ES2726573T3 - Process for the manufacture of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine - Google Patents

Abstract

A process for the manufacture of ** Formula ** or its pharmaceutically acceptable salts (Compound I), said method comprising reacting a compound of formula II ** Formula ** wherein X represents Br or I, with a compound of formula III ** Formula ** wherein Y represents CI or Br and R 'represents hydrogen or a metal ion, and a compound of formula IV ** Formula ** where R represents hydrogen or a protecting group, in the presence of a solvent, a base and a palladium catalyst consisting of a source of palladium and a phosphine ligand at a temperature between 50 ° C and 130 ° C, where, when R represents a protective group, said protective group is removed at a later stage.

Description

DESCRIPTION

Process for the manufacture of 1 - [2- (2,4-dimethyl-fenMsulfanM) -fenM] -piperazine

Field of the invention.

The present invention relates to a process for the manufacture of the compound 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine and pharmaceutically acceptable salts thereof.

Background of the invention.

International patent applications WO 03/029232 and WO 2007/144005 describe the compound 1- [2- (2,4-dimethylphenylsulfanyl) -phenyl] -piperazine which includes several preparation routes. In the remainder of this document, 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine and its pharmaceutically acceptable salts are referred to as Compound I or Compound IX X when a reference to salt XX is desired.

Compound I is an antagonist at ^5- HT ³ , ^5- HT ⁷ and 5-HT- ^id receptors, an agonist at the 5-HT- ^ia receptor and a partial agonist at the 5-HT-m receptor and an inhibitor of the serotonin transporter. In addition, Compound I has been shown to increase the levels of the neurotransmitters serotonin, noradrenaline, dopamine, acetylcholine and histamine in specific areas of the brain. All these activities are considered to be of clinical relevance and are potentially involved in the mechanism of action of the compound [J. Med. Chem., 54, 3206-3221,2011; Eur. Neuropshycopharmacol., 18 (Suppl. 4), S321, 2008; Eur. Neuropshycopharmacol., 21 (Suppl. 4), S407-408, 2011; Int. J. Psychiatry Clin. Pract. 5, 47, 2012].

Compound I has been shown in clinical trials as a safe and effective treatment for depression. A paper that reports the results of a proof of concept study to evaluate the efficacy and tolerance of the compound in patients with major depressive disorder (MDD) written by Alvares et al. has been made available online by Int. J. Neuropsychopharm. July 18, 2011. The results of this six-week, placebo-controlled, randomized study with approximately 100 patients in each branch indicate that Compound I separates significantly from placebo in the treatment of depressive and anxiety symptoms. in patients with MDD. It is also reported that no clinically relevant changes were observed in clinical laboratory results, vital signs, weight or ECG parameters. The results of a long-term study also show that Compound I is effective in preventing relapse in patients suffering from MDD [Eur. Neuropsychopharmacol. 21 (Suppl. 3), S396-397, 2011].

WO 2007/144005 describes a manufacturing process in which the compounds

they are mixed in the presence of a base and a palladium catalyst consisting of a source of palladium and a phosphine ligand. The palladium catalyst catalyzes the formation of the C-N bond as described in US 5,573,460. In the above process, piperazine can optionally be protected in one of the nitrogen. This process provides the desired compound with high yield and relatively high purity. However, impurities are formed that must be removed later. It is particularly difficult to remove impurities that, like Compound I, contain secondary amine, that is, a piperazine residue. Such compounds tend to have similar solubility properties, for example including pH dependent solubility properties, and are therefore difficult to separate from Compound I using methods that take advantage of differences in solubility, e.g. ex. crystallization WO 2010/094285 describes a purification process that effectively removes such impurities, e.g. ex. 1 - [2- (2,4-Dimethyl-phenylsulfanyl) -phenyl] -4- (2-piperazin-1 -yl-phenyl) -piperazine that is formed when both nitrogens of the piperazine group form a C-N bond. The purification process comprises precipitating an isopropanol solvate of Compound IHBr.

