The present invention reports improved processes for preparation as well as purification of Vortioxetine Hydrobromide and its intermediates.
BACKGROUND OF THE INVENTION:
Vortioxetine, sold under the trade names Trintellix among others, is a medication used to treat major depressive disorder. Effectiveness is viewed as similar to that of other antidepressants. It is only recommended in people who have not improved sufficiently on two other antidepressants. It is taken by mouth.
Common side effects include constipation and nausea. Serious side effects may include suicide in those under the age of 25, serotonin syndrome, bleeding and mania. A withdrawal syndrome may occur if the dose is rapidly decreased. Use during pregnancy and breastfeeding is not generally recommended. It is classified as a serotonin modulator. How it works is not entirely clear but is believed to be related to increasing serotonin levels.
It was approved for medical use in the United States in 2013. A month supply in the United Kingdom costs the NHS about £27.72 as of 2019. In the United States, the wholesale cost of this amount is about 368.40 USD. In 2016, it was the 260th most prescribed medication in the United States with more than a million prescriptions.
Vortioxetine is used as a treatment for major depressive disorder. Effectiveness appears to be similar to other antidepressants. It may be used when other treatments have failed.
It increases serotonin concentrations in the brain by inhibiting its reuptake in the synapse, and by modulating (activating certain receptors while blocking, or antagonizing, others) certain serotonin receptors. This puts it in the class of atypical antidepressants known as serotonin modulators and stimulators. Vortioxetine is a serotonin modulator and stimulator like Vilazodone.
Vortioxetine was discovered by scientists at Lundbeck who reported the rationale and synthesis for the drug (then called Lu AA21004) in a 2011 paper. In 2007, the compound was in Phase II clinical trials, and Lundbeck and Takeda entered into a partnership in which Takeda paid Lundbeck $40 million upfront with promises of up to $345 million in milestone payments, and Takeda agreed to pay most of the remaining cost of developing the drug. The companies agreed to co-promote the drug in the US and Japan, and that Lundbeck would receive a royalty on all such sales. The deal included another drug candidate, tedatioxetine (Lu AA24530), and could be expanded to include two other Lundbeck compounds.
Vortioxetine was approved by the US FDA for treatment of major depressive disorder (MDD) in adults in September 2013, and it was approved in Europe later that year.
US 7,144,884 first disclosed Vortioxetine and related compounds. The patent also discloses process for preparation of Vortioxetine which involves polystyrene bound amine intermediate and resin bound complex reagents wherein reaction takes place on the resin surface. The patent disclosure is limited by the use of expensive polymer support material, slow rate of reaction and low yield making the process unsuitable for large scale industrial manufacturing.
Vortioxetine is disclosed as Example 1e in WO 2003/029232 A1 and is described as being prepared analogously to Example 1. The process used to prepare Example 1 involves preparation of 1-(2-((2-(trifluoromethyl)phenyl)thio)phenyl)piperazine on a solid polystyrene support, followed by decomplexation using visible light irradiation, and purification by preparative LC-MS and ion-exchange chromatography. The overall yield for the preparation of Vortioxetine is described as 17%.
Several alternative palladium catalysed processes for the preparation of Vortioxetine are described in Examples 17 to 25 of WO 2007/144005 A1. These processes describe the preparation of Vortioxetine from 2,4-dimethylthiophenol and 2-bromoiodobenzene (or 1,2-dibromobenzene) starting materials via a 1-(2-bromo-phenylsulfanyl)-2,4-dimethyl-benzene intermediate. Each of these processes involves the use of a palladium catalyst and a phosphine ligand.
The preparation of Vortioxetine is also described by Bang-Andersen et al. in J. Med. Chem. (2011), Vol. 54, 3206-3221. Here, in a first step, tert-butyl 4-(2-bromophenyl)piperazine-1-carboxylate intermediate is prepared from Boc-piperazine and 2-bromoiodobenzene in a palladium catalyzed coupling reaction. Tert-Butyl 4-(2-bromophenyl)piperazine-1-carboxylate is then reacted with 2,4-dimethylthiophenol, again in the presence of palladium catalyst and a phosphine ligand to provide Boc-protected Vortioxetine. In the final step, Vortioxetine is deprotected using hydrochloric acid to give Vortioxetine hydrochloride.
WO 2013/102573 A1 describes a reaction between 1-halogen-2,4-dimethyl-phenyl, 2-halogen-thiophenol and an optionally protected piperazine in the presence of a base and a palladium catalyst consisting of a palladium source and a phosphine ligand.
Each of the above processes has disadvantages. The process described in WO 2003/029232 is low yielding and unsuitable for the large scale production of Vortioxetine whereas the processes described in WO 2007/144005 A1, WO 2013/102573 A1 and by Bang-Andersen et al. require the use of expensive starting materials, palladium catalyst and phosphine ligand. In addition, the toxicity of palladium is well known, Liu et al. Toxicity of Palladium, Toxicology Letters, 4 (1979) 469-473, and the European Medicines Agency's Guideline on the Specification for Residues of Metal Catalysts sets clear limits on the permitted daily exposure to palladium arising from palladium residue within drug substances, www.ema.europa.eu. Thus, it would be desirable to avoid the use of a palladium catalyst in the synthesis of Vortioxetine and the subsequent purification steps required to remove palladium residue from the final pharmaceutical product.
US 20140256943 Al discloses the process for preparation of Vortioxetine as shown in scheme I which involves reacting compound (x), (y) and (z) in presence of a solvent, base, palladium catalyst and phosphine ligands.

