FIELD OF THE INVENTION

The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of phenyl-piperazine derivatives which act as serotonin reuptake inhibitors, preferably l-[2-(2,4-dimethylphenylsulfanyl)phenyl]-5 piperazine hydrobromide salt and its intermediates thereof.

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 10 are useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder. Among them, Vortioxetine, chemically named l-[2-[(2,4-dimethylphenyl)sulfanyl] phenyljpiperaziiie, is a serotonergic antidepressant that acts as an antagonist on the 5-HT3, 5-HT and 5-HTJD receptors, antagonist on the 5-HT1A receptor, a partial agonist on the 5- 15 HTIB receptor, and an inhibitor of the serotonin transporter. Vortioxetine Hydrobromide is represented by the following structural formula:

Vortioxetine Hydrobromide was approved by the USFDA for the treatment of TM 25 major depressive disorder and it is sold under the trade name BRINTELLIX 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, afld pharmaceutical acceptable salts thereof are apparently described in U.S. Patent Nos. US 30 7,144,884 and US 8,722,684; 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 CN103788019A, CN103788020A, CN103936694A, CN104109135A, CN104130212A, CN 104230852, CN 104292183A, CN104356092A, CN 104447621 A; and Journal of Medicinal Chemistry 54, 3206-3221, 2011. Various polymorphic forms of Vortioxetine hydrobromide are disclosed in U.S. 5 Patent Nos. US 8,722,684, US 8,598,348, US 8,940,746; PCT Publication No. WO 2014/044721A; and Chinese Patent Application Nos. CN104119298, CN104119299 and CN 104447622. U.S. Patent No. 7,144,884 describes several synthetic routes for preparing Vortioxetine. One of the synthetic routes described in the US'884 patent is depicted in 10 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 corrosive acids like hydrochloric acid; use of tedious and cumbersome procedures like prolonged reaction time periods; and thus resulting in a poor product yield and quality.

Various alternative palladium catalyzed processes for the preparation of Vortioxetine are apparently described in PCT Publication Nos. WO 2007/144005 Al and WO 2013/102573 Al. These processes require the use of expensive materials like palladium catalyst and a phosphine ligand.

Bang-Andersen et al. J. Med. Chem. (2011), Vol..54, 3206-3221 describes a process for the preparation of Vortioxetine which is depicted in below Scheme-20:

The processes for the preparation of Vortioxetine and pharmaceutical acceptable salts thereof described in the aforementioned prior art suffer from various disadvantages 10 such as. the use of highly expensive and toxic reagents and/or catalysts like cesium carbonate, tetrabutylammonium bromide (TBAB), tris(dibenzylaetone)dipalladium (pd2dba3); bis-[2-(diphenylphosphino)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 15 tedious and cumbersome procedures like prolonged reaction times, multiple extractions using different solvents, multiple process steps, thus resulting in a poor product yield and 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 20 acceptable salts thereof in commercial scale operations.

A need still remains for novel and environmentally friendly processes of preparing 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.

5 SUMMARY OF INVENTION

The object of the present invention is to provide novel and environmentally friendly 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-[(2,4-10 dimethylphenyl)thio]aniline, a key intermediate in the preparation of Vortioxetine, can be prepared with high yield and purity by subjecting 2,2'-diamino-diphenyl disulfide to Grignard reaction with (2,4-dimethylphenyl)magnesium halide in a suitable solvent.
In one aspect, provided herein is a novel and industrially advantageous process for the preparation of Vortioxetine, or a pharmaceutical^ acceptable salt thereof, and its 15 intermediates with high yield and purity.

In another aspect, provided herein is an improved process for preparing highly pure Vortioxetine hydrobromide by reacting Vortioxetine hydrochloride salt with aqueous hydrobromic acid.

In another aspect, provided herein is an improved process for preparing highly pure 20 Vortioxetine hydrobromide by reacting 2-[(2,4-dimethylphenyl)thio]aniline with bis(2-chloroethyl)amine hydrobromide.

The term "highly pure Vortioxetine or a pharmaceutically acceptable salt thereof 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 25 greater than about 99.95% (measured by HPLC). For example, the purity of Vortioxetine or a pharmaceutical^ acceptable salt thereof, preferably vortioxetine hydrobromide, obtained by the process disclosed herein can be about 99.5% to about 99.99% as measured by HPLC.

