DESC:AN IMPROVED PROCESS FOR PREPARATION OF VORTIOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS

FIELD OF THE INVENTION
The present invention provides an improved, scalable process for preparation of Vortioxetine and its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION
Vortioxetine chemically known as 1-[2-(2,4-dimethylphenylsulphanyl)phenyl]piperazine, of formula (I), is an atypical antidepressant that performs a combined SERT-inhibitor, 5-HT3 antagonist and partial 5-HT1A agonist action.

Vortioxetine hydrobromide having formula C18H22N2S.HBr was approved by the USFDA and by EMA for the treatment of Major Depressive Disorder (MDD) as antidepressant drug and commercially sold under the brand name BRINTELLIX®.
WO 2003029232 A1 describes processes for the preparation of Vortioxetine as shown in Scheme 1 & 2. Ferrocene is suspended in 1,2-dichlorobenzene in the presence of anhydrous aluminium trichloride and powdered aluminium followed by addition of ammonium hexafluorophosphate to obtain ?-1,2-Dichlorobenzene-?-cyclopentadienyliron(II) hexafluorophosphate which is reacted with resin bound piperazine to obtain 4-({4-[?6-(2-chlorophenyl)-?5-cyclopentadienyl iron(II)]-1-tert-butoxycarbonylpiperazine, which is then reacted with 2,4-dimethylthiophenol to obtain an intermediate. The final product Vortioxetine is obtained by treating the intermediate with hydrochloric acid. The process results in only 17% yield of Vortioxetine as reported in EP 2894154 A1. The process involves extensive use of resins and ferrocene complexmaking the process industrially unattractive.
Scheme 1
In Scheme 2 WO 2003029232 A1 discloses an alternate process wherein Ortho-fluoronitrobenzene and 2,4-dimethyl thiophenol are reacted to obtain an intermediate (2,4-dimethylphenyl)(2-nitrophenyl)thioether which is subjected to catalytic hydrogenation with palladium/carbon to obtain another intermediate (2,4-dimethyl phenyl)(2-aminophenyl)thioether. In route la, this intermediate (2,4-dimethyl phenyl)(2-aminophenyl)thioether is reacted with a mixture of di(2-bromoethyl)amine and di(2-chloroethyl)amine to obtain the final product Vortioxetine. In route 1b, the intermediate (2,4-dimethylphenyl)(2-aminophenyl)thioether is reacted with N-(tert-butoxycarbonyl) iminodiacetic acid to obtain the intermediate 1-tert-butoxycarbonyl-4-[(2,4-dimethylphenylthio) phenyl]-3,5-dioxopiperazine which is reduced using lithium aluminum hydride or borane to obtain an intermediate 4-tert-butoxycarbonyl-[(2,4-dimethylphenylthio)phenyl]-1-piperazine. The obtained intermediate is treated with hydrochloric acid to obtain the final product Vortioxetine. This process uses multiple steps and involves cumbersome purification techniques.

Scheme 2
Research on Chemical Intermediates (2021), 47(12), 5061-5078 discloses thioetherification reaction as shown in Scheme 3. Ortho-chloro-methyl ester is condensed with 2,4-dimethylthiophenol in the presence of CsF-celite, ACN at reflux temperature to obtain ester intermediate. It is to be noted that thiol compound (1 equiv.) is condensed with ester compound (2 equiv.) in presence of CsF (1.5 equiv.) which is used for activation of the aryl halide groups by the Lewis acid type effect. This scheme does not provide yield of the reaction.

Scheme 3
“Thioetherification follows an addition–elimination two-step reaction; in the first step, aryl/cyclohexylsulfanyl as nucleophile attacks on aryl ring bearing chloride leaving group. In the second step, elimination of the chloride leads to generation of thioethers. Here, the utility of cesium fluoridecelite (CsF-Celite) was to activation of the aryl halide groups by the lewis acid type effect”.
The present invention provides a cost-effective industrial process for the preparation of Vortioxetine and its pharmaceutically acceptable salts.