Scheme I
WO 2013102573 Al discloses the process for preparation of Vortioxetine Hydrobromide (I) as shown in scheme IV which involves reacting compound (d), (e) and (f) in presence of a solvent, base, palladium catalyst and phosphine ligands.

Scheme II
The process of US '943 and US '573 applications results in a side reaction and an overreaction due to multiple reaction sites available which produces many impurities.
WO2014191548 discloses a process for preparation of Vortioxetine Hydrobromide which uses sulfone or sulfoxide intermediates which is reduced to get Vortioxetine as shown in scheme-III.

Scheme III
EP3141543 provides a new intermediate II and a method for synthesizing the same. The method comprises: (a) firstly diazotizing a compound of Formula I as a raw material, and then halogenating to obtain an intermediate II; and (b) reacting the intermediate II with a compound III to obtain a compound IV, hydrolyzing the obtained compound IV directly without being separated to obtain Vortioxetine represented by compound V. The intermediate II can be used for synthesizing Vortioxetine.

Chinese Patent CN02819025 discloses Vortioxetine ferrocene piperazine complex with the resin protection o-dichlorobenzene, and then 2,4-dimethylbenzene thiol reaction by light irradiation and then complexed with a solution. The method steps are long, need to use ferrocene and other dangerous toxic agents, and the yield is very low, the last step of the reaction yield is only 14%, not suitable for mass production.
After careful study of the available literature, keeping in view the target of developing the improved cost effective processes for the preparation of Vortioxetine Hydrobromide and its intermediates as well as new polymorphs of Vortioxetine Hydrobromide which can be used at commercial scale for production of Vortioxetine Hydrobromide in plant, the development work was started in the lab.
SUMMARY OF THE INVENTION:
The present invention relates to improved processes for preparation as well as purification of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide. There was an issue regarding additional signal in the residual solvent analysis of Vortioxetine Hydrobromide when prepared as per methods described in prior art. Various methodologies were adapted in order to make commercially viable and eco-friendly process for preparation of Vortioxetine Hydrobromide. To overcome these problems, tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C), a key intermediate of Vortioxetine Hydrobromide was isolated without isolation of 1-[(2-Bromophenyl)sulfanyl]-2,4-dimethylbenzene (B). Furthermore, various new polymorphs of Vortioxetine Hydrobromide (I) were also developed along with development of novel processes for preparation as well as purification of Vortioxetine Hydrobromide.
The chemical structures and codes of various stages of Vortioxetine Hydrobromide used are given below:
Stage Code Structure
I