30 DETAILED DESCRIPTION OF THE INVbN 11UJN

According to one aspect, there is provided a novel and industrially advantageous process for the preparation of Vortioxetine of formula 1: or a pharmaceutically acceptable salt thereof, which comprises: a) reacting 2,2'-diamino-diphenyl disulfide of formula 3: or an acid addition salt thereof, with a Grignard reagent of formula 5: wherein X is a halogen atom, to produce 2-[(2,4-dimethylphenyl)thio]aniline of formula 2: or an acid addition salt thereof; and 25 b) condensing the 2-[(2,4-dimethylphenyl)thio]aniline of formula 2 or an acid addition salt thereof with bis-(2-haloethyl)amine of formula 6:
or an acid addition salt thereof, wherein X is a halogen atom; to produce Vortidxetine of formula I or a pharmaceutically acceptable salt thereof, and optionally converting the compound of formula I or a pharmaceutically acceptable salt thereof obtained into highly pure Vortioxetine hydrobromide salt. Exemplary pharmaceutically acceptable salts of the Vortioxetine of formula I include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate,

5 acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, and tartrate. A most specific pharmaceutically acceptable salt of the Vortioxetine of formula I is hydrobromide salt.
Unless otherwise specified, the term 'salt' as used herein may include acid addition salts and base addition salts.

10 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 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 15 acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and.the like.

Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like.

In one embodiment, the halogen atom 'X' in the compounds of formulae 5 and 6 is, 20 each independently, selected from the group consisting of CI, Br and I; and most specifically the halogen atom is CI or Br..

In another embodiment, the reaction 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 hydrocarbon solvent, an aliphatic ether solvent, a cyclic ether solvent, a polar 25 aprotic solvent, a halogenated hydrocarbon 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, n-pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene and mixtures thereof. A most specific solvent used in step-(a) is tetrahydrofuran.

30 The reaction temperature and time period will ordinarily depend on the starting eompoctfTcfc and the sohent employed in the reaction. Specifically, the reaction in step-(a) is carried out at a temperature of about -10°C to about 50°C, and more specifically at a temperature of about -5°C to about 35°C. The reaction time may vary between about 30 minutes to about 5 hours, and specifically about 45 minutes to about 3 hours.

5 The reaction mass containing the 2-[(2,4-dimethylphenyl)thio]aniline of formula 2
or an acid addition salt thereof obtained in step-(a) may be subjected to usual work up methods such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, 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

10 formula 2 or an acid addition salt thereof may be isolated and/or recrystallized and then used in the next step.

In one embodiment, the compound of formula 2 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

15 anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.

Unless otherwise specified, the solvent 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, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is 20 selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl 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 acid addition salts of compounds of formulae 2 and 6 used

25 in step-(b) include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like Specifically, the acid addition salt of 2-[(2,4-dimethylphenyl)thio]aniline of formula 2 used in step-(b) is a hydrochloride salt or a hydrobromide salt.

30 Specifically, the acid addition salt of bis-(2-haloethyl)amine of formula 6 used in step-(b) is a hydrochloride salt or a hydrobromide salt. In one embodiment, the reaction 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 mixtures thereof.
5 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, di isopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, n- 10 pentane, n-hexane, n-heptane, cyclohexane, toluene, o-xylene, and mixtures thereof. Most 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 15 of about 100°C to about 140°C. The reaction time may vary from about 5 hours to about 80 hours.

The reaction mass containing the Vortioxetine of formula I or a pharmaceutically 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

20 recrystallization 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.

The conversion of the Vortioxetine of formula I or a pharmaceutically acceptable salt thereof into highly pure Vortioxetine hydrobromide salt can be carried out as per the 25 processes described herein below or by the known methods.

The highly pure Vortioxetine, or a pharmaceutically acceptable salt thereof, obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a 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 30 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.

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 5 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. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed dryer, spin flash dryer, flash dryer, and the 10 like.

The 2,2'-diamino-diphenyl disulfide of formula 3 used as starting material in the present invention can be prepared by the methods described hereinafter in the present application, or by the methods known in the art, for example, as per the processes described in GB Patent No. 558,887.

15 According to another aspect, there is provided a process for the preparation of 2,2f- diamino-diphenyl disulfide of formula 3:

20 or an acid addition salt thereof, comprising reacting 2-amino-thiophenol of formula 7:

25 or an acid addition salt thereof, with a suitable base in a suitable solvent to produce the compound of formula 3.

In one embodiment, the base used in the above reaction is an organic or an 30 inorganic base.

Exemplary bases 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 carbonate, sodium bicarbonate, potassium 5 bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and most specifically, the base is triethylamine. Exemplary solvents used in the above reaction include, but are not limited to, water, an alcohol, a hydrocarbon solvent, a nitrile solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof

10 Specifically, the solvent is selected from the group consisting of water, acetonitrile, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, toluene, xylene, tetrahydrofuran, 2- methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, N,N-dimethylformamide, N,N-dimethyIacetamide, dichloromethane, dichloroethane, and mixtures thereof. A most specific solvent is N,N-15 dimethylformamide. The reaction temperature and time period will ordinarily depend on the starting compounds and the solvent employed in the reaction. In one embodiment, the reaction between the compound of formula 7 and the base is carried out at a temperature of about 0°C to the reflux temperature of the solvent used,

20 specifically at a temperature of about 50°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 3 hours to about 25 hours. The reaction mass containing the 2,2'-diamino-diphenyl disulfide of formula 3 obtained may be subjected to usual work up methods as described hereinabove.

