CROSS REFERENCE TO RELATED APPLICATION This patent application claims the benefit of priority to Indian Provisional Patent Application No. 6843/CHE/2015, filed on December 23, 2015, which is incorporated herein by reference in its entirety.
5 FIELD OF THE INVENTION
The present invention relates to novel, commercially, viable and industrially advantageous processes for the preparation of 1 -[2-[(2,4-dimethylphehyl)sulfanyl] phenyl]piperazine, or a pharmaceutical^ acceptable salt thereof, using novel intermediates.
10 BACKGROUND OF THE INVENTION
U.S. Patent No. 7,144,884 B2 (hereinafter referred to as the '884 patent) discloses a variety of phenyl-piperazine derivatives as serotonin reuptake inhibitors. These compounds are useful in the treatment of an affective disorder, including depression, anxiety disorders and obsessive compulsive disorder. Among them, Vortioxetine Hydrobromide, l-[2-[(2,4-
15 dimethylphenyl)sulfanyl] phenyljpiperazine hydrobromide, is a serotonergic antidepressant that is indicated for the treatment of major depressive disorder (MDD). Vortioxetine Hydrobromide is represented by the following structural formula:
Vortioxetine Hydrobromide was approved by the FDA for use in the United States 25 to treat major depressive disorder and it is sold under the trade name BRTNTELLIX . BRINTELLIX is available in the market as 5 mg, 10 mg, 15 mg and 20 mg immediate release tablets.
Various processes for the preparation of Vortioxetine, its intermediates, and
pharmaceutical acceptable saits thereof are apparently described in U.S. Patent
30 Nos.7,144,884 and 8,722,684B2; U.S. Patent Application Publication No.
2014/0343287A1; PCT Publication Nos. WO2007/144005A1, WO 2013/102573A1,

WO2014/128207A1, WO2014/161976A1, WO2014/191548A1; Chinese Patent
Application Nos. CN103788019A, CN103788020A, CN103936694A, CN104109135A,
CN104130212A, CN104230852A, CN104292183A, CN104356092A, CN104447621A;
and Journal of Medicinal Chemistry 54, 3206-3221, 2011.
5 Various polymorphic forms of Vortioxetine hydrobromide are disclosed in U.S.
S Patent Nos. US 8,722,684, US 8,598,348, US 8,940,746; PCT Publication No.
WO2014/044721A1; and Chinese Patent Application Nos. CN104119298, CN104119299
and CN104447622. .
U.S. Patent No. 7,144,884' describes several synthetic routes for preparing 10 Vortioxetine. One of the synthetic routes described in the US'884 patent is depicted in scheme 1:

The processes for the preparation of Vortioxetine as described in the US'884 patent 5 suffer from several disadvantages such as the use of explosive reagents like n-butyl lithium and sodium hydride; use of highly flammable solvents like tetrahydrofuran and n-hexane; use of expensive reagents like ammonium hexafluorophosphate and polystyrene resins; use of expensive column chromatographic purifications; use of corrosive acids like hydrochloric acid; and use of tedious and cumbersome procedures like prolonged reaction 10 time periods; and thus resulting in a poor product yield and quality. Methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible.