The present invention provides a new manufacturing route that eliminates or reduces the difficult to remove impurities mentioned above.

Summary of the invention .

The author of the present invention has found that a reaction between 1-halogen-2,4-dimethyl-phenyl, 2-halogenothiophenol and an optionally protected piperazine in the presence of a base and a palladium catalyst provide a reaction with high yield and purity, and where impurities are reduced or eliminated. Accordingly, in one embodiment the invention relates to a process for obtaining

or its pharmaceutically acceptable salts (Compound I), said process comprising reacting a compound of formula II

wherein X represents Br or I, with a compound of formula III

wherein Y represents CI or Br and R 'represents hydrogen or a metal ion, and a compound of formula IV

wherein R represents hydrogen or a protecting group, in the presence of a solvent, a base and a palladium catalyst consisting of a source of palladium and a phosphine ligand at a temperature between 50 ° C and 130 ° C, where, when R represents a protective group, said protective group is removed at a later stage.

Detailed description of the invention.

In one embodiment, the compound of formula II and the compound of formula III can be reacted in a first step to prepare the intermediate compound

This intermediate compound can then be isolated before the additional reaction with a compound of formula IV to obtain Compound I. Alternatively, this additional reaction can take place without isolating the intermediate compound. Synthesis in a single reactor, that is to say the synthesis routes in which all the reactants are loaded into the reactor at the beginning of the reaction without intermediate isolation or purification, are generally preferred routes due to their inherent simplicity. On the other hand, the number of possible unwanted side reactions also increases in synthesis in a single reactor with the corresponding increase in products secondary and loss of performance. For the present process, it is noted that piperazine contains two identical secondary amines that could potentially take part in the formation of a CN bond. However, it has been found that the present manufacturing route is highly effective in avoiding such side reactions. In particular, it has been found that the present manufacturing process effectively prevents or reduces the formation of impurities formed by the formation of CN bonds that involve the secondary amine in Compound I. Examples of such impurities include 1- (2,4- dimethyl-phenyl) -4- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine.

WO 2010/094285 describes a purification process that can be used to remove impurities generated when the second amine of the piperazine residue also participates in the formation of a C-N bond. The purification process described in document W or 2010/094285 is applied to a process for the manufacture of Compound I in which 2,4-dimethyl-thiophenol, 1,2-dihalobenzene and optionally substituted piperazine are reacted, in the presence of a palladium catalyst. This process was first discussed in WO 2005/144005. The data provided in WO2010 / 094285 seems to indicate that impurities formed when the second amine also participates in the formation of a C-N bond in this reaction, e.g. ex. 1- [2- (2,4-Dimethyl-phenylsulfanyl) -phenyl] -4- (2-piperazin-1-yl-phenyl) -piperazine is generated in an amount of 0.5% to 4.8%. This is consistent with the data shown in Example 4 in the present application, where 1% of this impurity is generated. As discussed below, the palladium catalyst also catalyzes the formation of C-S bonds. Furthermore, it is noted that in the manufacturing process of the present invention, impurities generated by the reaction of two or more thiol compounds (compound of formula III) are not generated in a significant amount.

As shown in the examples, the present invention provides an alternative manufacturing process for Compound I in which little or no impurity is generated through the formation of C-N bonds in the second nitrogen of the piperazine. At the same time, the level of total impurity is also reduced compared to the process described in WO 2005/144005 and the overall yield is maintained at a high level. In addition, the manufacturing process of the present invention provides a simpler overall process in that the purification steps can be avoided to eliminate impurities generated through the formation of the C-N bond in the second piperazine nitrogen, e.g. ex. as described in WO 2010/094285. The data shown in examples 1 to 4 show that the impurities generated when the second amine participates in the formation of C-N bonds, p. ex. impurities A and B are not formed for all practical purposes. This compares favorably with the level of such impurities about 1% with the process of WO 2005/144005 as demonstrated in example 4 and the even larger numbers reported in WO 2010/094285. It is also noted that the overall level of impurities is significantly lower, that is, approximately 50% lower, with the manufacturing process of the present invention, which again means that the purity of Compound I as obtained in the Manufacturing process of the present invention is much greater.

