NZ710779B2 - Vortioxetine manufacturing process - Google Patents

Abstract

process for the manufacture of vortioxetine is provided in which a compound of formula I, formula I is reacted with optionally substituted piperazine and 2,4-dimethylthiophenol(ate) followed by de-complexation.

Description

VORTIOXETINE CTURING PROCESS Field of invention The present invention relates to a process for the manufacture of 1-[2-(2,4- dimethylphenylsulfanyl)phenyl]-piperazine or pharmaceutically acceptable salts thereof.

Background of the invention International patent applications including WO 03/029232 and WC 2007/144005 disclose the compound 1-[2-(2,4-dimethyl-phenylsulfanyl)-pheny1]-piperazine and pharmaceutically acceptable salts thereof. WHO has since hed that vortioxetine is the recommended ational Non—proprietary Name (INN) for 1-[2-(2,4- dimethyl—phenylsulfanyl)—phenyl]—piperazine. Vortioxetine was formerly referred to in the literature as Lu AA21004. FDA and EMA have since approved vortioxetine for the treatment of sion under the trade name BrintellixTM.

Vortioxetine is a 5-HT3, 5-HT7, and 5—HT“) receptor antagonist, 5-HTlB receptor partial agonist, 5-HT1A or t and inhibitor of the 5-HT transporter.

Additionally, xetine has demonstrated to enhance the levels of the neurotransmitters serotonin, noradrenalin, dopamine, acetylcho line and histamine in specific areas of the brain. All of these activities are considered to be of clinical relevance and potentially involved in the mechanism of action of the compound [JMed.Chem., 54, 221, 2011; Eur. Neuropshycopharmacol., 18(suppl 4), S321, 2008; Eur. Neuropshycopharmacol., 21(supp14), 8407-408, 2011; Int. J. Psychiatry Clin Pract. 5, 47, 2012].

Vortioxetine has in clinical trials shown to be a safe and efficacious treatment for depression. A paper reporting the results from a proof-of—concept study to evaluate the efficacy and tolerability of the compound in patients with major depressive disorder (MDD) authored by s et a! was made available on-line by Int. J.

Neuropsychopharm. 18 July 2011. The results from the six weeks, randomised, placebo—controlled study with approximately 100 patients in each arm show that vortioxetine separates icantly from placebo in the ent of depressive and anxious symptoms in patients with MDD. It is also reported that no clinically relevant changes were seen in the clinical laboratory results, vital signs, weight, or ECG parameters. Results from a long-term study also show that vortioxetine is effective in preventing relapse in patients suffering from MDD [Eur. Neuropsychopharmacol. 21(suppl 3), S3 96-397, 201 1]. A study in elderly depressed patients reported in Int.

Clin. Psychapharm., 27, 215-227, 2012 shows that vortioxetine may be used to treat cognitive dysfiinctions.

The manufacturing process used to prepare xetine disclosed in WC 03/029232 is based on solid-phase synthesis and exploits di-arene ssisted nucleophilic aromatic substitution reactions in a multistep process. In summary, 4- [piperaziney1]carbonyloxymethyl]phenoxymethy1 polystyrene was reacted with a di-arene iron salt, i.e. n6-1,2-dichlorobenzene-ns-cyclopentadienyliron(II) hexafluorophosphate followed by isolation and washing of the resin and further reaction with methylthiophenol. y, the thus obtained resin was treated with 1,10-phenanthroline and light to de—complex cyclopentadienyliron. The overall yield was low, only 17%. A similar s is disclosed in WO 01/49678 wherein phenoxyphenylpiperazines are prepared as intermediates.

Di-arene iron compounds have been known for long time, exemplified by ene which consists of two pentadienyl rings bound to iron in a sandwich structure. These compounds have proved to be usefial tools in the preparation of e.g. heterocyclic compounds. As an example, Pearson et al in J. Org. Chem. 61, 1297-1305, 1996 se displacement of chloro atoms from 1,4-dichlorobenzene- cyclopentadienyl-iron (II) by cyclic secondary amines, e.g. piperazine. Interestingly, this reaction results in a symmetric displacement, i.e. displacement ofboth chloro atoms from the benzene moiety. land et al in JHeterocyclz'c Chem., 19, 801-803, 1982 disclose that both chloro atoms in 1,2—dichlorobenzene-cyclopentadienyl-iron(II) are displaced by substituted 1,2-dithiophenol to obtain the corresponding thiaanthrenes. Pearson et al [J. Org Chem, 59, 4561-4570, 1994] disclose the use of 1- 4-dichlorobenzene- cyclopentadienyl—iron(II) hexafluorophosphate in the manufacture of tric compounds in which the two chloro atoms are substituted by phenoxy and morpho line, respectively. Notably, the two tutions require very different reaction ions and isolation of the intermediate, mono-substituted compound was required. d et al in J. Org. Chem, 67, 5257—5268, 2002 disclose synthesis of 1,2-disubstituted benzenes where selective substitution with different substitutions of the chemically identical chloro atoms is achieved via cyclopentadienyl activation in solid phase.