OBJECT OF THE INVENTION
The main object of the present invention is to provide an improved process for preparation of Vortioxetine and its pharmaceutically acceptable salts that is cost effective and scalable.

SUMMARY OF THE INVENTION
The present invention provides an improved process for the preparation of Vortioxetine and its pharmaceutically acceptable salts, comprising steps:
reacting a compound of formula (II) with a compound of formula (III) in presence of base, catalyst and solvent to obtain a compound of formula (IV);

wherein R1 is C1-C4 alkyl; R2 and R3 is Halogen or SH; wherein R2 and R3 are not identical at the same time;
hydrolysing the compound of formula (IV) in presence of base to obtain a compound of formula (V), optionally isolating the compound of formula (V);

reacting the compound of formula (V) either with sulfonyl chloride and azide added in any sequence, or a mixture of sulfonyl chloride and azide, in the presence of a base and solvent to obtain a compound of formula (VI); and

converting the compound of formula (VI) into Vortioxetine and its pharmaceutically acceptable salts.

DETAILED DESCRIPTION OF INVENTION
In one embodiment of the present invention, a compound of formula (II) is reacted with a compound of formula (III) in presence of base, catalyst and solvent to obtain a compound of formula (IV),

wherein R1 is C1-C4 alkyl; R2 and R3 is Halogen or SH; wherein R2 and R3 are not identical at the same time.
In another embodiment of the present invention, a compound of formula (V), is prepared in steps comprising:

reacting a compound of formula (II) with a compound of formula (III) in presence of base, catalyst and solvent to obtain a compound of formula (IV);

wherein R1 is C1-C4 alkyl; R2 and R3 is Halogen or SH; wherein R2 and R3 are not identical at the same time;
hydrolysing the compound of formula (IV) in presence of base to obtain a compound of formula (V).

In yet another embodiment of the present invention, a compound of formula (VI) is prepared in steps comprising, reacting the compound of formula (V) either with sulfonyl chloride and azide added in any sequence, or a mixture of sulfonyl chloride and azide, in the presence of base and solvent to obtain a compound of formula (VI).

In yet another embodiment of the present invention, a compound of formula (VI) is prepared in steps comprising:

hydrolysing the compound of formula (IV) in presence of base to obtain a compound of formula (V), optionally isolating the compound of formula (V);

reacting the compound of formula (V) either with sulfonyl chloride and azide added in any sequence, or a mixture of sulfonyl chloride and azide, in the presence of a base and solvent to obtain a compound of formula (VI).

In yet another embodiment of the present invention, Vortioxetine and its pharmaceutically acceptable salts, is prepared in steps comprising:
reacting a compound of formula (II) with a compound of formula (III) in presence of base, catalyst and solvent to obtain a compound of formula (IV);

wherein R1 is C1-C4 alkyl; R2 and R3 is Halogen or SH; wherein R2 and R3 are not identical at the same time;
hydrolysing the compound of formula (IV) in presence of base to obtain a compound of formula (V), optionally isolating the compound of formula (V);

reacting the compound of formula (V) either with sulfonyl chloride and azide added in any sequence, or a mixture of sulfonyl chloride and azide, in the presence of a base and solvent to obtain a compound of formula (VI); and