The compound of formula II is 1-halogen-2,4-dimethyl-phenyl wherein said halogen is selected from Br and I. In one embodiment, the compound of formula II is 1-iodo-2,4-dimethyl-phenyl .

The compound of formula III is 2-halogen-thiophenol, wherein said halogen is selected from CI and Br. In one embodiment, the compound of formula III is 2-bromo-thiophenol.

The compound of formula III is a thiol or the corresponding thiolate. Due to the basic reaction conditions, the reacting species is thiolate. From a occupational health perspective, it may be beneficial to use a thiolate, such as Li +, Na +, K + or Ca ++ thiolate, to avoid the odor problems associated with thiols. However, in one embodiment, R 'is hydrogen.

Compounds of formula II and III are typically added in equimolar amounts, and these compounds are also typically added in a limiting amount.

The compound of formula IV is a piperazine compound. Piperazine has two nitrogens, of which only one participates in the formation of the C-N bond. In one embodiment, bonding with the second nitrogen is avoided using a monoprotected piperazine, that is, an embodiment in which R is a protecting group. Many protecting groups are known in the art, and useful examples include -C (= O) O-W, -C (= O) -W, boc, Bn and Cbz, and in particular boc. W represents alkyl or aryl; Bn is the abbreviation for benzyl; boc is the abbreviation for t-butoxycarbonyl; and cbz is the abbreviation for benzyloxycarbonyl. If a protected piperazine is used in the reactions, the protective group should be removed at a later stage, generally by the addition of an aqueous acid solution. It has been found that the present process results in only low levels of impurities generated through the formation of a C-N bond in the second amine of the piperazine. This allows the use of unprotected piperazine (i.e., R is hydrogen). The use of unprotected piperazine allows an inherently simpler process because the deprotection step can be avoided.

The compound of formula IV is typically added in 1 to 100 equivalents, such as 1 to 10 equivalents, typically 1 to 3 equivalents. Alternatively, piperazine can be used as a solvent, that is, an embodiment in which the piperazine is both reactive and solvent.

The solvent used in the process of the present invention can be selected from aprotic organic solvents or mixtures of such solvents with a boiling temperature within the reaction temperature range, that is, 50 to 130 ° C. Typically, the solvent is selected from toluene, xylene, triethylamine, tributylamine, dioxane, N-methylpyrrolidone, pyridine or any mixture thereof. Special mention is made of toluene as a solvent.

In the present process it is essential to use a palladium catalyst, without which Compound I is not formed. As discussed above, the palladium catalyst catalyzes the formation of the CN bond but also the formation of the CS [Bull. Chem. Soc. Jpn., 53, 1385-1389, 1980]. The palladium catalyst consists of a source of palladium and a phosphine ligand. Useful sources of palladium include palladium in different oxidation states, such as 0 and II. Examples of palladium sources that can be used in the process of the present invention are Pd ² (dba) ³ , Pd (dba) ² and Pd (OAc) ² . The notation dba is short for dibenziliden-acetone. Particular mention is made of Pd (dba) ² and Pd (OAc) ² . The palladium source is typically applied in an amount of 0.1 and 6 mol%, such as 0.5 and 2 mol%, typically about 1 mol%. Throughout this application, the mole% and its equivalent are calculated with respect to the limiting reagent.