A

B

C

D

DETAILED DESCRIPTION OF THE INVENTION:
According to the first embodiment of the present invention, an improved process for purification of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide is disclosed to remove unwanted unknown signals appearing in the residual solvent analysis by HSGC, which comprises:
1. Dissolving 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in water or water-aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or water-aliphatic nitrile such as acetonitrile, propionitrile or a mixture thereof at 95-105°C to get a clear solution and stirring for 1-2 hours.
2. Cooling the mass to 0-10°C and stirring for 1-2 hours.
3. Isolating the product as wet cake by routine filtration and drying at 50-60°C for 10-20 hours under vacuum to get desired pure 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I).
According to the second embodiment of the present invention, an improved process for the preparation of tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C) is disclosed without isolation of 1-[(2-Bromophenyl)sulfanyl]-2,4-dimethylbenzene (B) which comprises:
1. Dissolving Palladium (0) bis(dibenzylideneacetone) [Pd(dba)2] in an aromatic hydrocarbon selected from toluene, xylenes or a mixture thereof.
2. Adding (±) – BINAP, 2,2’- Bis(diphenylphosphino)-1,1’- binaphthalene (Rac-BINAP) to solution of step 1. and stirring for 10-30 minutes at 20-30°C.
3. Adding sodium tert-Butoxide to reaction mass of step 2.
4. Slowly adding 2,4-dimethylbenzene-1-thiol (D).
5. Adding 1-Bromo-2-iodobenzene (A) solution in aromatic hydrocarbon of step 1.
6. Heating the reaction mass to 105-115°C for 6-10 hours till reaction completion.
7. Partial recovery of solvent under vacuum to reduce reaction volume.
8. Allowing the reaction mass to attain ambient temperature.
9. Again adding Palladium (0) bis(dibenzylideneacetone ) & (±) – BINAP, 2,2’- Bis(di phenylphosphino)-1,1’-binaphthalene to reaction mass.
10. Stirring the reaction mass for 10-20 minutes followed by addition of sodium tert-butoxide.
11. Heating the reaction mass to 105-115°C and stirring for 20-30 hours.
12. After completion of reaction, quenching of reaction mass by addition of water.
13. Layer separation and distilling out solvent under reduced pressure to get product, tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C) as oily mass.
According to the third embodiment of the present invention, an improved process for the preparation of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide is disclosed, which comprises:
1. Dissolving tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C) in an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or an aliphatic nitrile such as acetonitrile, propionitrile or a mixture thereof at 40-50°C.
2. Slowly adding hydrobromic acid.
3. Raising temperature to 55-65°C and stirring the reaction mass for 14-20 hours till reaction completion.
4. Cooling reaction mass to 0-10°C and stirring further for 1-2 hours for crystallization.
5. Isolating the product as wet cake by routine filtration and drying at 50-60°C for 4-8 hours under vacuum to get desired 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide or Vortioxetine Hydrobromide (I).
According to the fourth embodiment of the present invention, a new polymorph designated as Form V-1 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide is disclosed which comprises:
1. Dissolving 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in aliphatic nitrile such as acetonitrile, propionitrile or aliphatic cyclic or non-aqueous acyclic ethers like Methyl tert-butyl ether, Diisopropyl ether, Tetrahydrofuran, 2-Methyl Tetrahydrofuran or a mixture thereof by heating the reaction mass to 55-65°C followed by addition of water.
2. Stirring of the reaction mass for 1-2 hours.
3. Cooling of the reaction mass to 0-10°C and stirring further for 1-2 hours to ensure crystallization.
4. Isolating the product as wet cake by routine filtration and drying at 50-60°C for 4-8 hours under vacuum to get desired Form V-1 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide having XRD as given in figure 1 and 2 and characteristic peaks at 2-Theta values 7.01, 13.87, 14.60, 19.51 & 20.80.
According to the fifth embodiment of the present invention, a new polymorph designated as Form V-2 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide is disclosed which comprises:
1. Dissolving 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in chlorinated aliphatic hydrocarbons such as methylene chloride, chloroform, etc. in the presence of water by heating the reaction mass to reflux.
2. Stirring the reaction mass for 1-2 hours.
3. Cooling the reaction mass to 0-10°C and stirring further for 1-2 hours to ensure crystallization.
