GB2564887A

GB2564887A - New route of synthesis to vortioxetine salts

Info

Publication number: GB2564887A
Application number: GB1712046.0A
Authority: GB
Inventors: Frech Nabold Christian; Aebersold Christine; Grieco Gabriele; Gerber Aeschbacher Roman
Original assignee: Azad Pharmaceutical Ingredients AG
Current assignee: Azad Pharma AG
Priority date: 2017-07-26
Filing date: 2017-07-26
Publication date: 2019-01-30
Also published as: GB201712046D0

Abstract

A process for the preparation of vortioxetine (1-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine) salts comprising the steps of: reacting 1-X-2-nitrobenzene and 2,4-dimethylbenzenethiol in the presence of a base and a solvent to yield 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene and wherein X is a halogen or nitro group; then reacting the 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene with thiosulphate in a solvent to yield (2-((2,4-dimethylphenyl)thio)phenyl)sulfamic acid or a salt thereof: followed by reacting the (2-((2,4-dimethylphenyl)thio)phenyl)sulfamic acid with bis(2-Y-ethyl)amine, wherein Y is selected from the group consisting of halogen, tosyl, triflate or mixtures thereof, in the presence of a solvent to yield 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carbaldehyde; and finally reacting the 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-1-carbaldehyde with hydrogen bromide to yield vortioxetine bromide salt. The intermediate compound (2-((2,4-dimethylphenyl)thio)phenyl)sulfamic acid is also claimed. Pharmaceutical compositions comprising vortioxetine for use in the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD) are also disclosed.

Description

NEW ROUTE OF SYNTHESIS TO VORTIOXETINE SALTS

FIELD OF THE INVENTION

The present invention relates to a new route of synthesis for the preparation of vortioxetine free base and pharmaceutically acceptable vortioxetine salts. In particular, the invention relates to a process for the preparation of vortioxetine hydrobromide, pharmaceutical compositions and oral dosage forms comprising vortioxetine hydrobromide and the use for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).

BACKGROUND

Vortioxetine is a serotonergic compound and chemically known as l-[2-(2,4Dimethylphenylsulfanyl)phenyl]piperazine. The structure of the molecule is displayed in formula (I):

H

Formula (I)

The compound is used in the treatment of major depressive and generalized anxiety disorder. The compound shows antagonistic properties at 5-HT3A and 5-HT7 receptors, partial agonistic properties at 5-HT1B receptors, agonistic properties at 5HT1A receptors and potent serotonin reuptake inhibition via inhibition of the serotonin transporter (SERT).

Several different routes of vortioxetine synthesis are disclosed in the literature.

US 2005 014 740 and US 8,476,279 provides compounds represented by the general formula I,

wherein the substituents are defined in the application. The compounds are useful in the treatment of an affective disorder, including depression, anxiety disorders including general anxiety disorder and panic disorder and obsessive compulsive disorder.

Other routes of synthesis for Vortioxetine are disclosed in WO 2013 102 573 Al. This patent document disclose a process for the manufacture of l-[2-(2,4-dimethylphenylsulfanyl)-phenyl]-piperazine and pharmaceutically acceptable salts that involves reacting compounds of formula II, III, IV under Pd catalysis and in presence of phoshine ligands to give Compound I.

Y

III

R

H

IV

Nevertheless, besides the known routes of vortioxetine synthesis there is still the need for reliable and high yield processes, which are able to overcome the draw-backs of the existing processes and deliver pharmaceutically acceptable products in industrial environments.

BRIEF DESCRIPTION OF THE INVENTION

Above mentioned task is solved by a process for the preparation of vortioxetine (1-[2(2,4-dimethyl-phenylsulfanyl)phenyl] piperazine) salts at least comprising the steps of

a) reacting 1-X-2-nitrobenzene and 2,4-dimethylbenzenethiol in the presence of a base and a solvent to yield 2,4-dimethyl-l-[(2-nitrophenyl)sulfanyl]benzene

wherein X is selected from the group consisting of halogen and -NO2;

b) reacting the 2,4-dimethyl-l-[(2-nitrophenyl)sulfanyl]benzene obtained in step a) and thiosulphate in the presence of a solvent to yield (2-((2,4-dimethylphenyl)thio)phenyl)sulfamic acid or a salt thereof;

c) reacting the (2-((2,4-dimethylphenyl)thio)phenyl)sulfamic acid obtained in step b) and bis(2-Y-ethyl)amine, wherein Y is selected from the group consisting of halogen, tosyl, triflate or mixtures thereof; in the presence of a solvent to yield 4-(2-((2,4dimethylphenyl)thio)phenyl)piperazine -1 -carbaldehyde