converting the compound of formula (VI) into Vortioxetine and its pharmaceutically acceptable salts.
The condensation reaction step (a) of present invention is performed in presence of base, solvent and optionally in presence of catalyst.
The base of step (a) is selected from inorganic bases such as alkaline metal carbonates and bicarbonates. The carbonates are selected from potassium carbonate and sodium carbonate. The bicarbonates are selected from sodium bicarbonate and potassium bicarbonate. The preferred bases are potassium carbonate and sodium carbonate.
The catalyst of step (a) is selected from copper powder, copper chloride and copper acetate, preferably copper powder.
The base used in condensation reaction ranges from 1 to 2.5 mole per mole of compound of formula (II). In a preferred embodiment, the condensation reaction is performed in presence of 1.5 mole of base per mole of compound of formula (II).
The compound of formula (III) used for condensation reaction ranges from 1 to 2.2 mole per mole of compound of formula (II). In a preferred embodiment, the condensation reaction is performed in presence of 1.05 mole of compound of formula (III) per mole of compound of formula (II).
The catalyst is =0.2 per mole of compound of formula (II).
The solvent of the step (a) is amides selected from dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide, N-methyl pyrrolidinone and mixtures thereof. The preferred solvents are DMF and DMSO.
The reaction of step (a) is carried out at 60°C - 150°C, preferably at 100°C - 110°C for 2 to 16 hours, preferably for 8 to 10 hours.
The step (b) of the process is carried out in presence of inorganic base and solvent.
The inorganic base of step (b) is selected from hydroxides such as sodium hydroxide (NaOH), potassium hydroxide or Lithium hydroxide preferably sodium hydroxide.
The solvent of step (b) is selected from halogenated hydrocarbons, alcohol, water and mixtures thereof. The halogenated hydrocarbons are selected from dichlomethane (DCM), ethylene chloride, chloroform and mixtures thereof. The alcohols are selected from methanol, isopropanol, ethanol and mixtures thereof. The preferred solvent is water.
The reaction of step (b) is carried out at 40°C - 100°C, preferably at 60°C - 80°C for 1 to 6 hours, preferably for 2 to 3 hours.
The step (c) of the process is carried out in presence of base, azide, sulfonyl chloride and solvent.
The inorganic base of step (c) is selected from carbonates or bicarbonates. The carbonates are selected from potassium carbonate and sodium carbonate. The bicarbonates are selected from sodium bicarbonate and potassium bicarbonate. The preferred base is potassium carbonate.
The sulfonyl chloride of step (c) is selected from toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, trimethylsulfonyl chlorides, methanesulfonyl chloride, preferably toluene sulfonyl chloride.
The azide is selected from sodium azide, potassium azide and trimethylsilyl azide.
The base, sulfonyl chloride and azide are individually used in step (c) reaction ranges from 1 to 1.5 mole per mole of compound of formula (V). In a preferred embodiment, the step (c) reaction is performed in presence of 1.2 mole of base, sulfonyl chloride and azide individually per mole of compound of formula (V).
The solvent of the step (c) is selected from amides and nitriles. The nitriles are selected from acetonitrile, propionitrile, benzonitrile and mixtures thereof. The amides are selected from dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methyl pyrrolidinone and mixtures thereof. The preferred solvent is dimethylformamide.
The reaction of step (c) is carried out at 40°C - 100°C, preferably at 80°C - 90°C for 1 to 6 hours, preferably for 2 to 3 hours.
The present invention step (c) involves simultaneous addition of sulfonyl chloride and azide reagent to the acid compound of formula (V) in presence of base to obtain the amine compound of formula (VI). The step (c) reaction may also be carried out by direct addition of sulfonyl azide in the presence of base to obtain amine compound of formula (VI). The said sulfonyl azide is commercially available or it can be prepared from sulfonyl chloride and azide reagents.
The bi-product sulfonic acid is obtained in step (c) can be recovered/ recycled. The process of the present invention i.e. simultaneous addition of sulfonyl chloride and azide reagent is cost-effective and industrially scalable as compared to the process in which addition of commercially available sulfonyl azide is used.
In a specific embodiment, the present invention provides a process for the preparation of the compound of formula (VI) as depicted in Scheme 4.