4. Isolating the product as wet cake by routine filtration and drying at 50-60°C for 4-8 hours under vacuum to get desired Form V-2 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide having XRD as given in figure 3 and characteristic peaks at 2-Theta values 4.50, 5.80, 7.03, 11.86, 14.06, 14.20, 16.00, 16.25, 17.15, 18.19, 19.53, 18.78, 20.46, 20.69, 21.25, 22.90 and 23.40.
According to the sixth embodiment of the present invention, an improved process for preparation of beta form of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide is disclosed which comprises:
1. Heating 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in an aqueous solution of aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or an non-aqueous aliphatic amide such as DMF, DMA or DMSO or a mixture thereof at 55-75°C .
2. Stirring the reaction mass for 1-2 hours.
3. Cooling the reaction mass to 0-10°C and stirring further for 1-2 hours to ensure crystallization.
4. Isolating the product as wet cake by routine filtration and drying at 50-60°C for 4-8 hours under vacuum to get desired form beta of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide having XRD as given in figures 4, 5.
According to the seventh embodiment of the present invention, a new polymorph V-3 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide is disclosed which comprises:
1. Dissolving 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in aqueous aliphatic alcohols like methanol, ethanol, propanol by heating to reflux temperature.
2. Stirring the reaction mass for 1-2 hours.
3. Cooling the reaction mass to 0-10°C and further stirring for 1-2 hours to ensure crystallization.
5. Isolating the product as wet cake by routine filtration and drying at 50-60°C for 4-8 hours under vacuum to get the desired form V-3 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide having XRD as given in figure 6 and characteristic peaks at 2-Theta values 9.73, 14.62, 19.49, 20.72 and 29.40.
The above-mentioned invention is supported by the following non limiting examples:
Example 1: Preparation of tert-Butyl 4-(2-((2,4-dimethylphenyl)thio)phenyl) piperazine-1-carboxylate (C): 100 g of Palladium (0) bis(dibenzylideneacetone) [Pd(dba)2] was dissolved in toluene (500 ml) followed by the addition of 2g of (±) – BINAP, 2,2’- Bis(diphenylphosphino)-1,1’- binaphthalene (Rac-BINAP) and the reaction mass was stirred for 10-30 minutes at 20-30°C. Then, sodium tert Butoxide (40 g) and 48g of 2,4-Dimethylbenzene-1-thiol (D) were added to it and the reaction mass was stirred for 10-30 minutes at 20-30°C followed by addition of 1-Bromo-2-iodobenzene (A) solution in toluene (100g) and stirring the reaction mass for 6-10 hours at 105-115°C. The reaction mass was cooled to 20-30°C and DI water (500 ml) was added to it. The Toluene layer was separated followed by partial recovery to get 1-[(2-Bromophenyl)sulfanyl]-2,4-dimethylbenzene (B) toluene layer. Then, 1g of Palladium (0) bis(dibenzylideneacetone) [Pd(dba)2] was added followed by the addition of 2g of (±) – BINAP, 2,2’- Bis(diphenylphosphino)-1,1’- binaphthalene (Rac-BINAP) and the reaction mass was stirred for 10-20 minutes at 20-30°C followed by the addition of sodium tert butoxide (40g) and N-Butyloxycarbonylamino piperazine (80g). The reaction mass was stirred for 20-30 hours at 105-115°C for completion of the reaction. The reaction mass was cooled to 20-30°C and DI water (500 ml) was added to it. The toluene layer was separated followed by recovery to get 100g of tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C) as oily residue.
Example 2: Preparation of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine hydrobromide: To a solution of 100 g of tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C) in acetone (500ml) at 40-50°C, hydrobromic acid (80 ml) was added slowly followed by addition of DI water (20 ml) and the reaction mixture was stirred for 14-20 hours at 55-65°C. The reaction mass was cooled to 0-10°C and stirred for 1-2 hours. The product was isolated by filtration drying at 50-60°C for 4-8 hours to get 65g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine hydrobromide (I) having HPLC purity>99%.
Example 3: Preparation of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I): To a solution of 100 g of tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C) in acetonitrile (500ml) at 40-50°C, hydrobromic acid (80ml) was added slowly followed by adding DI water (20ml) and the reaction mixture was stirred for 14-20 hours at 75-85°C. Then, the reaction mass was cooled to 0-10°C and stirred for 1-2 hours. The product was isolated by filtration and drying at 50-60°C for 4-8 hours to get 65g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine hydrobromide (I) having HPLC Purity >99%.
