 to
30 °C. The temperature of reaction mixture was raised to 70 to 80° C, stirred for 1 hour
and added DM water (3 ml). Further, the reaction mass was stirred at 70 to 80° C for 1
to 2 hour, cooled to 20 to 30° C and stirred for 12 to 15 hours. Filtered, washed with
ethyl acetate and dried, under vacuum to obtain the title compound. (Yield: 8 g).
Example 16 /
Process for the preparation crystalline of Vortioxetine free base Vortioxetine free base oil (10 g) in acetonitrile (60 ml) was stirred at 20-30° C. Further, the reaction mass heated to 80 to 85°C and, stirred for 30 to 60 minutes. Then cooled to 20 to 30° C and stirred for 30 to 60 minutes. Filtered, washed with acetonitrile, dried . under vacuum to obtain the title compound. (Yield: 6.25g)

We claim:
1. A process for the preparation of vortioxetine or salts thereof comprising the steps of reacting benzothiazole compound of Formula 2
Formula 2
with compound of Formula 3

Formula 3
wherein X is F, CI, Br, I,
using suitable base in the presence of the suitable solvent, optionally in the presence of the catalyst, to provide amino intermediate of Formula 4; and

Formula 4
< • ■'
converting compound of formula 4 to vortioxetine or salts thereof.
2. The process as claimed in claim 1 for the preparation of vortioxetine or salts thereof,
comprising the steps of:
(a) reacting benzothiazole of Formula 2

Formula 2
with compound of Formula 3

1
J r
Formula 3
wherein X is F, CI, Br, I
using suitable base in the presence of a suitable solvent, optionally in the presence of catalyst, to provide amino intermediate of Formula 4;
_s
Formula 4
(b) coupling the compound of Formula 4 with disubstituted amino compound of Formula 5
or its salts thereof

Formula 5
wherein X is selected from F, CI, Br, I,
using suitable base in the presence of the suitable solvent, with or without use of-an activating agent, to provide vortioxetine free base; and
(c) optionally, converting vortioxetine free base into its salts thereof.
3. The process as claimed in claim 1 for preparation of vortioxetine hydrobrpmide via vortioxetine hydrochloride comprising the steps of:
(a) reacting benzothiazole of Formula 2

Formula 2
with compound of Formula 3 A


Formula 3A
using suitable base, optionally using catalyst, in the presence of suitable solvent to provide amino intermediate of Formula 4;

Formula 4
(b) coupling the compound of Formula 4 with bis(2-chloroethyl)amine hydrochloride of Formula 5 or its salts thereof

Formula 5A
y . . ■ .
using suitable base, optionally using catalyst, in the presence of suitable solvents to provides
to provide vortioxetine hydrochloride; and .
(c) converting vortioxetine hydrochloride into its hydrobromide salt thereof. .
4. The process as claimed in claim 1 to 3, wherein solvent is selected from the group
comprising of sulfoxide, sulfolane, amide, esters, ketone, nitrile, aliphatic or aromatic
hydrocarbons, chloro solvents, polar solvents, water and mixture thereof.
5. The process as claimed in claim 1 to 3, wherein in base is selected from inorganic or
organic base such as alkali or alkaline earth metal hydroxides, carbonates, bicarbonates,
alkoxides or tripotassiufn phosphate (K3PO4), tetramethyl ammonium
hydroxides(Me4NOH), tetraethylammonium hydroxide(Et4NOH), tetrabutyl ammonium
hydroxide(Bu4NOH), tetrabutylphosphonium hydroxide(Bu4POH), sodium with liquid
ammonia, sodamide, diisopropyl ethyl amine, triethyl amine, tributyl amine, TV-methyl
morpholine and pyridine.

6. The process as claimed in claim 1 to 3, wherein catalyst is selected from Cul, CuCl,
CuBr, Cui; £u2O, CuCh, CuBr2, CuSO4, FeCl3, Cu(OAc)2.H2O5 Cu(OAc)2.4H2O,
Ni(OAc)2.4H2O, Pd(OAc)2 and activating agent may be selected from sodium iodide (Nal),
potassium iodide (KI), Cul, CuCl , phase transfer catalyst such as tetra butylammonium
bromide (TBAB), tetrabutylammonium iodide (TBAI), tetrabutylammonium chloride
(TBAI). '
7. A process for the preparation of vortioxetine or salts thereof, comprising the steps of:
(a) reacting benzothiazole of Formula 2

Formula 2
with compound of Formula 3 A

Formula 3A
using aqueous tetrabutyl ammonium hydroxide solution, cuprous chloride to provide amino intermediate of Formula 4;
N.
I
< Formula 4
(b) coupling the compound of Formula 4 with bis(2-chloroethyl)amine hydrochloride of
Formula 5 or its salts thereof

Formula 5A

using potassium carbonate, potassium iodide in the presence of mixture of solvents

. sulfolane and toluene to provide vortioxetine free base; and .
.; ... .,
(c) optionally, converting vortioxetine free base into its salts thereof
8. A process for the preparation of vortioxetine hydrobromide, wherein amino intermediate compound of Formula 4 is prepared by the process comprising the steps of reacting benzothiazole of Formula 2

Formula 2
with compound of Formula 3 A
f
Formula 3A
using aqueous tetrabutyl ammonium hydroxide solution, cuprous chloride to provide amino intermediate of Formula 4.
s
Formula 4