Scheme 4
The amine compound of formula (VI) is converted into Vortioxetine by any method known in the art. The obtained Vortioxetine is optionally converted to its pharmaceutically acceptable salt, preferably bromide salt by any method known in the art.
The invention is illustrated with non-limiting examples.
Example(s):
Example 1: Preparation of methyl 2-((2, 4-dimethylphenyl)thio)benzoate
4-Bromo-m-xylene (5.79 g) was dissolved in N,N-diemthylformamide (50 mL). Then potassium carbonate (6.17 g) and copper powder (0.37 g) were added to the solution followed by addition of methyl 2-mercaptobenzoate (5 g) at room temperature. The reaction mixture was heated to 110°C and stirred for 10 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature and ice-cold water was added followed by extraction with ethyl acetate. The collected organic layer was washed with 1N HCl followed by saturated bicarbonate solution and brine solution. The resultant organic layer was dried over sodium sulphate and evaporated under vacuum. The resultant solid was recrystallized with hexane to obtain light yellow color solid with 90% yield.
Example 2: Preparation of methyl 2-((2,4-dimethylphenyl)thio)benzoate
2,4-Dimethylbenzenethiol (4.25 g) was dissolved in N,N-diemthylformamide (50 mL). Then potassium carbonate (6.07 g) and copper powder (0.37 g) were added to the solution followed by addition of methyl 2-chlorobenzoate (5 g) at room temperature. The reaction mixture was heated to 110°C and stirred for 10 hours. The reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to room temperature, and ice-cold water was added followed by extraction with ethyl acetate. The collected organic layer was washed with 1N HCl followed by saturated bicarbonate solution and brine solution. The resultant organic layer was dried over sodium sulphate and evaporated under vacuum. The resultant solid was recrystallized with hexane to obtain 6.78 g of light yellow color solid with 85% yield.
Example 3: Preparation of methyl 2-((2,4-dimethylphenyl)thio)benzoate
2,4-Dimethylbenzenethiol (2.12 g) was dissolved in dimethyl sulfoxide (25 mL). Then potassium carbonate (3 g) and copper powder (0.18 g) were added to the solution followed by addition of methyl 2-chlorobenzoate (2.5 g) at room temperature. The reaction mixture was heated to 110°C and stirred for 10 hours. The reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to room temperature, and ice-cold water was added followed by extraction with ethyl acetate. The collected organic layer was washed with 1N HCl followed by saturated bicarbonate solution and brine solution. The resultant organic layer was dried over sodium sulphate and evaporated under vacuum. The resultant solid was recrystallized with hexane to obtain 3.1 g of light yellow color solid with 80% yield.
Example 4: Preparation of methyl 2-((2, 4-dimethylphenyl)thio)benzoate
4-Bromo-m-xylene (0.58 g) and potassium carbonate (0.67 g) are dissolved in N,N-diemthylformamide (5 mL) and 0.5 g of methyl 2-mercaptobenzoate was added at room temperature. The reaction mixture was heated to 120°C and stirred for 32 hours. The reaction was monitored by TLC. After the completion of the reaction, the reaction cooled to room temperature followed by addition of ice-cold water and extraction with ethyl acetate. The organic layer was washed with saturated bicarbonate solution and brine solution followed by drying over sodium sulphate and evaporated under vacuum. The obtained crude product was purified by column chromatography using hexane to get 0.35 g of light yellow color solid with 45% yield.
Example 5: Preparation of methyl 2-((2,4-dimethylphenyl)thio)benzoate
2,4-Dimethylbenzenethiol (2.12 g) was dissolved in dimethyl sulfoxide (25 mL). Then sodium bicarbonate (1.82 g) and copper aceteate (0.5 g) were added to the solution followed by addition of methyl 2-chlorobenzoate (2.5 g) at room temperature. The reaction mixture was heated to 110°C and stirred for 10 hours. The reaction was monitored by TLC. After completion of reaction, the reaction mass was cooled to room temperature, and ice-cold water was added followed by extraction with ethyl acetate. The collected organic layer was washed with 1N HCl followed by saturated bicarbonate solution and brine solution. The resultant organic layer was dried over sodium sulphate and evaporated under vacuum. The resultant solid was recrystallized with hexane to obtain 2.7 g of light yellow color solid with 70% yield.
Example 6: Preparation of methyl 2-((2, 4-dimethylphenyl)thio)benzoate
4-Bromo-m-xylene (2.8 g) was dissolved in N,N-diemthylformamide (25 mL). Then sodium hydroxide (0.8 g in 2 mL water) and copper powder (0.38 g) were added to the solution followed by addition of methyl 2-mercaptobenzoate (2.5 g) at room temperature. The reaction mixture was heated to 110°C and stirred for 10 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature and ice-cold water was added followed by extraction with ethyl acetate. The collected organic layer was washed with 1N HCl followed by saturated bicarbonate solution and brine solution. The resultant organic layer was dried over sodium sulphate and evaporated under vacuum. The resultant solid was recrystallized with hexane to obtain 3.2 g of light yellow color solid with 80% yield.
Example 7: Preparation of 2-((2,4-dimethylphenyl)thio)benzoic acid