Example 4: Purification of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide or Vortioxetine Hydrobromide (I): 100gm of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) was dissolved in water (500ml) at 95-105°C under stirring. The resulting mass was cooled to 0-10°C and stirred for 1-2 hours. The product was isolated by filtration and drying at 50-60°C for 10-18 hours to get pure 90g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide (VX05) having HPLC Purity= 100 % and material free from additional signal in HSGC at about 3.5 minutes.
Example 5: Preparation of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide Form Beta: 100gm of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) was dissolved in acetone (500ml) at 55-65°C by the addition of DI water (100 ml) and stirring for 1-2 hours at 55-65°C. Then, the resulting mass was cooled to 0-10°C and stirred for 1-2 hours. The product was isolated by filtration and drying at 50-60°C for 10-18 hours to get pure 90g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine hydrobromide (I) or Vortioxetine Hydrobromide Form Beta having HPLC Purity= 100% free from additional signal in HSGC at about 3.5 minutes.
Example 6: Preparation of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide polymorphic Form V-1: 100gm of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) was dissolved in acetonitrile (500ml) at 75-85°C by the addition of DI water (100ml) and stirring for 1-2 hours. Then, the resulting mass was cooled to 0-10°C and stirred for 1-2 hours. The product was isolated by filtration and drying at 50-60°C for 10-18 hours to get 90g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine hydrobromide polymorphic Form V-1 having XRD as given in figure 1.
Example 7: Preparation of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide polymorphic Form V-1: 100gm of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) was stirred in Methyl tert-Butyl ether (500ml) at reflux temperature for 1-2 hours at 75-85°C. Then, the resulting mass was cooled to 0-10°C and stirred for 1-2 hours. The product was isolated by filtration and drying at 50-60°C for 10-18 hours to get 90g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine hydrobromide polymorphic Form V-1 having XRD as given in figure 2.
Example 8: Preparation of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide polymorphic Form V-2 : 100gm of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) was dissolved in methylene chloride (500ml) at reflux temperature by the addition of DI water (100ml) and stirring for 1-2 hours. Then, the resulting mass was cooled to 0-10°C and stirred for 1-2 hours. The product was isolated by filtration and drying at 50-60°C for 10-18 hours to get 87g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine hydrobromide polymorphic Form V-2 having XRD as given in figure 3.
Example 9: Preparation of Form beta of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I): 100gm of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) was dissolved in dimethylsulfoxide (300 ml) at 90-100°C for clarity and stirred the reaction mass for 1-2 hours. Then, the resulting mass was cooled to 0-10°C and stirred for 1-2 hours. The product was isolated by filtration and dried at 50-60°C for 10-18 hours to get 88g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine hydrobromide Form beta having XRD as in figure 4.
Example 10: Preparation of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide Form Beta: 100gm of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) was dissolved in N,N-Dimethylformamide (300ml). The reaction mass was refluxed at 90-100°C for clarity. The reaction mass was stirred for 1-2 hours at 90-100°C. Then, the resulting mass was cooled to 0-10°C and stirred for 1-2 hours. The reaction mass was then filtered and its running washing was performed with chilled N,N-Dimethylformamide. The wet cake was then dried at 60-70°C for 10-18 hours to get 86g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide Form Beta having XRD as in figure 5.
Example 11: Preparation of Polymorphic Form V-3 of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide Form V-3: 100gm of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) was dissolved in methanol (500 ml) at 55-65°C by the addition of DI water (100ml) and stirred the reaction mass for 1-2 hours. Then, the resulting mass was cooled to 0-10°C and stirred for 1-2 hours. The product was isolated by filtration and drying at 50-60°C for 10-18 hours to get 90g of 1-[2-[(2,4-dimethylphenyl) thio] phenyl] piperazine Hydrobromide (I) or Vortioxetine Hydrobromide Form V-3 having XRD as in figure 6.