Solid-phase try is not le for pharmaceutical production involving manufacturing in ton-scale. The massive handling of resins that would be required and the costs associated are prohibitive. Additionally, the low yield obtained for votioxetine (only 17%) makes this manufacturing route unattractive.

Large scale manufacturing of vortioxetine has been disclosed in WC 2007/144005 and . Piperazine, methylthiophenol and 1,2- dihalogenbenzene are mixed e.g. in toluene together with a ium st to afford xetine. Although this reaction provides high yield and can be handled in large scale, it requires the use of an expensive catalyst, i.e. palladium. Moreover, the reaction conditions are harsh employing elevated temperatures to obtain a satisfactory result, i.e. reflux temperatures or 80—1200C and the use of strong base.

The present invention es a manufacturing process for vortioxetine which uses inexpensive starting materials, which can be run at mild conditions and which gives high yields.

Summary of the invention The present inventors have found that l—[2-(2,4-dimethyl—phenylsulfanyl)- phenyl]-piperazine (vortioxetine) or pharmaceutically acceptable salts thereof can be prepared in a reaction in which a le di-arene iron salt, i.e. ally substituted l,2—dihalogenbenzene-cyclopentadienyl—iron(II) salt is reacted with an optionally protected piperazine and 2,4-dimethylthiopheno1(ate) followed by de-complexation of optionally substituted cyclopentadienyl iron and by de-protection ofpiperazine as required if protected piperazine is applied in the s to obtain l-[2-(2,4-dimethylphenylsulfanyl )-phenyl]-piperazine. A desired pharmaceutically acceptable salt may be obtained by subsequent reaction with a suitable acid.

Accordingly, in one embodiment the invention provides a process for the cture of vortioxetine or pharmaceutically acceptable salts thereof, which process comprises reacting a compound of formula I wherein each Hal independently ents fluoro or chloro; R’ represents H or R’ ents one or two moieties ndently selected from CHO, COOH, COOR” ’ or COONR”’2 or R’ represents one to five moieties independently selected from Clfi—alkyl; R’ ’ ’ independently represents H or Clfi-alkyl; and X" represents a non- coordinating and non—nucleophilic anion, with an optionally protected piperazine of formula II wherein R represents H or a protetive group, and with a compound of formula III [III] wherein R’ ’ represents H or a cation and a base as required in a solvent to obtain a compound of formula IV + x- S —\ /—\Q RN N Fe(||) [IV] followed by a de-complexation step in which the optionally substituted cyclopentadienyliron is de-complexed, and a de-protection step as required in which the optionally protected piperazine moiety is de-protected to obtain 1-[2-(2,4- dimethyl-phenylsulfanyl)-phenyl]-piperazine, i.e. vortioxetine.

The nd of formula I, the compound of a II and the compound of formula 111 may be added to the reaction mixture in any sequence or aneously.

According to the present invention there is provided a process for the manufacture ofvortioxetine or pharmaceutically acceptable salts thereof, which process comprises reacting a compound of formula I +, x- Hal _\ Fe(ll) wherein each Hal independently represents fluoro or ; R’ ents H or R’ represents one or two moieties ndently selected from CHO, COOH, COOR” ’ or COONR”’2, or R’ represents one to five moieties independently selected fiom C1- 5-alkyl; R’ ’ ’ independently represents H or Clfi-alkyl; and Xrepresents a 11011- coordinating and non—nucleophilic anion, with a piperazine of formula H [II] n R represents H, and with a nd of formula III R''S [III] wherein R’’ represents H or a cation and a base as required in a solvent to obtain a compound of formula IV 3 +, XS RN N Fe(II) [IV] followed by a de-complexation step in which the optionally substituted cyclopentadienyliron is de-complexed, to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl]-piperazine oxetine).