O

d) reacting the 4-(2-((2,4-dimethylphenyl)thio)phenyl)pipera-zine-l-carbaldehyde obtained in step c) and hydrogen bromide to yield vortioxetine bromide salt

Surprisingly it has been found that above given synthesis route is able to provide vortioxetine in high yields, high purity and only small amounts of side-products which can easily be separated by standard purification techniques. This can be attributed at least in part to the overall gentle processing conditions compared to other state-of the art processes. Furthermore, the overall reaction scheme is environmentally friendly with respect to the used solvents and metals, reaction times are short and the synthesis is readily up-scalable. It is especially surprising that it is possible to achieve high yields even without using a metal catalyst in the route of synthesis. The process is purely based on organic chemistry and hence less costly and more environmentally friendly compared to state of the art processes.

Synthesis step a) is performed in the presence of a base and a solvent. Suitable bases can be selected from inorganic or organic bases, wherein the organic bases are preferred. The solvent can be any pharmaceutically acceptable solvent, wherein rather polar aprotic solvents are preferred. High yields may especially be obtained in solvents comprising a dipole moment in between 3 and 5 or a dielectric constant in between 30 and 50 or a polarity from 30 to 50 (water=100). The solvent can also comprise a combination of all three parameter.

The solvent in step b) be any pharmaceutically acceptable solvent, wherein a rather polar solvent is preferred. Further preferred is to use an aqueous mixture of a solvent, which was already used in step a). Such mixture can especially tailor the solubility of the educts and increase the yield of the reaction.

In step c) the educt is reacted with a functionalized amine. The amine can generally be a bis-Yfunctionalized amine comprising two leaving groups. Besides for instance tosyl or triflate halogens like Cl, Br or I can be used. Tosyl or triflate modified amine can be synthesized by reaction of diethanolamine with TsCl or TfCl, respectively, to get the bis(2-OTf/OTsethyl)amine. The bis-chloro amine is preferred. In addition it is possible to increase the yield if not only the bi-functionalized amine is used. Preferable the amine is introduced in a salt form in the reaction. This is possible by converting the free amine in an ammonium salt by addition of an acid. Preferable acids may be inorganic acids, for instance hydrochloric acid. Suitable solvents in step c) can for instance be DMF (Ν,Ν-Dimethylformamid) or NMP (N-Methyl-2pyrrolidon) or mixtures thereof. Especially the use of DMF provides high yields at very moderate reaction conditions.

In a first embodiment of the process the base in step a) can be selected from the group consisting of K2CO3, Na2CC>3, KHCO3, NaHCCfi, NaH or mixtures thereof. Especially the inorganic carbonate salts are preferred in the first reaction step. By using this group of inorganic bases the yield is increased, presumably because of the solubility in the selected solvents. Amines (prim.tert.) are less preferred, because it was found that the overall amount of generated side-products is drastically increased and the reaction rates are significantly lower. The same is true for the use of alkaline or earth alkaline hydroxides in step a).

In another aspect of the process the solvent in step a) is selected from the group consisting of acetonitrile, DMSO (Dimethyl sulfoxide), DMF (Dimethylformamide), NMP (N-Methyl-2Pyrrolidonc ) or mixtures thereof. It was found that especially these solvent arc able to sufficiently dissolve the usable bases and hence increase the reaction rates and the overall yield. In addition, the amount of side-products may be decreased. Without being bound by the theory this may be attributed in addition to the better solubility of the de-protonated sulfide, which is able to reduce further side-reactions of the already generated product.

In a further characteristic of the process the reaction in step a) can be performed in DMF and the base is K2CO3. This combination is especially able to result in high yields at very short reaction times. In addition, the amount of generated side-products is very low. This may be attributed to the preferred solubility of the base in the solvent in correlation of the solubility of the generated product in the solvent. Both effects might drive the reaction to the formation of the desired product. Suitable pH-ranges are preferably above pH 8.0.