25 In one embodiment, the 2,2'-diamino-diphenyl disulfide of formula 3 is isolated and/or re-crystallized from a suitable solvent by the methods as described hereinabove. According to another aspect, there is provided a process for the preparation of 2,2f-diamino-diphenyl disulfide of formula

30 or an acid addition salt thereof, which comprises reducing 2,2'-dinitro-diphenyl disulfide of formula 4: with a reducing agent to produce the compound of formula 3 or an acid addition salt thereof. The 2,2!-dinitro-diphenyl disulfide of formula 4 used as starting material in the 10 present invention can be prepared by the methods known in the art, for example, as per the processes described in US Patent No. 5,502,256.

Exemplary reducing agents used for reducing the compound of formula 4 includes, but are not limited to, iron powder and ammonium chloride, zinc dust and ammonium chloride, iron powder and ammonium formate, zinc dust and ammonium formate, iron 15 powder and hydrochloric acid, zinc dust and hydrochloric acid, sodium dithionite and the like, or a combination thereof. A most specific reducing agent is iron powder and ammonium chloride.

In one embodiment, the reduction is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in the above reaction include, but are not 20 limited to, water, an alcohol, and mixtures thereof.

Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, and mixtures thereof. A most specific solvent is aqueous methanol.

The reaction temperature and time period will ordinarily depend on the starting 25 compounds and the solvent employed in the reaction.
In one embodiment, the above reduction reaction is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 40°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 5 hours 3 to about 25 hours.

The reaction mass containing the 2,2-diamino-diphenyI disulfide of formula 3 obtained may be subjected to usual work up methods as described hereinabove. In one embodiment, the 2,2'-diamino-diphenyl disulfide of formula 3 is isolated and/or re-crystallized from a suitable solvent by the methods as described hereinabove.

According to another aspect, there is provided an improved process for the preparation of highly pure Vortioxetine hydrobromide, comprising: 5

a) contacting an acid addition salt of Vortioxetine (other than hydrobromide salt) with an aqueous solution of hydrobromic acid in a first solvent to produce a reaction mass containing Vortioxetine hydrobromide;

b) optionally, isolating the Vortioxetine hydrobromide from the reaction mass obtained in step-(a), followed by extracting, suspending or dissolving the Vortioxetine 10 hydrobromide in a second solvent; and

c) isolating and/or recovering the highly pure Vortioxetine hydrobromide either from the reaction mass obtained in step-(a) or from the solution or suspension obtained in step- (b). In one embodiment, the acid addition salt of Vortioxetine used in step-(a) is 15 selected from the group consisting of, hydrochloride, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fiimarate, benzenesulfonate, toluenesulfonate, citrate and tartrate. A most specific acid addition salt of Vortioxetine used in step-(a) is hydrochloride salt. Exemplary first solvents used in step-(a) include, but are not limited to, water, an 20 alcohol, a chlorinated hydrocarbon, a hydrocarbon, an ester, an ether, a polar aprotic solvent, and mixtures thereof. In one embodiment, the first solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, ethyl acetate, methyl acetate, isopropyl acetate, tert- butyl methyl acetate, ethyl 25 formate, dichloromethane, dichloroethane, chloroform, n- pentane, n-hexane, n-heptane, cyclohexane, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, N,N-dimethylformamide,N,N-dimethylacetamide,dimethylsulfoxide, sulfolane, and mixtures thereof.

Specifically, the first solvent is selected from the group consisting of water, 30 methanol, ethanol, isopropyl alcohol, toluene, and mixtures thereof.

In one embodiment, the contacting in step-(a) is carried out under stirring at a temperature of below about reflux temperature of the solvent used for at least 10 minutes,

specifically at a temperature of about 0°C to about 80°C for about 30 minutes to about 10 hours, and more specifically at about 20°C to about 60°C for about 2 hours to about 6 hours.

Exemplary second solvents used in step-(b) include, but are not limited to, water, 5 an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, an ester, a nitrile, an ether, a polar aprotic solvent, and mixtures thereof

In one embodiment, the second solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, amyl alcohol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert- 10 butyl ketone, acetonitrile, ethyl acetate, methyl acetate, isopropyl acetate, tert- butyl methyl acetate, dichloromethane, dichloroethane, n-pentane, n-hexane, cyclohexane, toluene, xylene, tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, monoglyme, diglyme, N,N-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, and mixtures thereof.

15 Specifically, the second solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof; and a most specific second solvent is acetone. .