The processes for the preparation of Vortioxetine and pharmaceutical acceptable salts thereof described in the aforementioned prior art suffer from various disadvantages such as the use of highly expensive and toxic reagents and/or catalysts like cesium carbonate, tetrabutylammonium bromide (TBAB), tris(dibenzylaetone)dipalladium 5 (pdidba^); bis-[2-(diphenylphqsphino)phenyl]ether (BINAP); 2,2'-bis(diphenylphosphino)-l,l'-binaphthalene (DPEPhos); use of corrosive reagents like hydrochloric acid; use of highly flammable and hazardous solvents like tetrahydrofuran, dimethylsulfoxide; use of tedious and cumbersome procedures like prolonged reaction times, multiple extractions using different solvents, multiple process steps, thus resulting in a poor product yield and 10 quality.
Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of Vortioxetine, its intermediates, and pharmaceutical acceptable salts thereof in commercial scale operations.
A need remains for improved and commercially viable processes of preparing 15 Vortioxetine, its intermediates, and pharmaceutical acceptable salts thereof with high yield and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.
SUMMARY OF THE INVENTION
20 The object of the present application is to provide novel and industrially
advantageous processes for the preparation of Vortioxetine, its intermediates, and pharmaceutical^ acceptable salts thereof with high yield and purity.
The present inventors have surprisingly and unexpectedly found that 2-[(2,4-dimethylphenyl)thio]aniline or an acid addition salt thereof, a key intermediate in the
25 preparation of Vortioxetine, can be prepared with high yield and high purity by reacting 2-amino-thiophenol or an acid addition salt thereof with a chlorinating agent, preferably N-chlorosuccinimide, in a suitable solvent to produce a. novel intermediate compound 2-amino-benzenesulfenyl chloride or an acid addition salt thereof, which is further reacted with (2,4-dimethylphenyl)magnesium halide in a suitable solvent to produce 2-[(2,4-
30 dimethylphenyl)thio]aniline or an acid addition salt thereof.

In one aspect, provided herein is a novel and industrially advantageous process for the preparation of 2-[(2,4-dimethylphenyl)thio]aniline5 or a salt thereof with high yield and purity.
In another aspect, provided herein is a novel compound 2-amino-benzenesulfenyl 5 chloride or an acid addition salt thereof.
In another aspect, provided herein is an improved process for preparing highly pure Vortioxetine, or a pharmaceutical^ acceptable salt thereof, preferably Vortioxetine hydrobromide, by reacting 2-[(2,4-dimethylphenyl)thio]aniline or a salt thereof with an N-protected bis(2-chloroethyl)amine or a salt thereof to produce N-protected Vortioxetine or 10 a salt thereof, followed by deprotection to produce Vortioxetine, or a pharmaceutical^ acceptable salt thereof.
The term "highly pure Vortioxetine or a pharmaceutical^ acceptable salt thereof r refers to .the Vortioxetine or a pharmaceutical acceptable salt thereof having purity greater than about 99.5%, specifically greater than about 99.8%, and more specifically 15 greater than about 99.95% (measured by HPLC).
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a novel process for the preparation of
Vortioxetine of formula I:
or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting a 2-amino-benzenesulfenyl chloride compound of formula 4:

or an acid addition salt thereof, with a (2,4-dimethylphenyl)magnesium halide compound of formula 5
wherein X is a halogen atom, to produce 2-[(2,4-dimethylphenyl)thio]aniline of formula 3:

or an acid addition salt thereof; and
b) condensing the 2-[(2,4-dimethylphenyl)thio]aniline of formula 3 or an acid addition
15 salt thereof with bis-(2-haloethyl)amine compound of formula 2:

.

( or an acid addition salt thereof, wherein X is a halogen atom; and radical 'R' represents H or. a nitrogen-protecting group 'P'; to produce Vortioxetine of formula 1 or a pharmaceutical^ acceptable salt thereof; or an N-protected Vortioxetine of formula
1(a):
25
or a salt thereof, followed by converting the compound of formula 1(a) obtained into highly pure Vortioxetine of formula 1 or a pharmaceutically acceptable salt thereof.