Figures Figure 1: Schematic depiction of a flow chemistry set-up for the reaction of the present invention. Compound of formula I is mixed with compound of formula II and (25416898_1):AXG compound of formula III to obtain vortioxetine following plexation and deprotection as required.

Detailed description of the invention The compound of formula I comprises a di-halogen substituted benzene moiety which is 6-bound to the metal centre of a cyclopentadienyl fragment. Said halogen is independently ed from fluoro and chloro. In one embodiment, the halogens are identical; in particular both halogens are chloro. In this embodiment, the di-arene iron compound can be made from very inexpensive starting als, i.e. 1,2-di-chlorobenzene.

R’ represents H or R’ ents one or two moieties independently selected from CHO, COOH, COOR’’’ or COONR2’’’, or R’ represents one to five moieties independently selected from C1_6-a1ky1; R’ ” independently represents H or C1_6-alkyl.

In one embodiment, R’ represent one C1_6—a]kyl, such as methyl. In one embodiment, R’ is hydrogen, i.e. the cyclopentadienyl moiety is unsubstituted. In one embodiment, R’ ” represents methyl.

R represents an optional tive group on one of the pipirazine nitrogens.

Many protective groups are known in the art, and US€fill es e —C(=O)O- W, -C(=O)-W, Boc, Bn and Cbz, and in particular Boc. W represents alkyl or aryl; Bn abbreviates benzyl; Boc abbreviates t-butyloxycarbonyl; and Cbz iates carbobenzyloxy. If a mono-protected piperazine is used in the reaction of the present invention, the protective group has to be removed in a subsequent step, typically by the addition of an acid, such as an aqueous acid. If properly selected, said acid may remove the protective group and provide a desired pharmaceutically acceptable salt of vortioxetine in one and the same step. The use of aqueous HBr may e de- protection and the HBr salt of vortioxetine in one step. The reaction of the present invention may run with non-protected piperazine which is beneficial due the reduced number of process steps and thus inherent simplicity.

In the present context, the term “C1_6-alkyl” is intended to indicate a straight, branched and/or cyclic saturated hydrocarbon containing 1-6 carbon atoms which alkyl may be substituted. es include methyl, ethyl, isopropyl, cyclopentyl and 2-cyclopropyl-ethyl.

In the present context, the term “aryl” is intended to indicate an optionally substituted carbocyclic aromatic hydrocarbon R’ ’ ents either en or a cation which may be either organic or inorganic. Inorganic cation include metal—ion, such as a mono-valent or di-valent metal-ion, such as KI, Nat Li+ and Mg“. Examples of organic cation e 2- hydroxyethyl-trimethylammonium and l—3—methylimidazo1ium.The reaction of the present invention runs best if 2,4-dimethyl thiolate is present. This may be achieved e. g. by adding the thiolate salt (R” represents cation) to the reaction mixture, ’ represents H) and or by adding the thiophenol nd (R’ a suitable base as required to obtain the corresponding thiolate. A suitable mixture of thiophenol, thio late and a base may also be used. The process of the present invention does not require harsh basic conditions, and bases typically applied in process chemistry may be applied. Examples ofuseful bases include K2C03, NaOEt, NaO(t-Bu), KO(t-Bu), NaOH, KOH and NaH.

X" represents a non-coordinating and non-nucleophilic anion. In the present context a non-coordinating anion is intended to indicate an anion that essentially does not establish a coordinating bond to the iron in the compound of formula I or formula III. In the present context a non-nucleophilic anion is intended to indicate an anion that essentially does not substitute Hal in the compound of formula 1. Typical examples include BF4‘, PF6‘, ClO4‘, [B[3,5-(CF3)2C6H3]4]_, B(C6F5)4‘ and Al(OC(CF3)3)4'. The use of PF6' has the age that PF5' salts of the compound of formula I are easily isolated and stored. This means that the compound of formula I may be prepared in a process which is separated in time and place from the process of the t invention.

A wide range of solvents may be applied in the process of the present invention. Useful examples e toluene, THF (tetrahydrofuran), MTBE l tert—butyl ether), water, ethanol, 2-propanol, NMP (N-methylpyrrolidone), DMF (dimethylformamide), MIBK (methylisobutyl ketone), TEA (triethyl amine), DIPEA iisopropylethylamine), DCM (dichloromethane), ethylacetate, isopropylacetate and combinations of these.