Numerous phosphine ligands, both monodentate and bidentate, are known. Useful phosphine ligands include racemic 2,2'-bis-diphenylphostyl- [1,1 '] binaphthalenyl- (rac-BINAP), (S) -BINAP, (R) -BINAP, 1,1'-bis (diphenylphosphino ) ferrocene (DPPF), bis- (2-diphenylphosphinophenyl) ether (DPEphos), tri-f-butylphosphine (Fu salt), biphenyl-2-yl-di-f-butyl phosphine, biphenyl-2-yl-dicyclohexylphosphine , (2'-dicyclohexylphosphanil-biphenyl-2-yl) -dimethyl-amine, [2 '- (di-f-butylphosphanyl) biphenyl-2-yl] dimethylamine, and dicyclohexyl- (2', 4 ', 6'- tri-propyl-biphenyl-2-yl) -phosphan. In addition, chloride carbine ligands such as, for example, 1,3-bis (2,6-di-isopropyl-phenyl) -3H-imidazol-1-io, can be used instead of phosphine ligands. In one embodiment, the phosphine ligand is rac-BINAP, DPPF or DPEphos, and in particular rac-BINAP. The phosphine ligand is generally applied in an amount between 0.2 and 12 mol%, such as 0.5 and 4 mol%, typically about 2 mol%.

A base is added to the reaction mixture to increase the pH. In particular, the bases selected from NaOt-Bu, KOt-Bu, Na ² CO ³ , K ² CO ³ and Cs ² CO ³ are useful. Organic bases, such as 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and 1,4-diazabicyclo [2.2.2] octane (DABCO), can also be applied. Special mention is made of NaO (t-Bu) and KO (t-Bu). Typically, the base that is added is an amount of about 2 to 10 equivalents, such as 2 to 5 equivalents, such as 2.5 to 3.5 equivalents.

In some situations, it may be desirable to obtain an acid addition salt of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine instead of the free base. The acid addition salts can be achieved in an additional process step in which the free base obtained is reacted with an appropriate acid, such as e.g. ex. lactic acid, hydrochloric acid or hydrobromic acid. The acid can be added directly to the reaction mixture or, alternatively, the free base can be purified to any suitable degree initially before said step. If the free base has been isolated as a solid compound, it may be necessary to use a solvent to bring the free base to a solution before a reaction with the acid. In one embodiment, the aqueous hydrobromic acid is added directly to the reaction mixture without any initial purification of the free base. Alternatively, HBr can be added in alcoholic solution.

In processes in which a protected piperazine is used, the protective group must be removed p. ex. by adding an aqueous acid solution, as explained above. In one embodiment, said aqueous acid solution can be selected to achieve two transformations, that is, deprotection of the protected piperazine and the formation of an acid addition salt. In particular, aqueous hydrobromic acid solution can be used to deprotect the protected piperazine and to obtain the hydrobromic acid addition salt at one stage of the process.

In one embodiment, the process of the present invention is performed at 75 ° -120 °, or at 80 ° -120 °.

For all the reactions and reaction mixtures mentioned herein, it may be an advantage to purge them with an inert gas or put them under a layer of inert gas. Nitrogen is an example of cheap and readily available inert gas.

In one embodiment, Compound I is prepared in a process that comprises reacting

with

Y

in the presence of a solvent, a base and a palladium catalyst consisting of a source of palladium and a phosphine ligand at a temperature between 50 ° C and 130 ° C. In another embodiment, the compound obtained is reacted with an acid to obtain a desired pharmaceutically acceptable salt of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine.

In one embodiment, the invention provides a process for the manufacture of Compound I, which process comprises the steps of

a) Dissolve or disperse 0.1 mol% -3 mol% bis (dibenzylidenacetone) palladium (0) and 0.5 mol% -4 mol% 2,2'-bis-diphenylphosphanil- [1, 1 '] - racemic binaphthalenyl and 2-6 equivalents of base in toluene to obtain Mixture A;

b) add 1 equivalent of 1-iodo-2,4-dimethylbenzene, 0.8-1.2 equivalents of 2-bromo thiophenol and 1 -10 equivalents of piperazine to Mixture A to obtain Mixture B; Y

c) heat Mix B to 80 ° C -120 ° C or 75 ° C -120 ° C to obtain

d) optionally add an appropriate acid to the product obtained in step c) to obtain the corresponding salt. Particular mention is made of the addition of aqueous HBr solution.