Methyl 2-((2,4-dimethylphenyl)thio)benzoate (5 g) was added to aqueous solution of sodium hydroxide (2.2 g of sodium hydroxide in 15 mL of water) at room temperature. The reaction mass was heated to 60-65°C and stirred for 3 hours. The reaction was monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature. The reaction mass was diluted with water, followed by acidification with 4N HCl to get white precipitates. The precipitates were filtered, washed and dried under vacuum at 60°C to get 4.48 g white solid with 95% yield.
Example 8: Preparation of 2-((2,4-dimethylphenyl)thio)aniline
Sodium azide (0.5 g) was dissolved in N,N-diemthylformamide (10 mL) and 1.7 g p-toulenesulfonyl chloride was added at room temperature. The reaction mixture was stirred for 2 hours followed by addition of 2-(2,4-dimethylphenyl) thio)benzoic acid 2.0 g and potassium carbonate (1.28 g) to reaction mixture. The reaction mass was stirred for 2 hours at 90°C. After completion of the reaction, the reaction mass was cooled to room temperature and ice-cold water was added, followed by extraction with ethyl acetate. The organic layer obtained was acidified with 6N HCl and stirred for 20 minutes. Layers were separated and the aqueous layer was basified with 20% NaOH solution. Further, DCM was added and stirred for 10 minutes. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution and brine solution, followed by drying over sodium sulphate and evaporation under vacuum to obtain 1.5 g oily mass with 85% yield.
Example 9: Preparation of 2-((2,4-dimethylphenyl)thio)aniline
2-(2,4-dimethylphenyl) thio)benzoic acid (1.0 g) was dissolved in of N,N-diemthylformamide (5 mL). Then p-toulenesulfonyl chloride (0.85 g), Sodium azide (0.25 g) and potassium carbonate (0.64 g) were added to the solution at room temperature. The reaction mass was stirred for 2 hours at 90°C. After completion of the reaction, the reaction mass was cooled to room temperature and ice-cold water was added followed by extraction with ethyl acetate. The organic layer obtained was acidified with 6N HCl and stirred for 20 minutes. Layers were separated and the aqueous layer was basified with 20% NaOH solution. Further, DCM was added and stirred for 10 minutes. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution and brine solution, followed by drying over sodium sulphate and evaporation under vacuum to obtain the desired oily mass product 0.75 g with 85 % yield.
Example 10: Preparation of 2-((2,4-dimethylphenyl)thio)aniline
2-(2,4-dimethylphenyl)thio)benzoic acid (1.0 g) was dissolved in of acetonitrile (10 mL), 0.64 g potassium carbonate, 0.85 g p-toulenesulfonyl chloride and 0.25 g sodium azide and was added at room temperature. The reaction mass was stirred for 2 hours at 80°C. After completion of the reaction, the reaction mass was cooled to room temperature and ice-cold water was added followed by extraction with ethyl acetate. The organic layer obtained was acidified with 6N HCl and stirred for 20 minutes. Layers were separated and the aqueous layer was basified with 20% NaOH solution. Further, DCM was added and stirred for 10 minutes. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution and brine solution, followed by drying over sodium sulphate and evaporation under vacuum to obtain the desired oily mass product 0.62 g with 70 % yield.
Example 11: Preparation of 2-((2,4-dimethylphenyl)thio)aniline
2-(2,4-dimethylphenyl)thio)benzoic acid (1.0 g) was dissolved in N,N-diemthylformamide (10 mL), 0.4 g sodium bicarbonate , 0.85 g p-toulenesulfonyl chloride and 0.25 g sodium azide and was added at room temperature. The reaction mass was stirred for 2 hours at 80°C. After completion of the reaction, the reaction mass was cooled to room temperature and ice-cold water was added followed by extraction with ethyl acetate. The organic layer obtained was acidified with 6N HCl and stirred for 20 minutes. Layers were separated and the aqueous layer was basified with 20% NaOH solution. Further, DCM was added and stirred for 10 minutes. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution and brine solution, followed by drying over sodium sulphate and evaporation under vacuum to obtain the desired oily mass product 0.66 g with 75 % yield.
Example 12: Preparation of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide
2-((2,4-Dimethylphenyl)thio)aniline (1 g) and diisopropylethylamine (1.1 g) were dissolved in acetonitrile (5 mL) at room temperature. The reaction mixture was heated to reflux and 0.85 g of bis(2-chloroethyl)amine hydrochloride was added. The reaction mixture was stirred for 4 hours at reflux temperature. The reaction was monitored by TLC. After completion of reaction, cooled to room temperature followed by addition of ice cold water and extraction with ethyl acetate. The collected organic layer was dried over sodium sulphate and evaporated under vacuum. The crude product was dissolved in ethanol and 40% HBr was added slowly with heating until clear solution appears. The resultant solution obtained was cooled to 0°C leading to white solid precipitates. The precipitates obtained were filtered, washed with cold ethanol solution followed by drying under hot air vacuum to obtain 1.15 g of white solid product with 70% yield.
,CLAIMS:We Claim:
1. A process for the preparation of Vortioxetine and its pharmaceutically acceptable salts, comprising steps:
a) reacting a compound of formula (II) with a compound of formula (III) in presence of base, catalyst and solvent to obtain a compound of formula (IV);