Exemplary pharmaceutically acceptable salts of the Vortioxetine of formula 1 include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, and tartrate. A most specific pharmaceutical ly acceptable salt of 5 the Vortioxetine of formula 1 is hydrobromide salt.
Unless otherwise specified, the term 'salt' as used herein may include acid addition salts and base addition salts.
Unless otherwise specified, the term 'acid addition salts', as used herein, include the salts that are derived from organic and inorganic acids. For example, the acid addition 10 salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, tpluenesulfonic acid, malic acid, ascorbic acid, and the like.
Exemplary acid addition salts include, but are not limited .to,"hydrochloride, 15 hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like.
Unless otherwise specified, the solvents used for isolating and/or recrystallizing the compounds obtained by the processes described in the present application is generally selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl 20 alcohol, acetone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
In one embodiment, the halogen atom 'X' in the compounds of formulae 2 and 5 is, each independently, selected from the group consisting of CI, Br and I; and most 25 specifically the halogen atom is CI or Br.
In one embodiment, the radical 'R' in the compound of formula-2 is H. In another embodiment, the radical 'R' in the compound of formula 2 is a nitrogen-protecting group
cp,
Exemplary nitrogen protecting group 'P' in the compounds of formulae 2 and 1(a)
30 includes, but are not limited to, a substituted or unsubstituted arylsulfonyl, an
aklylsulfonyl, a substituted or unsubstituted trityl, an aliphatic acyl group including an

alkanoyl group, an aromatic acyl group including an arylcarbonyl group, an alkoxycarbonyl group, and the like.
In one embodiment, the nitrogen protecting group 'P' is selected from the group
consisting of methanesulfonyl, p-toluenesulfonyl, 4-nitrobenzenesulfonyI, tert-
5 butyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl,
isopropyloxycarbonyl acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl,
chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, cyclopropylcarbonyl,
cyclobutylcarbonyl, benzoyl, 4-chlorobenzoyl, p-nitrobenzoyl, trityl, and the like. v
Specifically, the nitrogen-protecting group CP' is selected from the group consisting 10 of methanesulfonyl, p-toluenesulfonyl, 4-nitrobenzenes.ulfonyl, tert-butyloxycarbonyl; and most specifically, the nitrogen-protecting group CP' is p-toluenesulfonyl or tert-butyloxycarbonyl.
The term "alkyl", as used herein, denotes an aliphatic hydrocarbon group which
may be straight or branched having 1 to 12 carbon atoms in the chain. Preferred alkyl
15 groups have 1 to 6 carbon atoms in the chain. The alkyl may be substituted with one or
more "cycloalkyl groups". Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-
propyl, n- butyl, iso-butyl, t-butyl, and n-pentyl.
The term "cycloalkyl", as used herein, denotes a non-aromatic mono- or
multicyclic ring system of 3 to 10 carbon atoms, preferably of about 5 to 10 carbon atoms.
20 Exemplary monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and
the like.
The term "aryl", as used herein, denotes an aromatic monocyclic or multicyclic ring system of 6 to 10 carbon atoms. The aryl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. 25 Exemplary aryl groups include phenyl, tolyl, nitrophenyl or naphthyl.
In one embodiment, the reaction between the compounds of formula 4 and formula
5 in step-(a) is carried out in the presence of a solvent or a mixture of solvents. Exemplary
solvents used in step-(a) include, but are not limited to, a halogenated hydrocarbon solvent,
an aromatic hydrocarbon solvent, an aliphatic hydrocarbon solvent, a cyclic ether solvent,
30 an aliphatic ether solvent, and mixtures thereof.
Specifically, the solvent used in step (a) is selected from the group consisting of, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether,