In one embodiment, the invention is related to Compound I and in particular Compound I HBr obtained in a process comprising or consisting of steps a) to d) above.

In one embodiment, the invention provides a process for the manufacture of Compound I, a process comprising the steps of

a) dissolve or disperse 0.1 mol% - 3 mol% bis (dibenzylidenacetone) - palladium (0) and 0.5 mol% - 4 mol% 2,2'-bis-diphenylphosphanil- [1 , 1 '] racemic binaphthalenyl, 1-10 equivalents of piperazine and 2-6 equivalents of base in toluene to obtain Mixture A;

b) add 1 equivalent of 1-iodo-2,4-dimethylbenzene and 0.8-1.2 equivalents of 2-bromo thiophenol to Mixture A to obtain Mixture B; Y

c) heat Mix B to 80 ° C -120 ° C or 75 ° C -120 ° C to obtain

d) optionally add an appropriate acid to the product obtained in step c) to obtain the corresponding salt. Particular mention is made of the addition of aqueous HBr solution.

Compound I and in particular Compound IH Br obtained in a process comprising or consisting of steps a) to d) above are also described herein.

It should be considered that the use of the terms "a" and "the" and similar references in the context of the description of the invention covers both the singular and the plural, unless otherwise indicated or clearly indicated herein. in contradiction with the context. For example, the phrase "the compound" is to be understood as a reference to various compounds of the invention or aspects described in particular, unless otherwise indicated.

The description herein of any aspect or aspect of the invention using terms such as "comprising", "having", "including" or "containing" with reference to an element or elements is intended to provide support for a similar aspect or aspect of the invention that "consists of", "consists essentially of", or "substantially comprises" that particular element or elements, unless otherwise stated or clearly contradict the context (by For example, a composition described in this text as a composition comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicts the context).

Examples

Example 1.

Mixed racemic bis (dibenzylidenacetone) palladium (0) (0.610 g, 1.06 mmol), 2,2'-bis (biphenylphosphino) -1,1'-binaphthyl (1.34 g, 2.15 mmol), sodium ferc-butoxide (31.0 g, 323 mmol) and toluene (150 mL, degassed). The reaction mixture was stirred for 2 hours at room temperature (23 ° C) under a nitrogen atmosphere.

To this mixture was added piperazine (23.0 g, 267 mmol), 1-iodo-2,4-dimethylbenzene (25.0 g, 108 mmol) and 2-bromothiophenol (20.5 g, 108 mmol). The reaction mixture was then heated at 100 ° C for 5 hours, after which it was cooled to room temperature. Water was added to the reaction mixture (80 mL) (IPC (In Process Control) sampled here) and then Celite 545 (8.0 g). The reaction mixture was stirred for 20 minutes before filtration. The phases were separated and the toluene phase was washed twice with water (2 x 80 mL).

The toluene phase was heated to 60 ° C. To the hot toluene phase, hydrobromic acid (8.9 M, 13.0 mL, 116 mmol), seed crystals (HBr salt of the title compound, 10 mg) were added and the solution was allowed to cool to room temperature.

1- [2- (2,4-Dimethyl-phenylsulfanyl) -phenyl] -piperazineHBr was isolated by filtration and the filter cake was washed twice with toluene (2 x 30 mL).

Yield 80.1% of 1- [2- (2,4-dimethyl-phenylsulfanyl) phenyl] -piperazine HBr (33.5 g, 88.3 mmol).

Purity 97.9% (HPLC, UV detection at 254 nm).

1H NMR (DMSO-da; 500 MHz): 8.83 (bs, 2H), 7.34 (d, 1H), 7.26 (s, 1H), 7.15 (m, 3H), 6.98 (dd, 1H), 6.43 (d, 1H), 3.26 (bm, 4H), 3.21 (bm, 4H), 2.33 (s, 3H), 2.25 (s, 3H) .