WE CLAIM:

1.An improved process for purification of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide to remove unwanted unknown signals appearing in the residual solvent analysis by HSGC, which comprises:
I. dissolving 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in water and/or water-aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone and/or water-aliphatic nitrile such as acetonitrile, propionitrile or a mixture thereof at 95-105°C;
II. stirring for 1-2 hours;
III cooling the reaction mass to 0-10°C;
IV. stirring further for 1-2 hours; and
V. isolating crude product as wet cake by filtration and drying the material at 50-60°C for 10-20 hours to get desired pure 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I).
2. An improved process for preparation of tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C) without isolating 1-[(2-Bromophenyl)sulfanyl]-2,4-dimethyl benzene (B), which comprises:
I. dissolving Palladium (0) bis(dibenzylideneacetone) [Pd(dba)2] in an aromatic hydrocarbon selected from toluene, xylenes or a mixture thereof;
II. adding (±) – BINAP, 2,2’- Bis(diphenylphosphino)-1,1’- binaphthalene (Rac-BINAP);
III. stirring for 10-30 minutes at 20-30°C;
IV. adding sodium tert-butoxide followed by slow addition of 2,4-dimethylbenzene-1-thiol (D);
V. adding 1-Bromo-2-iodobenzene (A) solution in aromatic hydrocarbon of step I;
VI. performing partial recovery of solvent of reaction mass;
VIII. allowing the reaction mass to attain room temperature;
IX. again adding Palladium (0) bis(dibenzylideneacetone ) & (±) – BINAP, 2,2’- Bis(di phenylphosphino)-1,1’-binaphthalene to reaction mass;
X. stirring the reaction mass for 10-20 minutes followed by addition of sodium tert-butoxide;
XI. again, heating the reaction mass to 105-115°C and stirring for 20-30 hours;
XII. adding water to quench the reaction; and
XIII. separating the layer and distilling out solvent under reduced pressure to get product, tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C) as oily mass.
3. An improved process for preparation of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide, which comprises:
i. dissolving tert-Butyl 4-(2-((2,4-dimethylphenyl) thio) phenyl) piperazine-1-carboxylate (C) in an aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or an aliphatic nitrile selected form acetonitrile, propionitrile or a mixture thereof at 40-50°C;
ii. slowly adding hydrobromic acid;
iii. raising temperature to 55-65°C and stirring reaction mass for 14-20 hours till reaction completion;
iv. cooling reaction mass to 0-10°C;
v. stirring further for 1-2 hours; and
vi. isolating crude product as wet cake by filtration and drying the material at 50-60°C for 4-8 hours under vacuum to get the desired pure 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I).
4. A novel polymorph Form V-1 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide and preparation thereof which comprises:
i. dissolving 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in aliphatic nitrile selected from acetonitrile, propionitrile or aliphatic cyclic and/or non-aqueous acyclic ethers selected from methyl tert-butyl ether, diisopropyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or a mixture thereof by heating the reaction mass to 55-65°C;
ii. adding water;
iii. stirring of the reaction mass for 1-2 hours;
iv. cooling of the reaction mass to 0-10°C and stirring further for 1-2 hours; and
v. isolating product as wet cake by routine filtration and drying at 50-60°C for 4-8 hours under vacuum to get desired Form V-1 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide having XRD as given in figure 1 and 2 and characteristic peaks at 2-Theta values 7.01, 13.87, 14.60, 19.51 & 20.80.
5. A novel polymorph Form V-2 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide and preparation thereof which comprises:
i. dissolving 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in chlorinated aliphatic hydrocarbon selected from methylene chloride, chloroform in the presence of water by heating the reaction mass to reflux;
ii. stirring of the reaction mass for 1-2 hours;
iii. cooling of the reaction mass to 0-10°C and stirring further for 1-2 hours; and
iv. isolating product as wet cake by routine filtration and drying at 50-60°C for 4-8 hours under vacuum to get the desired Form V-2 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide having XRD as given in figure 3 and characteristic peaks at 2-Theta values 4.50, 5.80, 7.03, 11.86, 14.06, 14.20, 16.00, 16.25, 17.15, 18.19, 19.53, 18.78, 20.46, 20.69, 21.25, 22.90 & 23.40.
6. An improved process for preparation of beta form of 1-[2-[(2,4-Dimethyl phenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide which comprises:
i. dissolving 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in aqueous solution of aliphatic ketone selected from acetone, ethyl methyl ketone, diethyl ketone, dimethyl ketone, dipropyl ketone, dibutyl ketone or an non-aqueous aliphatic amide such as DMF, DMA or DMSO or a mixture thereof by heating at 55-75°C;
ii. stirring of the reaction mass for 1-2 hours;
iii. cooling of the reaction mass to 0-10°C and stirring further for 1-2 hours; and
iv. isolating product as wet cake by routine filtration and drying at 50-60°C for 4-8 hours under vacuum to get desired Form Beta of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide having XRD as given in figure 4 & 5.
7. A novel polymorphic Form V-3 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide and preparation thereof which comprises:
i. dissolving 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) in aqueous aliphatic alcohol selected from methanol, ethanol, propanol by heating to reflux temperature;
ii. stirring of the reaction mass for 1-2 hours;
iii. cooling of the reaction mass to 0-10°C and stirring further for 1-2 hours; and
iv. Isolating product as wet cake by routine filtration and drying at 50-60°C for 4-8 hours under vsacuum to get desired Form V-3 of 1-[2-[(2,4-Dimethylphenyl)thio]phenyl]piperazine Hydrobromide (I) or Vortioxetine Hydrobromide having XRD as given in figure 6 and characteristic peaks at 2-Theta values 9.73, 14.62, 19.49, 20.72 and 29.40.