The reaction mass obtained in step-(a) or the solution obtained in step-(b) is, each 20 independently, optionally subjected to carbon treatment or silica gel treatment. The carbon treatment or silica gel treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon or silica gel at a temperature of below about 80°C for at least 10 minutes, specifically at a temperature of about 40°C to about 70°C for at least 20minutes; and filtering the resulting mixture through hyflo to obtain a

25 filtrate containing Vortioxetine hydrobromide by removing charcoal or silica gel. Specifically, the finely powdered carbon is an active carbon. A specific mesh size of silica gel is 40-500 mesh, and more specifically 60-120 mesh.
The isolation of Vortioxetine hydrobromide in step-(b) and step-(c) is, each independently, carried out by forcible crystallization, spontaneous crystallization, 30 substantial removal of the solvent from the solution or suspension, or a combination thereof.

Spontaneous crystallization refers to crystallization without the help of an external aid such as seeding, cooling etc., and forcible crystallization refers to crystallization with the help of an external aid.

Forcible crystallization may be initiated by a method usually known in the art such 5 as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, or a combination thereof.

The term "anti-solvent" refers to a solvent which when added to an existing solution of a substance reduces the solubility of the substance.

Exemplary anti-solvents include, but are not limited to, water, an alcohol, a ketone, 10 a chlorinated hydrocarbon, a hydrocarbon, an ester, a nitrile, an ether, a polar aprotic solvent, and mixtures thereof.

In one embodiment, the crystallization is carried out by cooling the solution under stirring at a temperature of below 35°C for at least 10 minutes, specifically at about -10°C to about 30°C for about 30 minutes to about 10 hours.

15 Removal of solvent is accomplished, for example, by substantially complete evaporation of the solvent, concentrating the solution or distillation of solvent, under inert atmosphere to obtain pure Vortioxetine hydrobromide.

In one embodiment, the solvent is removed by evaporation. Evaporation can be achieved at sub-zero temperatures by lyophilisation or freeze-drying techniques. The 20 solution may also be completely evaporated in, for example, a pilot plant Rota vapor, a Vacuum Paddle Dryer or in a conventional reactor under vacuum above about 720 mm Hg by flash evaporation techniques by using an agitated thin film dryer, or evaporated by spray drying to obtain a dry amorphous powder.

The distillation process can be performed at atmospheric pressure or reduced 25 pressure. Specifically, the solvent is removed at a pressure of about 760 mm Hg or less, more specifically at about 400 mm Hg or less, still more specifically at about 80 mm Hg or less, and most specifically from about 30 to about 80 mm Hg.

Solvents can also be removed by spray-drying, in which a solution of Vortioxetine hydrobromide is sprayed into the spray drier at the flow rate ranging from 10 to 250 ml/hr, 30 specifically 40 to 200ml/hr. The air inlet temperature to the spray drier used may range from about 30°C to about 150°C, specifically from about 65°C to about 120°C and the outlet air temperature used may range from about 30°C to about 90°C.

The recovering in step-(c) is carried out by methods such as filtration, filtration under vacuum, decantation, centrifugation, or a combination thereof. In one embodiment, pure Vortioxetine hydrobromide is recovered by filtration employing a filtration media of, for example, a silica gel or celite.

The substantially pure Vortioxetine hydrobromide obtained by above process may be further dried as per the methods described hereinabove.

According to another aspect, there is provided an improved process for the preparation of highly pure Vortioxetine hydrobromide, comprising a) reacting 2-[(2,4-dimethylphenyl)thio]aniline of formula 2:

10 or an acid addition salt thereof with a hydrobromide salt of bis-(2-haloethyl)amine of

15 formula 6(a):

20 wherein X is a halogen atom, in a first solvent to produce a reaction mass containing Vortioxetine hydrobromide salt; b) optionally, recovering the Vortioxetine hydrobromide from the reaction mass obtained in step-(a), followed by extracting, suspending or dissolving the Vortioxetine hydrobromide in a second solvent; and 25 c) isolating and/or recovering the highly pure Vortioxetine hydrobromide either from the reaction mass obtained in step-(a) or from the solution or suspension obtained in step-(b).

In one embodiment, the acid addition salt of 2-[(2,4-dimethyIphenyl)thio]aniline of formula 2 used in step-(a) is selected from the group consisting of, hydrochloride, sulfate, 30 nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate and tartrate. A most specific acid addition salt of the compound of formula 2 is hydrochloride salt.

In one embodiment, the halogen atom 'X' in the compound of formula 6(a) is selected from the group consisting of CI, Br and I; and most specifically the halogen atom is CI or Br.

Exemplary first solvents used in step-(a) include, but are not limited to, an alcohol, 5 a ketone, an ester, a halogenated solvent, a hydrocarbon solvent, a cyclic ether, an aliphatic ether, and mixtures thereof. Most specifically, the first solvent used in step-(a) is toluene, o-xylene or diglyme.