Within another embodiment of the process the reaction in step a) can be performed in an inert atmosphere. It has been found advantageous to perform the reaction step a) for instance under a nitrogen-atmosphere because this increases the overall yield of the reaction and reduces the formation of side-products. Especially the oxidation of 2,4-dimethylbenzenethiol to the compound l,2-bis(2,4.dimethlyphenyl)disulfane can be prevented by this measure.

In a further aspect of the process the solvent in step b) can be a mixture of water and DMF and the volume ratio of DMF to water (DMF:water) is > 1 and < 5. Very high yields are obtainable in step b) by using this preferred solvent mixture range. Without being bound by the theory the “right” solubility for the educts is achieved by using such mixtures. Higher water contents might result in agglomeration of the organic educts, resulting in overall lower yields. Higher DMFcontent might result in the precipitation of sodium hydrogensulfite or the bisulfite respectively, which in turn might also reduce the reaction rate. Preferred, DMF:water ratios might be > 1,5 and < 2,5 and further >1,7 and < 2,5.

In an additional characteristic of the process the solvent in step c) can be DMF. It has been found suitable to also use DMF as a solvent for the reaction in step c). Especially this solvent is able to increase the reaction rate and results in high yields. This might also be attributed to the solubility characteristics of the solvent with respect to the educts, the base or the product.

In a further embodiment of the process in step c) the reaction can be performed at a pH of > 8.0 and < 14.0. The ring-formation in step c) can be accelerated by the presence of a base and especially in the above defined pH-range. The reaction is nearly quantitative and the amount of side-products negligible.

Within a further preferred embodiment of the process in step d) the molar ratio of HBr to 4-(2((2,4-dimethylphenyl)thio)phenyl)pipera-zine-l-carbaldehyde (HBr:carbaldehyde) is > 2 and <

15. Especially a large excess of HBr is able to drive the equilibrium to the salt formation also by cleavage of the formyl-groups. In a further preferred embodiment the ratio can be > 5 and < 10, and further preferred > 7.5 and < 9. Within these concentration ranges fast reaction rates can be obtained.

It is further within the scope of invention to disclose compound (2-((2,4dimethylphenyl)thio)phenyl)sulfamic acid according to the following structure:

or a salt thereof. The suitable salt forms can be generated by acid/base-reactions known to the skilled artisan. Within this acid/base-reactions the sulfamic acid proton is removed, resulting in the formation of a sulfamic acid anion. Suitable bases may include organic or inorganic cations, wherein alkaline or alkaline earth cations are preferred as counter ions. A preferred salt form is the sodium salt.

It is additionally within the scope of the invention to disclose another Intermediate in the production of vortioxetine at least comprising (2-((2,4-dimethylphenyl)thio)phenyl)sulfamic acid

or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salt forms can be generated by acid/base-reactions known to the skilled artisan. Within this acid/base-reactions the sulfamic acid proton is removed, resulting in the formation of a sulfamic acid anion. Suitable pharmaceutically acceptable bases may include organic or inorganic cations, wherein alkaline or alkaline earth cations are preferred as counter ions. A preferred salt form is the sodium salt.

Also pharmaceutical compositions comprising vortioxetine obtained via the inventive process for use in the treatment of major depressive and/or generalized anxiety disorder arc within the scope of invention. Within the pharmaceutical composition the vortioxetine hydrobromide may be at least one of the APIs (active pharmaceutical ingredient) of the composition. Furthermore, suitable pharmaceutically acceptable excipients can be present in the composition. Examples for suitable excipients include antioxidants, binders, buffering agents, bulking, agents, disintegrants, diluents, fillers, glidants, lubricants, preservatives, surfactants and co-surfactants.

Furthermore, a pharmaceutical compositions within the scope of invention, wherein the pharmaceutical composition is an oral dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 exhibits one possible inventive route of Vortioxetine synthesis. The overall reaction can be split into four different reaction steps, wherein in a first step a functionalized nitrobenzene is reacted with a thiophenol to yield the corresponding nitrophenylsulfanylbenzene. The latter is converted in a second reaction step to sulfamic acid or the quenched acid, which in turn is converted in the third reaction step to the piperazine-carbaldehyde. In the last reaction step the piperazinecarbaldehyde is converted to Vortioxetine hydrobromide.

