NZ710779A - Vortioxetine manufacturing process - Google Patents

Abstract

A 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

XETINE MANUFACTURING S 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 published that xetine is the recommended International oprietary 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 depression under the trade name BrintellixTM.

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

Additionally, vortioxetine 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 ered to be of al relevance and potentially involved in the mechanism of action of the compound [JMed.Chem., 54, 3206-3221, 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 Alvares 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 imately 100 patients in each arm show that xetine separates significantly from o in the treatment 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 y depressed patients reported in Int.

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

The cturing s used to prepare vortioxetine sed in WC 03/029232 is based on solid-phase synthesis and exploits di-arene iron-assisted nucleophilic ic substitution reactions in a multistep process. In y, 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 on with 2,4—dimethylthiophenol. Finally, the thus obtained resin was treated with 1,10-phenanthroline and light to plex cyclopentadienyliron. The overall yield was low, only 17%. A similar process is disclosed in WO 01/49678 wherein phenoxyphenylpiperazines are prepared as intermediates.

Di-arene iron compounds have been known for long time, exemplified by ferrocene 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, 305, 1996 disclose displacement of chloro atoms from 1,4-dichlorobenzene- cyclopentadienyl-iron (II) by cyclic secondary amines, e.g. piperazine. Interestingly, this reaction s in a symmetric cement, i.e. displacement ofboth chloro atoms from the benzene moiety. Sutherland 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 asymmetric compounds in which the two chloro atoms are substituted by y and morpho line, respectively. Notably, the two substitutions require very different reaction conditions and isolation of the intermediate, mono-substituted compound was required. Ruhland 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 entadienyl activation in solid phase.

Solid-phase chemistry is not feasible 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 cturing of vortioxetine has been disclosed in WC 2007/144005 and . Piperazine, 2,4-dimethylthiophenol and 1,2- genbenzene are mixed e.g. in toluene together with a palladium catalyst to afford vortioxetine. Although this reaction provides high yield and can be handled in large scale, it requires the use of an expensive st, i.e. palladium. Moreover, the on conditions are harsh ing 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 .

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 suitable di-arene iron salt, i.e. optionally substituted l,2—dihalogenbenzene-cyclopentadienyl—iron(II) salt is reacted with an optionally ted 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 process to obtain l-[2-(2,4-dimethylphenylsulfanyl )-phenyl]-piperazine. A desired ceutically acceptable salt may be obtained by subsequent on with a suitable acid.

Accordingly, in one embodiment the invention provides a process for the manufacture of vortioxetine or pharmaceutically acceptable salts thereof, which process comprises reacting a compound of formula I wherein each Hal independently represents fluoro or chloro; R’ represents H or R’ represents one or two moieties independently ed 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 ive 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 nd 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 tection 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 compound of formula I, the compound of formula II and the compound of formula 111 may be added to the reaction mixture in any sequence or simultaneously.

According to the present invention there is provided a s 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 ents fluoro or ; 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 ndently ed 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] wherein R represents H, and with a compound of formula III R''S [III] wherein R’’ represents H or a cation and a base as required in a t 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 (vortioxetine).

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 nd of formula II and (25416898_1):AXG compound of formula III to obtain vortioxetine following de-complexation and deprotection as ed.

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

R’ represents H or R’ represents one or two moieties independently selected from CHO, COOH, ’ 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 . In one embodiment, R’ is hydrogen, i.e. the cyclopentadienyl moiety is unsubstituted. In one embodiment, R’ " represents .

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

Many protective groups are known in the art, and US€fill es include —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 abbreviates carbobenzyloxy. If a mono-protected piperazine is used in the reaction of the present invention, the protective group has to be d in a subsequent step, typically by the addition of an acid, such as an aqueous acid. If ly selected, said acid may remove the protective group and provide a d pharmaceutically acceptable salt of vortioxetine in one and the same step. The use of aqueous HBr may achieve de- protection and the HBr salt of vortioxetine in one step. The on 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 tuted. es e 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 hydrogen 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 include 2- hydroxyethyl-trimethylammonium and 1-butyl—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 compound (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 t context a non-coordinating anion is intended to indicate an anion that essentially does not establish a nating 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 tute 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 advantage that PF5' salts of the compound of formula I are easily isolated and . 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 present invention.

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

The optionally 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 decomplexation 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 solvents, such as pyridine or DMSO. ysis which is also known as issociation or photodecomposition is a chemical reaction where a chemical bond is broken upon irradiation with light. For the reaction of the present ion, de-complexation by ysis 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 ion 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 reacted at 95°C followed by aqueous work-up and treatment with ammonium hexafluorophosphate. Compounds of formula I where X" represents a anion different from hexafluorophosphate may be ed in a similar way by means of a different and appropriate salt, e.g. ammonium BF4. If suitably substituted ferrocene is used, compound of formula I wherein R’ is different from H may be obtained. 2,4-Dimethyl-thiophenol, salts thereof and (optionally protected) piperazine are all well-known compounds and readily available in large quantities.