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 10 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 35 hours.

Exemplary second solvents used in step-(b) include, but are not limited to, water, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, an ester, a nitrile, an ether, 15 a polar aprotic solvent, and mixtures thereof.

Specifically, the second solvent is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof; and more specifically acetone.

20 The reaction mass obtained in step-(a) or the solution obtained in step-(b) is, each independently, optionally subjected to carbon treatment or silica gel treatment as per the methods described hereinabove. The isolation of Vortioxetine hydrobromide in step-(b) and step-(c) is, each independently, carried out by forcible crystallization, spontaneous crystallization, 25 substantial removal of the solvent from the solution or suspension, or a combination thereof. The recovering in step-(c) is carried out by methods as described hereinabove. The substantially pure Vortioxetine hydrobromide obtained by above process may be further dried as per the methods described hereinabove.

30 Unless otherwise specified, the 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 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 hereinabove. Aptly the processes of the invention are adapted to the production of vortioxetine or a pharmaceutical^ acceptable salt thereof in high yield and high purity.

5 In another embodiment, the highly pure Vortioxetine or a pharmaceutically acceptable salt thereof, preferably Vortioxetine hydrobromide salt, obtained by the processes disclosed herein has a purity of greater than about 99%, specifically greater than about 99.5%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC.

10 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. EXAMPLES Example 1 15 Preparation of 2,2,-dinitro-diphenyl disulfide Tetra-butylammonium bromide (0.32 g) was added to a solution of l-chloro-2-nitrobenzene (22.5 g) in a mixture of isopropyl alcohol and water (85:15 w/w, 16.6 g). The resulting solution was heated to 70°C while stirring, followed by drop-wise addition of a solution of sodium sulfide (10 g, Na2S-3H20), sulfur (2.5 g) and water (18 ml) over a 20 period of 4 hours at the same temperature. The resulting mass was further stirred for 4 hours at 80°C, followed by cooling the mass to 70°C. The separated yellow colored solid was filtered under vacuum, washed with a mixture of isopropyl alcohol and water until it was free from chloride ions. The resulting product was dried under vacuum at 50-55°C to produce 20 g of 2,2'-dinitro-diphenyl disulfide (Melting Point: 194°C-196°C; Purity by 25 HPLC: 98.7%; and Yield: 90.9 %).

Example 2 Preparation of 2,2,-diamino-diphenyl disulfide Iron powder (32.6 g) was added to a mixture of 2,' 2'-dinitro-diphenyl disulfide (15 g), 30 ammonium chloride (15.6 g) and methanol (210 ml), and the resulting mixture was stirred for 20-22 hours at 45±2°C. The reaction mass was filtered through a celite bed and washed with methanol (2 x 100 ml) and the filtrate was concentrated to get a residue. Water (150 ml) and dichloromethane (100 ml) were added to the residue and then stirred, followed by separation of the organic layer and extracting the aqueous layer with dichloromethane (100 ml). The combined organic layer was dried over anhydrous sodium sulfate, followed by treatment with activated carbon (1 g). The resulting mixture was filtered, followed by 5 evaporation of the solvent under vacuum at 40-45°C to produce 11.5 g of 2,2'-diamino-diphenyl disulfide as an yellow crystalline solid (Melting point: 89°C -91 °C; HPLC purity: 99.7%; Yield: 95%).

Example 3 10 Preparation of 2,2'-diamino-diphenyl disulfide Triethylamine (28.7 g) was added drop-wise to a solution of 2-aminothiophenol (25 g) in N,N-dimethylformamide (44 ml). The reaction mixture was heated to 65-70°C for a period of 20-22 hours. The reaction mass was cooled to 10-15°Cwith ice-water, followed by drop-wise addition of water (125 ml) for a period of 30-40 minutes. The yellow colored 15 reaction mixture was further stirred for 30 minutes atlO-15°C. The separated material was filtered under vacuum, washed twice with water (2 x 25 ml) to get crude product. The crude product was purified by recrystallization from n-hexane and then dried the material under vacuum at room temperature to afford 23 g of pure 2,2'-diamino-diphenyl disulfide as an yellow colored solid (Melting range: 90°C-91°C; HPLC purity: 99.7%; and Yield:

20 92.7%). Example 4 Preparation of 2-[(2,4-dimethyIphenyl)thio]aniIine Potassium tert-butoxide (7 g) was added portion-wise to a mixture of 2,2'-diamino-25 diphenyl disulfide (5g) and 2,4-dimethylbromobenzene(7.4 g) in dimethylsulfoxide (50 ml), and the resulting mixture was stirred for 15 minutes at 40°C, followed by heating the mass for 8 hours at 80°C. The reaction mass was cooled to room temperature and then poured into chilled water (100 ml), followed by extracting twice with ethyl acetate (2 x 50ml). The combined organic layer was initially washed with water (50 ml) and then with 30 brine solution (50ml), followed by drying over anhydrous sodium sulfate. The resulting organic layer was concentrated under vacuum to form a residue, followed by the addition of n-hexane (20 ml) and then stirring the mass for 35-40 minutes at 0-5°C. The precipitated solid was filtered and washed with twice with chilled n-hexane (2x3 ml). The resulting mother liquors were taken and then concentrated under vacuum at 35 -40°C and then dried the product to yield 3.37 g of 2-[(2,4-dimethylphenyl)thio]aniline as a brownish yellow colored solid (HPLC purity: 96.3%). 5

Example 5 Preparation of 2-[(2,4-dimethyIphenyl)thio]aniline Step-A: Synthesis of 2,4-dimethyIphenylmagnesium bromide A mixture of activated Magnesium turnings (5.1 g), iodine (55 mg) and dry 10 tetrahydrofuran (10 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 (37 g) in dry tetrahydrofuran (80 ml) was slowly added drop-wise to the resulting mass over a period of 90 minutes. The resulting mixture was stirred for 2 hours at 60-65°C under nitrogen atmosphere to yield the Grignard reagent, 2,4-

15 dimethylphenylmagnesium bromide in tetrahydrofuran.
Step-B: Synthesis of 2-[(2,4-dimethylphenyl)thio]aniline The solution of 2,4-DimethylphenyImagnesium bromide in tetrahydrofuran (obtained in step-A) was added to a solution of 2,2'-diamino-diphenyl disulfide (10 g) in dry tetrahydrofuran (20 ml), followed by cooling the mass to -5°C under nitrogen atmosphere.

20 The solution was then stirred at room temperature for 1 hour and then saturated aqueous ammonium chloride solution (280 ml) was added at 0-5°C. The reaction mass was then extracted twice with dichloromethane (2 x 150ml) at room temperature. The resulting organic layers were combined and then washed with aqueous 10% sodium chloride solution (100 ml). The organic layer was dried over anhydrous sodium sulfate, and then 25 evaporated under vacuum at 35-40°C to produce 32g of crude 2-[(2,4-dimethylphenyl)thio]aniline.

Step-C: Purification of 2-[(2,4-dimethylphenyl)thio]aniline

The crude product (obtained in step-A) was purified by column chromatography using Silica gel (60-120 mesh size) as the stationary phase. The crude compound was adsorbed 30 on silica gel (60-120 mesh size) and loaded on the pre-packed silica gel column (Specifications : 4'long and 6" wide). The column was eluted with hexane :ethyl acetate (75:25) 3.0-3.5 litres to yield 10 g of pure 2-[(2,4-dimethylphenyl)thio]aniline as a brownish yellow colored solid after recovery of the solvents under vacuum. The resulting product was dried at 45-55°C under vacuum (HPLC purity: 95.39%).

Example 6 5 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 maintaining for 72 hours at the same temperature. The reaction mass was cooled to 40- 10 45°C. The separated solid was filtered, washed twice with o-xylene (2x5 ml) and then dried the material under vacuum at 45°C-50°C to produce crude Vortioxetine hydrochloride. The crude product was further purified by recrystallization twice with acetone (40 ml) and then dried to produce 6 g of pure Vortioxetine hydrochloride as an off-white to beige colored powder (Melting range: 227°C-229°C; HPLC purity: 99.5%; 15 and Yield: 63%).

Example 7 Preparation of Vortioxetine hydrochloride 2-[(2,4-dimethylphenyl)thio]aniline (6.5 g) and bis(2-chloroethyl)amine hydrochloride (7.6g) were added to diglyme (13 ml) while stirring, followed by heating the reaction 20 mixture to 130°C and then stirring for 72 hours at the same temperature. After the completion of reaction, the reaction mass was cooled to 25°C ± 2°C and the water (20ml) was added. The resulting mass was further cooled to 10°C ± 2°C while stirring. The resulting precipitate was filtered, washed with chilled water (10 ml) and then dried the material under vacuum at 45 -50°C to get crude Vortioxetine hydrochloride. The crude 25 product was further purified by recrystallization with acetone (40 ml) twice and then dried at 45 -55°C under vacuum to obtain 6 g of pure Vortioxetine hydrochloride as an off-white to white colored powder (Melting range: 227°C-229°C; HPLC purity: 99.5%; Yield: 63%).
Example 8 30 Preparation of Vortioxetine hydrobromide Vortioxetine hydrochloride (9.5 g) was added to toluene (95ml) in a reaction flask, 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 (2 x 10ml) 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 5 Vortioxetine hydrobromide as an off-white to beige colored solid (HPLC purity: 99.5%-99.9%; and Yield: 93%).