Example 2

Mixed bis (dibenzylidenacetone) palladium (0) (665 mg, 1.15 mmol), 2,2'-bis (diphenylphosphino) -1,1'-racemic binaphthyl (1.44 g, 2.30 mmol), ferc - sodium butoxide (22.2 g, 231 mmol), piperazine (16.6 g, 193 mmol), and toluene (110 mL, degassed). The reaction mixture was stirred for 1 hour at room temperature (23 ° C) under a nitrogen atmosphere.

To this mixture was added 1-iodo-2,4-dimethylbenzene (15.1 g, 65.0 mmol) and 2-bromothiophenol (11.8 g, 62.4 mmol), then the reaction mixture was heated to 100 ° C for 4 hours, after which it was cooled to room temperature. Water was added to the reaction mixture (60 mL) (sampled IPC here) and then Celite 545 (9.5 g). The reaction was stirred for 20 minutes before filtration. The phases were separated and the toluene phase was washed twice with water (2 x 60 mL).

The toluene phase was heated to 60 ° C. To the hot toluene phase, hydrobromic acid (8.9 M, 9.3 mL, 82.8 mmol) was added, seed crystals (HBr salt of the title compound, 10 mg) were added and the solution was allowed to cool. at room temperature.

1- [2- (2,4-Dimethyl-phenylsulfanyl) -phenyl] -piperazineHBr was isolated by filtration and the filter cake was washed 3 times with toluene (3 x 25 mL).

Yield 77.1% of 1- [2- (2,4-dimethyl-phenylsulfanyl) phenyl] -piperazine HBr (18.6 g, 49.0 mmol).

Purity 98.2% (HPLC, UV detection at 254 nm).

¹ H NMR (DMSO-d ⁶ ): 8.83 (bs, 2H), 7.34 (d, 1H), 7.26 (s, 1H), 7.14 (m, 3H), 6.97 ( dd, 1H), 6.42 (d, 1H), 3.26 (bm, 4H), 3.21 (bm, 4H), 2.33 (s, 3H), 2.25 (s, 3H).

Example 3

Mixed palladium (II) acetate (580 mg, 2.58 mmol), 2,2'-bis (diphenylphosphino) -1,1'-racemic binaphthyl (3.20 g, 5.16 mmol), ferc-butoxide of sodium (49.5 g, 516 mmol), piperazine (37.0 g, 430 mmol) and toluene (250 mL, degassed). The reaction mixture was stirred for 2 hours at room temperature (23 ° C) under a nitrogen atmosphere.

To this mixture was added 1-iodo-2,4-dimethylbenzene (40.0 g, 172 mmol) and 2-bromo thiophenol (32.6 g, 172 mmol). The reaction mixture was then heated at 100 ° C for 1 hour, after which it was cooled to room temperature. Water (80 mL) was added to the reaction mixture (a sample of IPC was taken here) and then Celite 545 (12 g). The reaction was stirred for 20 minutes before filtration. The phases were separated and the toluene phase was washed twice with water (2 x 80 mL).

The toluene phase was heated to 60 ° C. To the hot toluene phase, hydrobromic acid (8.9 M, 20.8 mL, 185 mmol) was added, seed crystals (HBr salt of the title compound, 10 mg) were added and the solution was allowed to cool to temperature ambient.

1 - [2- (2,4-Dimethyl-phenylsulfanyl) -phenyl] -piperazine-HBr was isolated by filtration and the filter cake was washed 3 times with toluene (3 x 40 mL).

Yield 84.3% of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine HBr containing 0.60 eq of tert-butanol (62.1 g, 147 mmol).

Purity 98.6% (HPLC, UV detection at 254 nm).

1H NMR (DMSO-da): 8.82 (bs, 2H), 7.34 (d, 1H), 7.26 (s, 1H), 7.15 (mp, 3H), 6.98 (dd, 1H), 6.43 (d, 1H), 3.27 (bm, 4H), 3.21 (bm, 4H), 2.34 (s, 3H), 2.25 (s, 3H), 1, 12 (s, 5.4H).

Example 4 (reference).