The compound of formula 111 may for example be obtained from the corresponding arylbromide or arylchloride, i.e. 1-bromo-2,4-dimethyl-benzene or 1- -2,4-dimethyl—benzene in a Grignard-type reaction where said compound is reacted with Mg followed by tal 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 t(s) chosen is sufficiently fluid at the temperature (and pressure) used. In one embodiment, the ature 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 ed to te acid addition salts of acids that are non-toxic. Said salts include salts made from organic acids, such as maleic, furnaric, benzoic, ic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, lic, citric, gluconic, lactic, malic, mandelic, cinnamic, onic, aspartic, c, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, theophylline acetic acids, as well as the 8-halotheophyllines, for example otheophylline. Said salts may also be made from inorganic acids, such as hydrochloric, 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 equivalent 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 compound 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 obtained by r reaction with an appropriate acid. It may also be feasible to de—protect piperazine as required prior to de-complexation.

In one embodiment, 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 equivalents) and piperazine (1—5 lents, such as 1-3 lents) in a solvent.

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

In one embodiment, 1 equivalent of 116—1,2-dichlorobenzene- 71 5-cyclopenta- iron(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 ed is d to obtain the compound of formula IV, e.g. at 10°C-50°C.

Votioxetine is obtained by de-complexation, e.g. by photolysis.

De-complexation by photolysis may be carried out e.g. in batch mode or in flow mode. De-complexation may conveniently be carried out in the following way.

The reaction mixture 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 ated glass tube where photolysis occurs to obtain vortioxetine. As an example, the aqueous phase may be circulated through an ated glass tube.

Alternatively, the compound of formula I may be prepared and used immediately in the s of the present ion without isolation. For example 1212 l,2-dichlorobenzene (2-20 equivalents, 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 compound of formula I. The compound of formula I may then be further reacted as described above to obtain vortioxetine.

The process of the present invention may be run in batch mode, n the reactants are added to a vessel or container. Alternatively, the process of the t 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 on of the present invention may also be carried out partly in batch mode and partly in a flow .

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 provides a non-resin based manufacturing process for vortioxetine and pharmaceutically acceptable salts f in which an tric cement of two identical halogen atoms from a symmetric reactant (l ,2—dihalogenbenzene) is effected in a t synthesis, i.e. without the need for isolation of intermediates, such as intermediates where only one halogen is substituted. The process ofthe present ion avoids the use of expensive reactants and sts; 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 invention is well-suited for industrial scale.

All references, ing publications, 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 specifically indicated to be incorporated by reference and were set forth in its entirety herein, regardless of any tely provided incorporation of particular documents made ere herein.

The use of the terms "a" and "an" and "the" and similar referents in the t 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 particular described aspect, unless otherwise indicated.

The description herein of any aspect or aspect of the invention using terms such as "comprising", "having," ding," or "containing" with reference to an element or elements is intended to provide support for a r 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 contradicted by context (e.g, a composition bed herein as comprising a particular element should be understood as also describing a composition consisting of that t, 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 carbonate (16.7 g, 121 mmol) and piperazine (10.3 g, 120 mmol) was ved 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 extracted once with water (15 mL).

The THF/water phase was ated at room temperature through an irradiated glass spiral (100 W incandescent . During this step water and THF separated and only the lower water phase was pumped through the photolysis ent, 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 d at 40 °C at reduced pressure. The ing solution was added slowly to a e 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 vortioxetine HBr.

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

Elemental is 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), ium 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 minutes.

ON: the treatment of unreacted ium trichloride with water is highly exothermic).

The mixture was treated with Celite 545® (14 g) and stirred at ambient 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 aluminium oxides was removed by filtration, and the filter cake was washed with water (25 mL).

The ted aqueous phases was added to a e 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 de-complexation 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 removed at 40 °C at reduced pressure. The toluene on 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. 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 .

Al 6 ppm, Fe 18 ppm, Na 3 ppm, P 7 ppm (as determined by ICP-AES) Purity: 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 analysis). tal is 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 f, which process comprises reacting a compound of formula I +, X- Hal _| Fe(l|) n 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 es independently selected from C1- 5-alkyl; R” ’ independently represents H or C1alkyl; and X‘ represents a non- coordinating and non-nucleophilic anion, with a piperazine of formula II 10 [| I] wherein R represents H, and with a compound of a 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 cyclopentadienyliron is de-complexed, to obtain 1-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl]-piperazine (vortioxetine).

2. The process according to claim 1, wherein Hal represents chloro.

3. The process according to claim 1 or claim 2 wherein R’ represents en. 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 ing to any of claims 1-5, wherein said solvent is selected from toluene, THF (tetrahydrofuran), MTBE (methyl ry-butyl ether), water, ethanol, 2-propanol, NMP (N-Methylpyrrolidone), DMF (dimethylformamide), MIBK (methylisobutyl ketone), TEA (triethyl , DIPEA (N,N- diisopropylethylamine), DCM (dichloromethane), ethylacetate, isopropylacetate and 20 combinations of these.

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

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

9.The s according to claim 1, wherein 1 equivalent of a compound of formula I is mixed with a nd of formula 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 lent) 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 nd 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- dichlorobenzene- 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 compound 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.