Example 9 Preparation of Vortioxetine hydrobromide 10 Step-A: Preparation of bis(2-chloroethyl)amine hydrobromide salt.

Aqueous hydrobromic acid (48.8 g; 46%) was added drop-wise to a mixture of bis(2-chloroethyl) amine hydrochloride (25 g) and toluene (25 ml), and the resulting solution was stirred for 90 minutes. Layers were separated and the toluene layer was distilled-off under vacuum. The resulting product was isolated by recrystallization with a mixture of 15 acetone and diisopropyl ether (1:3), the solid was filed and then dried under vacuum at 25°C to yield 27 of pure bis(2-chloroethyl)amine hydrobromide salt (Melting range: 184-186°C; Yield: 86%).

Step-B: Preparation of l-[2-(2,4-dimethy!phenyIsuIfanyI)phenyI]-piperazine hydrobromide.
20 A mixture of 2-[(2,4-dimethylphenyl)thio]aniline (15 g), bis-(2-chloroethyl)amine hydrobromide (22 g) and diglyme (45ml) was stirred at 130°C for 30 hours. After completion of reaction, the reaction mass was cooled to 25°C and water (30ml) was added. The reaction mass was cooled to 10 ± 2°C, the precipitated solid was then filtered and then washed twice with chilled water (2x7 ml). The material was dried at room temperature

25 under vacuum for 1 hour. The resulting solid was recrystallized with acetone (80 ml). The separated solid was filtered, washed with acetone (30 ml) and then dried under vacuum at room temperature to produce 12 g of pure Vortioxetine hydrobromide (Yield: 63.0%; DSC: 225.4°C -227.0°C; and HPLC purity: 99.26%).

We claim:

1. A process for the preparation of Vortioxetine of formula 1
or a pharmaceutical^ acceptable salt thereof, which comprises:

10 a) reacting 2,2'-diamino-diphenyl disulfide of formula 3:
15 or an acid addition salt thereof, with a Grignard reagent of formula 5:

20 wherein X is a halogen atom, to produce 2-[(2,4-dimethylphenyl)thio]aniline of
formula 2:

25 or an acid addition salt thereof; and b) condensing the 2-[(2,4-dimethylphenyl)thio]aniline of formula 2 or an acid addition salt thereof with bis-(2-haloethyl)amine of formula 6: or an acid addition salt thereof, wherein X is a halogen atom; to produce Vortioxetine of formula I or a pharmaceutically acceptable salt thereof, and optionally converting the compound of formula I or a pharmaceutically acceptable salt thereof obtained into highly pure Vortioxetine hydrobromide salt. 5 2. The process of claim 1, wherein the pharmaceutically acceptable salt of the Vortioxetine of formula I is selected from the group consisting of hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate and tartrate; wherein the acid addition salt of compounds of formulae 2 and 6 used in step-(b) is, each 10 independently, selected from the group consisting of hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate and tartrate; and wherein the halogen atom 6X' in the compounds of formulae 5 and 6 is, each independently, selected from the group consisting of CI, Br and I.

15 3. The process of claim 2, wherein the pharmaceutically acceptable salt of the Vortioxetine of formula I is hydrochloride or hydrobromide salt; wherein the acid addition salt of 2-[(2,4-dimethylphenyl)thio]aniline of formula 2 used in step-(b) is a hydrochloride salt or a hydrobromide salt; wherein the acid addition salt of bis-(2- haloethyl)amine of formula 6 used in step-(b) is a hydrochloride salt or a hydrobromide 20salt; and wherein the halogen atom 'X' is CI or Br.

4. The process of claim 1, wherein the reaction in step-(a) is carried out in the presence of a solvent selected from the group consisting of a hydrocarbon solvent, an aliphatic ether solvent, a cyclic ether solvent, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof; wherein the reaction in step-(b) is carried out in the

25 presence of a solvent selected from the group consisting of an alcohol, a ketone, an ester, a halogenated solvent, a hydrocarbon solvent, a cyclic ether, an aliphatic ether, and mixtures thereof.

5. The process of claim 4, wherein the solvent used in step-(a) is tetrahydrofuran; and
wherein the solvent used in step-(b) is toluene, o-xylene or diglyme. 30

6. A process for the preparation of 2,2'-diamino-diphenyl disulfide of formula 3: or an acid addition salt thereof, comprising reacting 2-amino-thiophenol of formula 7: or an acid addition salt thereof, with a suitable base in a solvent to produce the compound of formula 3.

7. The process of claim 6, the base used in the reaction is an organic or an inorganic base selected from the group consisting of triethylamine, diisopropylethylamine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and wherein the solvents used in the reaction is selected from the group consisting of water, an alcohol, a hydrocarbon solvent, a nitrile solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.