The ally substituted cyclopentadienyl-iron fragment is removed in a de- complexation step. This step is well-know from the literature and can be achieved in various ways. JHeterocycl.C/¢em., 19, 801-803, 1982 discloses that lexation can be achieved by pyrolysis at 200—2500C; J.0rg Chem,67, 5257-5268, 2002 and JPolymerSczl, 35, 447-453, 1997 apply photolysis in the presence of CH3CN and l,lO-phenantholine; and Chem. Soc. Perkin Trans 1., 197—201, 1994 discloses the use ofpotassium tert—butoxide at ed temperatures in high-bio ling ts, such as pyridine or DMSO. Photolysis which is also known as issociation or ecomposition is a chemical on where a chemical bond is broken upon irradiation with light. For the reaction of the present invention, de-complexation by photolysis may conveniently be carried out under irradiation with light in the visible or near UV spectrum.

The manufacture of compound of formula I used in the present invention is known from literature. J.Org. Chem, 67, 5257—5268, 2002 discloses a process in which l,2-dichlorobenzene, anhydrous aluminium trichloride, aluminium powder and 101O ferrocene are d at 95°C followed by aqueous work-up and treatment with ammonium orophosphate. Compounds of a I where X" represents a anion different from hexafluorophosphate may be obtained in a similar way by means of a different and appropriate salt, e.g. ammonium BF4. If suitably substituted ferrocene is used, compound of a I wherein R’ is different from H may be obtained. 2,4-Dimethyl-thiophenol, salts thereof and (optionally ted) piperazine are all well-known compounds and readily available in large quantities.

The compound of a 111 may for example be obtained from the corresponding arylbromide or arylchloride, i.e. 1-bromo-2,4-dimethyl-benzene or 1- chloro-2,4-dimethyl—benzene in a Grignard-type reaction where said compound is reacted with Mg followed by elemental sulfur to obtain a compound of formula 111 where R’ ’ represent MgCl+ or MgBr+’ An advantage of the process of the present invention is that it runs at low temperature, such as ambient temperature, e.g. 15—30°C. The reaction of the present invention, however, runs both at much higher and much lower temperatures as long as the solvent(s) chosen is sufficiently fluid at the temperature (and pressure) used. In one embodiment, the temperature is between -25°C and 140°C, such as between 0°C and 100°C. In one embodiment the temperature is between 10°C and 80°C, such as l 5°C-5 0°C.

Pharmaceutically acceptable salts are intended to indicate acid addition salts of acids that are non-toxic. Said salts include salts made from organic acids, such as maleic, furnaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, , gluconic, , malic, mandelic, cinnamic, onic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Said salts may also be made from inorganic acids, such as hloric, hydrobromic, sulfuric, sulfamic, phosphoric and nitric acids. Particular mention is made of salts made from hydrobromic acid and lactic acid. Distinct mention is made ofthe hydrobromide acid salt.

In one embodiment, 1 lent of a compound of formula I is mixed with a compound of formula II (l-5 equivalents, such as 1—3 equivalents), a compound of 1111 formula III (1-5 equivalents, such as 1—3 equivalents) in a solvent together with a base as needed (more than 0.5 equivalent, such as n 0.5 and 20 equivalents, such as 1-5 equivalents), e. g. at lO-SOOC, such as 15—250C to obtain a compound of formula IV. The nd of formula IV is then de—complexed, e.g. by photolysis and the protective group on the piperazine is removed as required e.g. by addition of acid to obtain vortioxetine. A pharmaceutically acceptable salt may be ed by further reaction with an appropriate acid. It may also be feasible to de—protect piperazine as required prior to de-complexation.

In one ment, 1 equivalent of a compound of formula I is mixed with a base (more than 0.5 equivalent, such as between 0.5 and 20 equivalents, such as 1-5 lents) and zine (1—5 equivalents, such as 1-3 equivalents) in a solvent.

The mixture is stirred (e. g. at lO—SOOC, such as 15—25°C) and 2,4-dimethyl thiophenol (1-5 equivalents, such as 1-3 equivalents) is added and the reaction is stirred to obtain a compound of formula IV. The compound of formula IV is then de-complexed, e.g. by photolysis to obtain xetine. A pharmaceutically acceptable salt may be obtained by fiarther on with an appropriate acid.