EXPERIMENTAL EXAMPLES

Step 1.

X=C1, Br, I, N0₂

Under nitrogen, in a 50 mL double-neck round bottomed flask was weighed potassium carbonate (311 mg, 2.2 mmol) and DMF (12 mL) was added, followed by 2,4dimethylbenzenethiol (291 mg, 285 mL, 2.0 mmol). The suspension was heated up to 90°C for 30 minutes and then 1,2-dinitrobenzene (347 mg, 2.0 mmol) was added at once. The dark-yellow suspension so obtained was stirred at 120°C for 4 hour. The solvent was evaporated and the residue was partitioned between a saturated solution of NaCl (60 mL) and AcOEt (70 mL). The organic phase was dried over MgSCfl and the volatiles were removed to afford 595 mg of a yellow solid (MW= 259.32). The yield is quantitative.

'H-NMR (500 MHz, CD₂C1₂): δ 8.42 (d, 1H), 7.49 (d, 1H), 7.46 (dd, 1H), 7.27 (s, 1H), 7.16 (d, 1H), 6.63 (d, 2H), 2.43 (s, 3H), 2.32 (s, 3H).

¹³C-NMR (125 MHz, CD₂C1₂): δ 145.1, 143.1, 141.6, 138.7, 137.0, 136.4, 132.3, 128.49, 128.48, 125.5,21.0, 20.1.

In a 250 mL single neck round bottomed flask, at +4°C to a solution of (2,4dimethylphenyl)(2-nitrophenyl)sulfane (1000 mg, 3.86 mmol) in DMF (60 mL) was added dropwise in 10 minutes by means of a syringe pump a solution of sodium thiosulphate (3073 mg, 15 mmol) in distilled water (30 mL). After approx, lh the yellow solution became a white suspension. The white solid formed was filtered and the solid was washed with EtOH (40 mL). Addition of ethanol precipitated further salt. The volatiles were removed and the white residue was triturated in EtOH (50 mL) and filtered. The solid was washed with further ethanol (40 mL) and the liquids were reunited. The alcohol was evaporated yielding the product as a white solid. Since the compound is hygroscopic and it is not possible to evaporate the crystallization water, the yield will be calculated over two steps (reaction 2 and reaction 3). 1652 mg of the sodium salt as recovered as white powder.

Ή-ΝΜΚ(500 MHz, DMSO-d6): δ 7.85 (s, 1H), 7.43 (d, 1H), 7.14 (td, 1H), 6.93 (d, 1H), 6.67 (s, 1H), 6.62 (d, 1H), 6.60 (s, 1H), 6.54 (dd, 1H), 2.92 (s, 3H), 2.77 (s, 3H) ¹³C-NMR(125 MHz, DMSO-d6): δ 164.95, 140.49, 137.06, 134.28, 131.23, 130.24, 129.73, 129.56, 123.47, 122.23, 118.95,20.17, 19.59.

In a 250 mL single neck round bottomed flask the sodium salt of (2-((2,4dimethylphenyl)thio)phenyl)sulfamic acid (3.86 mmol, number of moles based on the starting material of the previous reaction) and bis(2-chloroethyl)amine hydrochloride (2812 mg, 15.44 mmol) were weighed and DMF (80 mL) was added. The yellow solution was heated to 150°C and the reaction was performed for 15 hours. The solvent was evaporated and the crude was partitioned between AcOEt (80 mL) and water (80 mL). The aqueous phase was extracted with further AcOEt (40 mL), the organic phases reunited and washed with saturated NaCl-solution (50 mL). The organic phase was dried on dry MgSO₄ and the volatiles were removed to afford 1160 mg of a brown semi solid. The yield was 92% (calculated over steps 2. and 3.).

'H-NMR (500 MHz, CDCh): δ 8.13 (s, 1H), 7.36 (d, 1H), 7.17 (s, 1H), 7.09 (td, 1H),

7.03 (m, 2H), 6.91 (td, 1H), 6.54 (d, 1H), 3.75 (t, 2H), 3.57 (t, 2H), 3.07 (dt, 4H), 2.37 (s, 3H), 2.33 (s, 3H).