8. The process of claim 7, wherein the base is triethylamine; and wherein the solvent is N,N-dimethylformamide.

9. A process for the preparation of 2,2'-diamino-diphenyl disulfide of formula 3: or an acid addition salt thereof, which comprises reducing 2,2'-dinitro-diphenyl disulfide of formula 4: with a reducing agent to produce the compound of formula 3 or an acid addition salt thereof.

10. The process of claim 9, wherein reducing agent used for reducing the compound of formula 4 is selected from the group consisting of iron powder and ammonium 5 chloride, zinc dust and ammonium chloride, iron powder and ammonium formate, zinc dust and ammonium formate, iron powder and hydrochloric acid, zinc dust and hydrochloric acid, sodium dithionite and the like, or a combination thereof; and wherein the reduction is carried out in the presence of a solvent selected from the group consisting of water, an alcohol, and mixtures thereof. 10

11. The process of claim 10, wherein reducing agent is iron powder and ammonium chloride; and wherein the solvent is aqueous methanol.

12. A process for the preparation of highly pure Vortioxetine hydrobromide, comprising:
a) contacting an acid addition salt of Vortioxetine (other than hydrobromide salt) with
an aqueous solution of hydrobromic acid in a first solvent to produce a reaction

15 mass containing Vortioxetine hydrobromide;

b) optionally, isolating the Vortioxetine hydrobromide from the reaction mass obtained in step-(a), followed by extracting, suspending or dissolving the Vortioxetine hydrobromide in a second solvent; and

c) isolating and/or recovering the highly pure Vortioxetine hydrobromide either from

20 the reaction mass obtained in step-(a) or from the solution or suspension obtained in step-(b).

13. The process of claim 12, wherein the acid addition salt of Vortioxetine used in step-(a) is selected from the group consisting of, hydrochloride, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate,

25 toluenesulfonate, citrate and tartrate; wherein the first solvent used in step-(a) is selected from the group consisting of water, an alcohol, a chlorinated hydrocarbon, a hydrocarbon, an ester, an ether, a polar aprotic solvent, and mixtures thereof; and wherein the second solvent used in step-(b) is selected from the group consisting of water, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, an ester, a

30 nitrile, an ether, a polar aprotic solvent, and mixtures thereof.

14. The process of claim 13, wherein the acid addition salt of Vortioxetine used in step-(a)
is hydrochloride salt; wherein the first solvent used in step-(a) is selected from the

group consisting of water, methanol, ethanol, isopropyl alcohol, toluene, and mixtures thereof; and wherein the second solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof. 15. A process for the preparation of highly pure Vortioxetine hydrobromide, comprising a) reacting 2-[(2,4-dimethylphenyl)thio]aniline of formula 2: 10 or an acid addition salt thereof with a hydrobromide salt of bis-(2-haloethyl)amine of formula 6(a): 15 wherein X is a halogen atom, in a first solvent to produce a reaction mass containing Vortioxetine hydrobromide salt;

20 b) optionally, recovering the Vortioxetine hydrobromide from the reaction mass obtained in step-(a), followed by extracting, suspending or dissolving the Vortioxetine hydrobromide in a second solvent; and

c) isolating and/or recovering the highly pure Vortioxetine hydrobromide either from the reaction mass obtained/in step-(a) or from the solution or suspension obtained 25in step-(b). 16. The process of claim 15, wherein the acid addition salt of 2-[(2,4- dimethylphenyl)thio]aniline of formula 2 used in step-(a) is selected from the group consisting of, hydrochloride, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fiimarate, benzenesulfonate, toluenesulfonate, citrate and tartrate;

30 wherein the halogen atom 'X' in the compound of formula 6(a) is selected from the group consisting of CI, Br and I.

17. The process of claim 16, the acid addition salt of 2-[(2,4-dimethylphenyl)thio]aniline of formula 2 used in step-(a) is hydrochloride salt; and wherein the halogen atom 'X' in the compound of formula 6(a) is CI or Br.

18. The process of claim 15, wherein the first solvent used in step-(a) is selected from the

5 group consisting of an alcohol, a ketone, an ester, a halogenated solvent, a hydrocarbon
solvent, a cyclic ether, an aliphatic ether, and mixtures thereof; and wherein the second solvents used in step-(b) is selected from the group consisting of water, an alcohol, a ketone, a chlorinated hydrocarbon, a hydrocarbon, an ester, a nitrile, an ether, a polar aprotic solvent, and mixtures thereof. 10 19. The process of claim 18, wherein the first solvent used in step-(a) is toluene, o-xylene or diglyme; and wherein the second solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, n-propanol, isopropyl alcohol, isobutanol, n-butanol, tert-butanol, acetone, methyl ethyl ketone, methyl isobutyl ketone, methyl tert-butyl ketone, and mixtures thereof.