In one embodiment, 1 equivalent of 116—1,2-dichlorobenzene- 71 5-cyclopenta- dienyliron(II) hexafluorophosphate is mixed with 1-5 equivalent base and piperazine (1-3 equivalent, such as 2 equivalents) in a solvent, such as THF/water. After stirring, 2,4-dimethylthiophenol (1-3 equivalent, such as 2 equivalents) is added and the mixture obtained is stirred to obtain the nd of formula IV, e.g. at 10°C-50°C.

Votioxetine is obtained by de-complexation, e.g. by photolysis. plexation by photolysis may be carried out e.g. in batch mode or in flow mode. plexation may conveniently be d out in the following way.

The reaction e comprising the compound of formula IV is mixed with aqueous acid (e.g. aqueous HCl) and organic impurities are optionally removed e. g. by addition of an immiscible organic solvent, such as n-heptane, followed by phase separation. The phase containing the compound of formula IV obtained above above is passed through an irradiated glass tube where photolysis occurs to obtain vortioxetine. As an example, the s phase may be circulated through an irradiated glass tube.

Alternatively, the compound of formula I may be prepared and used immediately in the process of the present invention without isolation. For example 1212 l,2-dichlorobenzene (2-20 lents, such as 3-6 equivalents) is mixed with a suitably substituted ferrocene (1 equivalent), aluminium chloride (0.1-2 equivalent, such as 0.2-1 equivalent) and fine aluminium powder (0.01-0.5 equivalent, such as 0.05-0.2 equivalent) and heated to 80—1200, such as lOO-l 10° to obtain a nd of formula I. The compound of a I may then be further reacted as described above to obtain vortioxetine.

The process of the present invention may be run in batch mode, wherein the reactants are added to a vessel or container. atively, the process of the present invention is amenable to flow chemistry wherein the reactants are mixed and pumped through tubes wherein the reaction takes place. Figure 1 depicts a schematic flow set- up for the reaction of the present invention. The reaction of the present invention may also be carried out partly in batch mode and partly in a flow set-up.

In one embodiment, the invention relates to vortioxetine and pharmaceutically acceptable salts thereof manufactured by a process of the present invention.

As demonstrated in the examples, the present invention es a non-resin based manufacturing process for xetine and pharmaceutically acceptable salts thereof in which an asymmetric displacement of two cal halogen atoms from a symmetric reactant (l ,2—dihalogenbenzene) is effected in a one-pot synthesis, i.e. without the need for isolation of intermediates, such as intermediates where only one halogen is tuted. The process ofthe present invention avoids the use of ive reactants and catalysts; it can be run at low temperatures and lly at mild conditions. Thus, simple and inexpensive manufacturing equipment can be applied, and the risk ofunwanted side-reactions is minimized. High yields and high purity are achieved, and the process of the present ion is well-suited for industrial scale.

All references, including ations, patent applications, and patents, cited herein are hereby incorporated by reference in their entirety and to the same extent as if each reference were individually and cally indicated to be incorporated by reference and were set forth in its entirety herein, regardless of any separately ed incorporation of particular documents made elsewhere herein.

The use of the terms “a” and “an” and “the” and similar nts in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. For 1313 example, the phrase "the compound" is to be understood as referring to various compounds of the invention or ular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention using terms such as ising”, “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 ially of”, or “substantially ses” that particular element or elements, unless otherwise stated or clearly contradicted by context (e.g, a composition described herein as comprising a particular element should be understood as also describing a composition consisting of that element, unless otherwise stated or clearly contradicted by context).

Examples Example 1 776-l,2-Dichlorobenzene- 77 5-cyclopentadienyliron(II) hexafluorophosphate (25 g, 61 mmol), potassium ate (16.7 g, 121 mmol) and zine (10.3 g, 120 mmol) was dissolved in a mixture of THF (200 mL) and water (50 mL). The reaction mixture was stirred for l h at ambient temperature. To the reaction mixture was added 2,4- dimethyl thiophenol (8.8 g, 63.7 mmol) and stirring was continued overnight.

The reaction mixture was poured into aqueous hydrochloric acid (2 M, 200 mL) over a period of 20 min. To the mixture was added n-heptane (15 mL) and the phases were separated. The organic phase was ted once with water (15 mL).

The THF/water phase was circulated at room temperature through an irradiated glass spiral (100 W escent light). During this step water and THF separated and only the lower water phase was pumped through the photolysis equipment, and the liberated l-[2-(2,4-din1ethy1—phenylsulfanyl)—phenyl]-piperazine concentrated in the upper THF phase.