¹³C-NMR (125 MHz, CDCh): δ 161.08, 148.38, 142.27, 139.37, 136.06, 134.69,

131.76, 127.87, 127.55, 126.40, 125.61, 125.00, 120.07, 52.38, 51.12, 46.26, 40.57, 21.20, 20.59.

Step 4.

/=0

In a 250 mL one neck round bottomed flask, at room temperature and in an open vessel to a solution of 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-l-carbaldehyde (1000 mg, 3.06 mmol) in ethanol (60 mL) and a 48% solution of HBr (8.84 M) in water (2.8 mL) was added. The mixture was stirred overnight at room temperature. The volatiles were removed and the brown solid was dried overnight at 70°C in high vacuum. The solid was dissolved in refluxing EtOH and then the heating source was removed and the yellow mixture was cooled down to room temperature. Overnight a solid precipitated which was filtered and washed firstly with cold EtOH (10 mL) and secondly with diethyl ether (10 mL) to afford 744 mg product as a white powder. The filtrate was placed at +4°C over the week-end to yield further 227 mg product (1 -(2((2,4-dimethylphenyl)thio)phenyl)piperazine hydrobromide). The combined precipitates resulted in a yield of 84%.

Ή-NMR (500 MHz, DMSO-d6): δ 8.74 (br s, 2 H). 7.34 (d, 1 H), 7.24 (s, 1 H), 7.187.13 (m, 2 H), 7.12 (dd, 1 H), 6.97 (td, 1 H), 6.42 (dd, 1H), 3.34-3.18 (m, 8 H), 2.33 (s, 3 H), 2.25 (s, 3 H).

¹³C-NMR(125 MHz, DMSO-d6): δ 148.32, 142.12, 139.78, 136.20, 133.83, 132.24, 128.56, 127.29, 126.49, 126.24, 125.56, 120.76, 48.84, 44.10, 21.20, 20.56.

Claims

What is claimed:

1) Process for the preparation of vortioxetine (l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl] piperazine) salts at least comprising the steps of

a) reacting 1-X-2-nitrobenzene and 2,4-dimethylbenzenethiol in the presence of a base and a solvent to yield 2,4-dimethyl-l-[(2-nitrophenyl)sulfanyl]benzene wherein X is selected from the group consisting of halogen and -NO2;

O

d) reacting the 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-l-carbaldehyde obtained in step c) and hydrogen bromide to yield vortioxetine bromide salt

2) Process according to claim 1, wherein the base in step a) is selected from the group consisting of K2CO3, Na2CC>3, KHCO3, NaHCCh, NaHor mixtures thereof.

3) Process according to any of claims 1 to 2, wherein the solvent in step a) is selected from the group consisting of acetonitrile, DMSO, DMF, NMP or mixtures thereof.

4) Process according to any of claims 1 to 3, wherein the reaction in step a) is performed in DMF and the base is K2CO3.

5) Process according to any of claims 1 to 4, wherein the reaction in step a) is performed in an inert atmosphere.

6) Process according to any of claims 1 to 5, wherein the solvent in step b) is a mixture of water and DMF and the volume ratio of DMF to water (DMF:water) is > 1 and < 5.

7) Process according to any of claims 1 to 6, wherein the solvent in step c) is DMF.

8) Process according to any of claims 1 to 7, wherein in step c) the reaction is performed at a pH of > 8.0 and < 14.0.

9) Process according to any of claims 1 to 8, wherein in step d) the molar ratio of HBr to 4-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine-l-carbaldehyde (HBr:carbaldehyde) is > 2 and <15.

10) Compound (2-((2,4-dimethylphenyl)thio)phenyl)sulfamic acid according to the following structure:

11) Intermediate in the production of vortioxetine at least comprising (2-((2,4dimethylphenyl)thio)phenyl) sulfamic acid or a pharmaceutically acceptable salt thereof.

12) Pharmaceutical composition comprising vortioxetine obtained via a process according to any of the claims 1-9 for use in the treatment of major depressive and/or generalized anxiety disorder

13) Pharmaceutical composition according to claim 12, wherein the pharmaceutical composition is an oral dosage form.