wherein R1 is C1-C4 alkyl; R2 and R3 is Halogen or SH; wherein R2 and R3 are not identical at the same time;
b) hydrolysing the compound of formula (IV) in presence of base to obtain a compound of formula (V), optionally isolating the compound of formula (V);

c) reacting the compound of formula (V) either with sulfonyl chloride and azide added in any sequence, or a mixture of sulfonyl chloride and azide, in the presence of a base and solvent; and

d) converting the compound of formula (VI) into Vortioxetine and its pharmaceutically acceptable salts.

2. The process as claimed in claim 1, wherein the base used in step (a) is selected from inorganic bases such as alkaline metal carbonates and bicarbonates.

3. The process as claimed in claims 1 - 2, wherein,
the carbonates are selected from potassium carbonate and sodium carbonate, and
the bicarbonates are selected from sodium bicarbonate and potassium bicarbonate.

4. The process as claimed in claim 1 - 3, wherein the catalyst used in steps (a) is selected from copper powder, copper chloride and copper acetate.

5. The process as claimed in claim 1 - 4, wherein the solvent used in steps (a) is amides selected from dimethylformamide (DMF), dimethylsulfoxide (DMSO), dimethylacetamide and N-methyl pyrrolidinone.

6. The process as claimed in claim 1, wherein the sulfonyl chloride of step (c) is selected from toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, trimethylsulfonyl chlorides, methanesulfonyl chloride, preferably toluene sulfonyl chloride.

7. The process as claimed in claim 1, wherein the azide of step (c) is selected from sodium azide, potassium azide and trimethylsilyl azide.

8. The process as claimed in claim 1, the base of step (c) is selected from potassium carbonate, sodium carbonate, sodium bicarbonate and potassium bicarbonate.

9. The process as claimed in claim 1, wherein the solvent used in steps (c) is selected from amides and nitriles.

10. A process for preparation of methyl 2-((2, 4-dimethylphenyl)thio)benzoate of formula (IV) comprising, reacting a compound of formula (II) with a compound of formula (III) in presence of base, catalyst and solvent to obtain a compound of formula (IV);

wherein R1 is C1-C4 alkyl; R2 and R3 is Halogen or SH; wherein R2 and R3 are not identical at the same time.