Mixed racemic bis (dibenzylidenacetone) palladium (0) (307 mg, 0.530 mmol), 2,2'-bis (diphenylphosphino) -1,1-carbophilic, (0.66 g, 1.06 mmol), tert-butoxide sodium (44.7 g, 466 mmol), piperazine (40.3 g, 469 mmol) and toluene (200 mL, degassed). The reaction mixture was stirred for 35 minutes at room temperature (23 ° C) under a nitrogen atmosphere.

To this mixture was added 1-bromo-2-iodo-benzene (39.2 g, 135 mmol) and 2,4-dimethyl benzenethiol (18.3 g, 133 mmol), the reaction mixture was then heated to reflux for 6 hours, after which it was cooled to room temperature. Water (60 mL) was added to the reaction mixture (a sample of IPC was taken here) and then Celite 545 (9.0 g). The reaction mixture was stirred for 20 minutes before filtration. The phases were separated and the toluene phase was washed twice with water (2 x 60 mL).

The toluene phase was heated to 60 ° C. To the hot toluene phase, hydrobromic acid (8.9 M, 16.8 mL, 150 mmol) was added, seed crystals (HBr salt of the title compound, 10 mg) were added and the solution was allowed to cool to temperature ambient.

1- [2- (2,4-Dimethyl-phenylsulfanyl) -phenyl] -piperazineHBr was isolated by filtration and the filter cake was washed 3 times with toluene (3 x 25 mL).

Yield 81.5% of 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -piperazine HBr containing 0.70 eq of ferc-butanol (51.2 g, 118 mmol).

Purity 96.0% (HPLC, UV detection at 254 nm).

¹ H NMR (DMSO-d ⁶ ): 8.78 (bs, 2H), 7.34 (d, 1H), 7.26 (s, 1H), 7.15 (m, 3H), 6.98 ( dd, 1H), 6.43 (d, 1H), 3.27 (bm, 4H), 3.20 (bm, 4H), 2.34 (s, 3H), 2.26 (s, 3H), 1.12 (s, 6.3H).

The following table shows analytical data on impurities (% Area by HPLC) for IPC and final product for examples 1-4.

HPLC method.

• Column type: Acquity UPLC BEH C18 1,7pm; 2.1 x 150mm

• Column temperature: 60 ° C.

• Detection at 254nm

• Flow: 0.6 mL / min.

• Solvents:

A: Water containing 0.05% TFA (trifluoroacetic acid)

B: Acetonitrile containing 5% water and 0.035% TFA

Gradient: Time, min. % B Curve

0.00 10.0 6

1.80 99.9 6

1.81 10.0 6

2.00 10.0 6

Impurity A is 1,2-bis (l'-piperazinyl) benzene.

Impurity B is 1-phenyl-piperazine.

Impurity C is 1- (2-bromo-phenyl) piperazine.

Impurity D is 1- (2,4-dimethyl-phenyl) piperazine.

Impurity E is 1- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] -4- (2-piperazin-1-yl-phenyl) -piperazine Impurity F is 1- (2,4-dimethyl- phenyl) -4- [2- (2,4-dimethyl-phenylsulfanyl) -phenyl] piperazine. The impurity G is 2,4-dimethi-M-phenylsulfanylbenzene.

Claims (18)

1. A procedure for the manufacture of

or its pharmaceutically acceptable salts (Compound I), said method comprising reacting a compound of formula II

wherein X represents Br or I, with a compound of formula III

wherein Y represents CI or Br and R 'represents hydrogen or a metal ion, and a compound of formula IV