methyl tert-butyl ether, monoglyme, diglyme, n-pentane, n-hexane5 n-heptane,
cyclohexane, toluene, o-xylene, dichloromethane, and mixtures thereof. Most specifically,-
the solvent used in step-(a) is selected from the group consisting of tetrahydrofiiran, 2-
methyl-tetrahydrofuran, toluene, dichloromethane, and mixtures thereof.
5 In one embodiment, the reaction in step-(a) is carried out at a temperature of about
0°C to about the reflux temperature of the solvent used, and more specifically at a temperature of about 15°C to about 45°C. The reaction time may vary between about 2 hours to about 10 hours, and specifically about 3 hours to about 9 hours.
The reaction mass containing the 2-[(2,4-dimethylphenyl)thio]aniline of formula 3
10 or an acid addition salt thereof obtained in step-(a) may be subjected to usual work up methods such as a washing,1 an extraction, a pH adjustment, an evaporation, a layer separation, decolonization, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula 1, or the compound of formula 3 or an acid addition salt thereof may be isolated and/or recrystallized and then
15 used in the next step.
In one embodiment, the compound of formula 3 or an acid addition salt thereof may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
20 In one embodiment, the acid addition salts of compounds of formulae 2, 3 and 4
include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like
Specifically, the acid addition salt of compounds of formulae 2, 3 and 4 is a
25 hydrochloride salt or a hydrobromide salt.
In one embodiment, the reaction of the compound of formula 2 with the compound of formula 3 in step-(b) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(b) include, but are not limited to, an alcohol, a ketone, an ester, a halogenated solvent, a hydrocarbon solvent, a cyclic ether, an aliphatic ether, and
30 mixtures thereof
Specifically, the solvent used in step (b) is selected from the group consisting of, methanol, ethanol, n-propanol, 2-propanol, n-butanol, sec-butanol, tert-butanol, ethyl

acetate, isopropyl acetate, tert-butyl methyl acetate, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, o-xylene, and mixtures thereof. Most 5 specifically, the solvent used in step-(b) is toluene, o-xylene or diglyme.
In one embodiment, the reaction in step-(b) is carried out at a temperature of about 30°C to the reflux temperature of the solvent used, specifically at a temperature of about 70°C to the reflux temperature of the solvent used, and more specifically at a temperature of about 100°C to about 140°C. The reaction time may vary from about 5 hours to about
10 75 hours.
The reaction mass containing the Vortioxetine of formula 1 or a pharmaceutical^ acceptable salt thereof obtained in step-(b) may be subjected to usual work up such as a washing, an extraction, an evaporation, a pH adjustment etc., followed by isolation and/or recrystallization from a suitable solvent by conventional methods such as cooling, seeding,
15 partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The conversion of the N-protected Vortioxetine of formula 1(a) into highly pure Vortioxetine of formula 1, or a pharmaceutically acceptable salt thereof, is carried out by deprotecting the compound of formula 1(a) with a suitable reagent as per the processes
20 described herein below or by the known methods.
In one embodiment, the deprotection of the compound of formula 1(a) is carried out by reacting the compound of formula 1(a) with a suitable deprotecting agent such as an acid or a base, in a reaction inert solvent.
The base used for deprotection is an organic or an inorganic base. Exemplary bases
25 include, but are not limited to, methylamine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and 1-alkylimidazole; and hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals. Specific bases are triethylamine, diisopropylethylamine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium
30 carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.

The acid used for deprotection is an organic or inorganic acid. Exemplary acids
include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric
acid, phosphoric acid, acetic acid, formic acid, and the like, or a combination thereof. A
most specific acid is hydrochloric acid or hydrobromic acid.
5 For example, the acid used may be in the form of aqueous solution or in the form of
a solution in an organic solvent. The organic solvent used for dissolving the acid is selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone.
In one embodiment, the solvent used for deprotection is selected from the group
10 consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, acetone, ethyl
acetate, toluene, xylene, tetrahydrofuran, 2-methyl-tetrahydrofuran, dioxane, diethyl ether,
diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, N,N-dimethylformamide,
N,N-dimethylacetamide, dichloromethane, dichloroethane, chloroform, and mixtures
thereof.
15 The reaction temperature and time periods for deprotection of the compound of
formula 1(a) will ordinarily depend on the starting compounds and the solvent employed in the reaction. In one embodiment, the deprotection is carried out at a temperature of about 0°C to the reflux temperature of the solvent used and specifically at a temperature of about 30°C to the reflux temperature of the solvent used.
20 According to another aspect, there is provided a novel process for the preparation
of 2-[(2,4-dimethylphenyl)thio]aniline of formula 3:

25
or an acid addition salt thereof, comprising reacting a 2-amino-benzenesulfenyl chloride compound of formula 4:

or an acid addition salt thereof, with a (2,4-dimethylphenyl)magnesium halide compound
of formula 5: .
wherein X is a halogen atom, to produce 2-[(2,4-dimethylphenyl)thio]aniline of formula 3
or an acid addition salt thereof, and optionally converting the compound of formula 3 10 obtained into highly pure Vortioxetine of formula 1 or a pharmaceutical^ acceptable salt
thereof, preferably Vortioxetine hydrobromide salt.
In one embodiment, the halogen atom 'X' in the compound of formula 5 is selected
from the group consisting of CI, Br and I; and most specifically the halogen atom is CI or
Br.
15 The reaction between the 2-amino-benzenesulfenyl chloride of formula 4 and (2,4-
dimethylphenyl)magnesium halide compound of formula 5 is carried out by the methods
using the conditions, parameters and solvents as described hereinabove.
According to another aspect, there is provided a novel 2-amino-benzenesulfenyl
chloride compound of formula 4:
or an acid addition salt thereof.
25 In one embodiment, the acid addition salt of 2-amino-benzenesulfenyl chloride of
. formula 4 is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like.
Specifically, the acid addition salt of compound of formula 4 is a hydrochloride salt 30 or a hydrobromide salt.
According to another aspect, there is provided a process for the preparation of 2-amino-benzenesulfenyl chloride compound of formula 4:

4

5 or an acid addition salt thereof, comprising reacting 2-amino-thiophenol of formula 6:

10 or an acid addition salt thereof, with a suitable chlorinating agent to produce 2-amino-benzenesulfenyl chloride of formula 4 or an acid addition salt thereof.
In one embodiment, the chlorinating agent used in the above reaction is selected
from the group consisting of N-chlorosuccinimide, thionyl chloride and phosphorous
. pentachloride. A most preferable chlorinating agent is N-chlorosuccinimide.
15 In one embodiment, the reaction between the 2-amino-thiophenol of formula 6 and
the chlorinating agent is carried out in the presence of a solvent or a mixture.of solvents.
Exemplary solvents used in the chlorination reaction include, but are not limited to, a
halogenated hydrocarbon solvent, an aromatic hydrocarbon solvent, an aliphatic
hydrocarbon solvent, a cyclic ether solvent, an aliphatic ether solvent, and mixtures
20 thereof.
Specifically, the solvent used in the chlorination reaction is selected from the group consisting of tetrahydrofuran, "2-methyl-tetrahydrofuran, toluene, dichloromethane, and mixtures thereof. A most specific solvent is toluene.
In one embodiment, the reaction between the 2-amino-thiophenol of formula 6 and 25 the chlorinating agent is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, and more specifically at a temperature of about 20°C to about 40°C. The reaction time may vary between about 30 minutes to about 4 hours.
In another embodiment, the reaction between the 2-amino-thiophenbI of formula 6 and the chlorinating agent is optionally carried out in the presence of a suitable base. The 30 base can be an organic or an inorganic base selected from the group as described hereinabove.

.V
The reaction mass containing the 2-amino-benzenesuIfenyl chloride of formula 4 or an acid addition salt thereof obtained in the above reaction may be subjected to usual work up and/or isolation methods as described hereinabove.
According to another aspect, there is provided a novel process for the preparation 5 of Vortioxetine of formula I:

or a pharmaceutically acceptable salt thereof, which comprises: a) reacting 2-[(2,4-dimethylphenyl)thio]aniline of formula 3:
NH2 CH3
or an acid addition salt thereof with a protected bis-(2-haloethyl)amine compound of formula 2(a):