After complete de-complexation, the phases were separated and the water phase was extracted twice with THF (2 x 70 mL). The combined THF phases were diluted with toluene (50 mL) and subsequently washed twice with aqueous sodium hydroxide solution (1.0 M, 50 mL and 30 mL).

The organic phase was separated, and the THF was removed at 40 °C at d pressure. The resulting on was added slowly to a mixture of aqueous hydrobromic acid (48 w/w %, 7.0 mL, 62 mmol), water (20 mL) and toluene (10 mL) at 40 °C. The desired 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine HBr was isolated by filtration. The filter cake was washed with toluene (40 mL) and water (10 mL) yielding 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine HBr (13.3 g, 35.0 mmol 64.1 %) as a white powder.

Al 1ppm, Fe 401 ppm, Na 291 ppm, P 2453 ppm (as determined by ICP-AES).

Purity: Area %: Vortioxetine 99.73, 1-[2-(3,5-dimethyl-phenylsulfanyl)- phenyl]-piperazine 0.08%, unknowns 0.19 (as determined by GC). 1H NMR (DMSO-d6): 8.84 (bs, 2H), 7.34 (d, 1H, 7.7 hz), 7.26 (s, 1H), 7.16 (m, 2H), 7.11 (dd, 1H, 7.8 and 1.7 hz), 6.97 (dd, 1H, 7.8 and 1.7 hz), 6.41 (dd, 1H, 7.8 and 1.3 hz), 3.26 (bm, 4H), 3.20 (bm, 4 H), 2.33 (s, 3H), 2.25 (s, 3H).

Crystal form: β-form (as determined by XRPD). Please see for definition of the -form and -form of xetine HBr.

Water content: <0.1 % (as determined by Karl Fisher) and <0.2 % (as determined by thermo etric analysis).

Elemental analysis C18H23N2SBr requires C 56.99 H 6.11 N 7.38, found C 57.10, H 6.12, N 7.26.

Example 2 1,2-Dichloro benzene (158.4 g, 1.08 mol), ferrocene (40.6 g, 218 mmol), aluminium trichloride (13.8 g, 104 mmol) and fine aluminium powder (7.0 g, 26 mmol) were mixed and heated at 110 °C for 6 h. The reaction mixture was cooled to 25 °C and added slowly to a mixture of ice (240 g) and n-heptane (100 mL) over 25 s.

(CAUTION: the treatment of unreacted aluminium oride with water is highly rmic).

The mixture was treated with Celite 545® (14 g) and stirred at t temperature for 20 minutes prior to filtration. The filter cake was washed with water (15 mL). The filtrates were combined, and the phases were separated. The water phase was washed with toluene (2 x 50 mL). To the water phase was slowly added aqueous sodium hydroxide (10.8 M, 70 mL, 0.76 mol) until the pH was 6.5. The precipitated ium oxides was removed by filtration, and the filter cake was washed with water (25 mL).

The collected aqueous phases was added to a mixture of potassium carbonate (20 g, 0.14 mol) and piperazine (9.4 g, 0.11 mol) in THF (100 mL) and stirred for 3 hours at ambient temperature. To this mixture was added 2,4-dimethyl thiophenol (8.9 g, 64 mmol) and stirring was continued overnight.

The reaction mixture was poured slowly into aqueous hloride acid (4.0 M, 130 mL, 0.52 mol). The reaction mixture was pumped through an irradiated glass tube (100 W incandescent light). During this step water and THF separated and only the lower water phase was pumped through the photolysis equipment, and the liberated 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine concentrated in the upper THF phase.

After complete plexation the phases were separated and the water phase was extracted twice with e (2 x 70 mL). The combined organic phases was washed with sodium hydroxide (1.0 M, 70 mL, 70 mmol) and then with water (25 mL). The THF was d at 40 °C at reduced pressure. The toluene solution was added slowly to a mixture of aqueous hydrobromic acid (48 w/w %, 7.5 mL, 67 mmol), water (20 mL) and toluene (10 mL) at 35 °C. 1-[2-(2,4-Dimethyl-phenyl- sulfanyl)-phenyl]-piperazine HBr was isolated by filtration. The filter cake was washed with toluene (40 mL) and water (10 mL) yielding 1-[2-(2,4-dimethylphenylsulfanyl )-phenyl]-piperazine HBr (7.3 g, 19.2 mmol, 8.8 % from ferrocene) as an off-white powder.