wherein R represents hydrogen or a protecting group, in the presence of a solvent, a base and a palladium catalyst consisting of a source of palladium and a phosphine ligand at a temperature between 50 ° C and 130 ° C, where, when R represents a protective group, said protective group is removed at a later stage. 2. The process according to claim 1, wherein X represents I. 3. The process according to claims 1 or 2, wherein Y represents Br and R 'represents H. 4. The process according to any of claims 1 to 3, wherein R represents H. 5. The process according to any one of claims 1 to 3, wherein R represents a protecting group selected from -C (= O) OW, -C (= O) -W, boc, Bn and Cbz, wherein W represents alkyl or aryl. 6. The process according to any of claims 1 to 5, wherein said solvent is an aprotic solvent. 7. The process according to claim 6, wherein said solvent is toluene. 8. The process according to any one of claims 1 to 7, wherein said palladium source is selected from Pd (dba) ² , Pd (OAc) ² and Pd2dba3. 9. The process according to claim 8, wherein said palladium source is Pd (dba) ² or Pd (OAc) ² . 10. The process according to any one of claims 1 to 9, wherein said phosphine ligand is selected from racemic 2,2'-bis-diphenylphostyl- [1,1 '] binaphthalenyl- (rac-BINAP), 1,1' -bis (diphenylphosphino) ferrocene (DPPF), bis- (2-diphenylphosphinophenyl) ether (DPEphos), tri-í-butylphosphine (Fu salt), biphenyl-2-yl-di-f-butyl phosphine, biphenyl-2 -yl-dicyclohexylphosphine, (2'-dicyclohexylphosphanyl-biphenyl-2-yl) -dimethyl-amine, [2 '- (di-f-butylphosphanyl) biphenyl-2-yl] dimethylamine, and dicyclohexyl- (2', 4 ' , 6'-tripropyl-biphenyl-2-yl) -phosphan. 11. The process according to claim 10, wherein said phosphine ligand is 2,2'-bis-diphenylphosphanyl- [1,1 '] binaphthalenyl (rac-BINAP). 12. The process according to any of claims 1 to 11, wherein said base is selected from NaO (t-Bu), KO (t-Bu), K ² CO ³ , Na ² CO ³ , Cs ² CO ³ , DBU and DABCO. 13. The process according to claim 12, wherein said base is NaO (t-Bu). 14. The process according to any one of claims 1 to 13, further comprising reacting the product obtained in said claims with an appropriate acid to remove the protecting group (when R is a protective group) and / or to obtain the pharmaceutically acceptable salt desired. 15. The process according to claim 1, comprising reacting

with

Y

in the presence of a solvent, a base and a palladium catalyst consisting of a source of palladium and a phosphine ligand, at a temperature between 50 ° C and 130 ° C. 16. The process according to claim 15, further comprising reacting the compound obtained in said claim with an acid to obtain a desired pharmaceutically acceptable salt of said compound. 17. The process according to claim 1, comprising the steps of a) dissolve or disperse 0.1 mol% - 3 mol% bis (dibenzylidenacetone) palladium (0) and 0.5 mol% - 4 mol% 2,2'-bis-diphenylphosphanil- [1, 1 '] racemic binaphthalenyl and 2 to 6 equivalents of base in toluene to obtain Mixture A; b) add 1 equivalent of 1-iodo-2,4-dimethylbenzene, 0.8 to 1.2 equivalents of 2-bromothiophenol and 1 to 10 equivalents of piperazine to Mixture A, to obtain Mixture B; Y c) heat Mix B to 80 ° C -120 ° C to obtain

d) optionally add an appropriate acid to the product obtained in step c) to obtain the corresponding salt. 18. A process according to claim 1 comprising the steps of a) dissolve or disperse 0.1 mol% - 3 mol% bis (dibenzylidenacetone) -palladium (0) and 0.5 mol% - 4 mol% 2,2'-bis-diphenylphosphanil- [1 , 1 '] racemic binaphthalenyl, 1 to 10 equivalents of piperazine and 2 to 6 equivalents of base in toluene to obtain Mixture A; b) add 1 equivalent of 1-iodo-2,4-dimethylbenzene and 0.8 to 1.2 equivalents of 2-bromothiophenol to Mixture A to obtain Mixture B; Y c) heat Mix B to 80 ° C -120 ° C to obtain

d) optionally adding an appropriate acid to the product obtained in step c) to obtain the corresponding salt.