25 or a salt thereof, wherein X is a halogen atom; and *P' represents a nitrogen-protecting
group; to produce an N-protected Vortioxetine of formula 1(a):

or a salt thereof, wherein T5 represents a nitrogen-protecting group; and
b) deprotecting the compound of formula 1(a) with a deprotecting agent is suitable solvent
to produce highly pure Vortioxetine of formula 1 or a pharmaceutical^ acceptable salt
thereof, preferably Vortioxetine hydrobromide salt.
5 In one embodiment, the halogen atom 'X' in the compounds of formula 2(a) is
selected from the group consisting of CI, Br and I; and most specifically the halogen atom is CI or Br.
In one embodiment, the nitrogen-protecting group 'P' in the compound of formula
2(a) is selected from the group as described hereinabove.
10 Specifically, the nitrogen-protecting group T' is selected from the group consisting
of methanesulfonyl, p-toluenesulfonyl, 4-nitrobenzenesulfonyl and tert-butyloxycarbonyl; and most specifically, the nitrogen-protecting group CP' is p-toluenesulfonyl or tert-butyloxycarbonyl.
In one embodiment, the reaction of the compound of formula 2(a) with the
15 compound of formula 3 in step-(a) is carried out in the presence of a solvent or a mixture
of solvents. Exemplary solvents used in step-(a) include, but are not limited to, an alcohol,
a ketone, an ester, a hajogenated n solvent, a hydrocarbon solvent, a cyclic ether, ah
aliphatic ether, and mixtures thereof.
Specifically, the solvent used in step (a) is selected from the group consisting of,
20 . methanol, ethanol, n-propanol, 2-propanol, n-butanol, sec-butanol, tert-butanol, ethyl
acetate, isopropyl acetate, tert-butyl methyl acetate, acetone, methyl ethyl ketone, methyl
isobutyl ketone,, methyl tert-butyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran,
dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, n-
pentane, n-hexane, n-heptane, cyclohexane, toluene, o-xylene, and mixtures thereof.
25 In one embodiment, the reaction in step-(a) is carried out at a temperature of about
30°C to the reflux temperature of the solvent used, specifically at a temperature of about
50°C to the reflux temperature of the solvent used, and more specifically at a temperature
of about 50°C to about 140°C. The reaction time may vary from about 5 hours to about 30
hours.
30 The reaction mass containing the N-protected Vortioxetine of formula 1(a) or a salt
thereof obtained in step-(a) may be subjected to usual work up and/or isolation methods as described hereinabove.

v The reaction mass containing the N-protected Vortioxetine of formula 1(a) or a salt
thereof obtained in step-(a) may be used directly in the next step to produce the compound
of formula 1, or the compound of formula 1(a) or a salt thereof may be isolated and/or
recrystallized and then used in the next step.
5 In one embodiment, the deprotection in step-(b) is carried out by deprotecting the
compound of formula 1(a) with a suitable reagent as per the processes described herein below or by the known methods.
In one embodiment, the deprotecting agent used in step-(b) is an acid or base selected from the group as described hereinabove.
10 In another embodiment, the solvent used for deprotection is selected from the
group as described hereinabove.
The reaction temperature and time periods for deprotection of the compound of formula 1(a) will ordinarily depend on the starting compounds and the solvent employed in the reaction. In one embodiment, the deprotection is carried out at a temperature of about
15 0°C to the reflux temperature of the solvent used and specifically at a temperature of about 30°C to the reflux temperature of the solvent used.
Unless otherwise specified, the products and/or intermediate compounds prepared
. by the processes described in the present application may be collected by filtration,
filtration under vacuum, decantation, centrifugation, filtration employing a filtration media
20 of a silica gel or celite, or a combination thereof. For example, the compounds obtained by
the processes disclosed herein above may be further dried as per the methods described
hereinbelow.
Unless otherwise specified, the products and/or intermediate compounds obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a
25 Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.
30 In one embodiment, the drying is carried out at atmospheric pressure or reduced
pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 90°C, and specifically at about 50°C to about 85°C. The

drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications.
As used herein, the term "reflux temperature" means the temperature at which the 5 solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term "room temperature" or "RT" refers to a temperature of about 20°C to about 35°C, preferably to a temperature of about 25°C to about 30°C.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
10
EXAMPLES
Example 1
Preparation of 2-[(2,4-dimethylphenyl)thio]aniline Step-A: Synthesis of 2-amino-benzenesulfenylchloride
15 2-Amino-thiophenol (27 g) and toluene (135 ml) were taken into a reaction flask at room temperature. To the resulting mass, N-chlorosuccinimide (31.6 g) was added slowly by maintaining the temperature at 25-30°C and maintained for 1 hour to 1 hour 30 minutes at the same temperature. After completion of the reaction, the reaction mass was filtered to give 2-amino-benzesulfenylchloride.
20 Step-B: Synthesis of 2,4-dimethylphenylmagnesium bromide
A mixture of activated Magnesium turnings (10.5 g), iodine (10 mg) and dry tetrahydrofuran (75 ml) was taken into a reaction flask under nitrogen atmosphere, followed by heating the mixture while stirring to 55-60°C. A solution of 2,4-dimethylbromobenzene (30 g) in dry tetrahydrofuran (30 ml) was slowly added drop-wise
25 to the resulting mass over a period of 30-45 minutes. The resulting mixture was stirred for 2 hours at 55-60°C under nitrogen atmosphere to yield the Grignard reagent, 2,4-dimethylphenylmagnesium bromide as a solution in tetrahydrofuran. Step-C: Synthesis of 2-[(2,4-dimethylphenyl)thio]aniline The filtrate containing the 2-amino-benzenesulfenylchloride (obtained in step-A) was
30 added to a solution of 2,4-dimethylphenylmagnesium bromide in tetrahydrofuran (obtained in step-B) at room temperature. A rise in the temperature of the reaction mass up to 40°C was observed. The resulting mass was cooled to room temperature and then stirred for 8 to

9 hours at the same temperature. To the resulting mass, ethyl acetate (200 ml) and water (200 ml) were added. The precipitated solid was filtered. The filtrate was initially washed with potassium carbonate (90 ml), followed by water (100 ml). The solvent was removed by distillation to obtain a residue. To the residue, a mixture of water: acetone: HC1 (1:1:1) 5 (150 ml), followed by washing with butyl acetate (100 ml). The aqueous layer was extracted twice with dichloromethane (100 ml x 2). The MDC layer was washed with water (50 ml x 3), followed by removing the solvent by distillation under vacuum to produce 2-[(2,4-dimethylphenyl)thio]aniline.
10 Example 2
Preparation of Vortioxetine hydrochloride
A mixture of 2-[(2,4-dimethylphenyl)thio]aniline (6.5 g), bis(2-chloroethyl)amine hydrochloride (7.6 g) o-xylene (26 ml) were taken into a reaction flask at room temperature. The resulting mixture was heated to 145°C under stirring, followed by
15 maintaining for 72 hours at the same temperature. The reaction mass was cooled to 40-45°C. The separated solid was filtered, washed twice with o-xylene (2x5 ml) and then dried the material under vacuum at 45-50°C to produce crude Vortioxetine hydrochloride. The crude product was further purified by recrystallization with acetone (2 x 40 ml) and then dried to produce 6 g of pure Vortioxetine hydrochloride as an off-white to beige
20 colored powder (Melting range: 227°C-229°C; HPLC purity: 99.5%; and Yield: 63%).
Example 3 Preparation of Vortioxetine hydrobromide
Vortioxetine hydrochloride (9.5 g) was added to toluene (95ml) in a reaction flask, 25 followed by the addition of 46-48% aqueous hydrobromic acid (6.62 ml). The resulting mixture was stirred for 6 hours at room temperature, the separated solid was filtered, washed with toluene (2x10 ml) twice and then dried under vacuum at 45°C to 50°C to produce crude Vortioxetine hydrobromide. The crude product was recrystallised from acetone and then dried under vacuum at room temperature to afford 10 g of pure 30 Vortioxetine hydrobromide as an off-white toNbeige colored solid (HPLC purity: 99.9%; and Yield: 93%).