Al 6 ppm, Fe 18 ppm, Na 3 ppm, P 7 ppm (as determined by S) : Area %: Vortioxetine 99.96, 1-[2-(3,5-dimethyl-phenylsulfanyl)- phenyl]-piperazine 0.04, unknown 0 % (as determined by GC) 1H NMR (DMSO-d6): 8.86 (bs, 2H), 7.34 (d, 1H, 7.7 hz), 7.26 (s, 1H), 7.16 (m, 2H), 7.11 (d, 1H, 7.9), 6.97 (dd, 1H, 7.8 and 1.8 hz), 6.41 (dd, 1H, 7.7 and 1.4 hz), 3.27 (bm, 4H), 3.21 (bm, 4 H), 2.33 (s, 3H), 2.25 (s, 3H).

Crystal form: Mixture of α and β-form (as determined by XRPD).

Water content: 0.14% (as determined by Karl Fisher) and <0.2% (as determined by thermo gravimetric is).

Elemental analysis C18H23N2SBr requires C 56.99 H 6.11 N 7.38, found C 56.94, H 6.09, N 7.31. 1616

Claims (12)

Claims 1.

1. A process for the manufacture ofvortioxetine or pharmaceutically acceptable salts thereof, which process comprises reacting a compound of formula I +, X- Hal _| Fe(l|) wherein each Hal independently represents fluoro or chloro; R’ represents H or R’ represents one or two moieties independently selected from CHO, COOH, COOR” ’ or COONR”’2, or R’ represents one to five moieties independently ed from C1- 5-alkyl; R” ’ independently represents H or C1alkyl; and X‘ represents a non- coordinating and non-nucleophilic anion, with a piperazine of a II 10 [| I] n R represents H, and with a nd of formula HI [Ill] wherein R” represents H or a cation and a base as required in a solvent to obtain a 15 compound of formula IV 3 +, XS RN N Fe(II) [IV] followed by a de-complexation step in which the optionally substituted entadienyliron is de-complexed, to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)- ]-piperazine (vortioxetine).

2. The process according to claim 1, n Hal represents .

3. The process according to claim 1 or claim 2 wherein R’ represents hydrogen. 10

4. The process according to any of claims 1-3 wherein X- is selected from PF6−, AlCl4−, ClO4−, BF4−, [B[3,5-(CF3)2C6H3]4]−, B(C6F5)4- and Al(OC(CF3)3)4−.

5. The process according to claim 4, wherein X- is PF6−. 15

6. The process according to any of claims 1-5, wherein said solvent is selected from toluene, THF (tetrahydrofuran), MTBE (methyl tertiary-butyl ether), water, ethanol, 2-propanol, NMP (N-Methylpyrrolidone), DMF hylformamide), MIBK (methylisobutyl ketone), TEA (triethyl amine), DIPEA (N,N- diisopropylethylamine), DCM (dichloromethane), ethylacetate, isopropylacetate and 20 combinations of these.

7. The process according to any of claims 1-6 wherein R’’ represents H. (25416898_1):AXG 1818

8. The process according to any of claims 1-7, wherein said de-complexation step ses photolysis.

9 The s ing to claim 1, wherein 1 equivalent of a compound of formula I is mixed with a compound of a H (1-5 equivalents) and a compound of formula HI (1-5 equivalents) in a solvent together with a base as required (more than 0.5 equivalent) to obtain a compound of formula IV followed by de- complexation to obtain l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine.

10 10. The process according to claim 1, wherein 1 equivalent of a compound of compound of formula I is mixed with a base (between 0.5 and 20 equivalents), piperazine (1-5 equivalents) and 2,4-dimethyl thiophenol (1-5 equivalents) in a solvent to obtain a compound of formula IV, followed by de—complexation to obtain]- [2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine.

11. The process according to claim 1, wherein 1 equivalent of ”64,2- robenzene- I] 5-cyclopentadienyliron(II) hexafluorophosphate is mixed with 1-5 equivalent base, 1—3 equivalents 2,4—dimethylthiophenol and 1-3 equivalents piperazine in a solvent at 10°C-50°C to obtain the nd of the formula +,PF6' s —\ HN N Fe(ll) followed by de-complexation to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]- piperazine.

12. The process according to any of claims 1-11, wherein the obtained 1-[2-(2,4- yl-phenylsulfanyl)-phenyl]-piperazine is reacted with a suitable acid to obtain the equivalent pharmaceutically acceptable salt.