GB2557867A - New synthetic path to vortioxetine salts - Google Patents
New synthetic path to vortioxetine salts Download PDFInfo
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- GB2557867A GB2557867A GB1520332.6A GB201520332A GB2557867A GB 2557867 A GB2557867 A GB 2557867A GB 201520332 A GB201520332 A GB 201520332A GB 2557867 A GB2557867 A GB 2557867A
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- YZTJYBJCZXZGCT-UHFFFAOYSA-N C(C1)NCCN1c1ccccc1 Chemical compound C(C1)NCCN1c1ccccc1 YZTJYBJCZXZGCT-UHFFFAOYSA-N 0.000 description 1
- HMPYPMLGOAMQIC-UHFFFAOYSA-N CN(CC1)CC[N+]11[O-]Nc2c1cccc2 Chemical compound CN(CC1)CC[N+]11[O-]Nc2c1cccc2 HMPYPMLGOAMQIC-UHFFFAOYSA-N 0.000 description 1
- DCHBGNCHTBJGRH-UHFFFAOYSA-N Cc(cc1C)ccc1Sc(cccc1)c1[N+]1(CCN(C)CC1)O Chemical compound Cc(cc1C)ccc1Sc(cccc1)c1[N+]1(CCN(C)CC1)O DCHBGNCHTBJGRH-UHFFFAOYSA-N 0.000 description 1
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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Abstract
The preparation of vortioxetine free base 4 and pharmaceutically acceptable vortioxetine salts, is achieved by one of: oxidation of a 1-{2-[(2,4-dimethylphenyl)sulfanyl]cyclohexyl}piperazine derivative of formula 21 (where the cyclohexyl moiety is mono- or di-unsaturated); activation of 1-phenylpiperazine by oxidisation to give compound (10) and reacting (10) with 2,4-dimethylbenzensulfenyl chloride, before reduction to vortioxetine 4; or reaction of (2-(piperazin-1-yl)aniline) 2 with tert-butyl nitrite and tetrafluoroboric acid to give (2-piperazin-1-yl)benzenediazonium tetrafluoroborate salt 3 and then reacting compound 3 in the presence of alkali 2,4-dimethylbenzenethiolate and a metal catalyst to give vortioxetine 4. A process for the preparation of a particular polymorphic form of vortioxetine hydrobromide with an X-ray powder diffraction pattern with peaks at 2 theta (±0.2º 2-theta): 7.9, 14.8, 17.8 and 26.8 is also disclosed comprising cooling crystallisation using chloroform (CHCl3) as a solvent over various cooling cycles. The invention also relates to pharmaceutical compositions comprising the polymorph of vortioxetine hydrobromide for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).
Description
(54) Title of the Invention: New synthetic path to vortioxetine salts
Abstract Title: Preparation of vortioxetine and a polymorph of vortioxetine hydrobromide (57) The preparation of vortioxetine free base 4 and pharmaceutically acceptable vortioxetine salts, is achieved by one of: oxidation of a 1-{2-[(2,4-dimethylphenyl)sulfanyl]cyclohexyl}piperazine derivative of formula 21 (where the cyclohexyl moiety is mono- or di-unsaturated); activation of 1-phenylpiperazine by oxidisation to give compound (10) and reacting (10) with 2,4-dimethylbenzensulfenyl chloride, before reduction to vortioxetine 4; or reaction of (2(piperazin-1 -yl)aniline) 2 with tert-butyl nitrite and tetrafluoroboric acid to give (2-piperazin-1-yl)benzenediazonium tetrafluoroborate salt 3 and then reacting compound 3 in the presence of alkali 2,4-dimethylbenzenethiolate and a metal catalyst to give vortioxetine 4. A process for the preparation of a particular polymorphic form of vortioxetine hydrobromide with an X-ray powder diffraction pattern with peaks at 2 theta (±0.2° 2-theta): 7.9, 14.8, 17.8 and 26.8 is also disclosed comprising cooling crystallisation using chloroform (CHCI3) as a solvent over various cooling cycles. The invention also relates to pharmaceutical compositions comprising the polymorph of vortioxetine hydrobromide for the treatment of major depressive disorder (MDD) and generalized anxiety disorder (GAD).
Figure 1 .
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Figure 3
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NEW SYNTHETIC PATH TO VORTIOXETINE SALTS
FIELD OF THE INVENTION
The present invention relates to new synthetic paths 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 in a new polymorphic form. In addition, the invention relates to pharmaceutical compositions and oral dosage forms comprising the new polymorphic vortioxetine hydrobromide polymorph for 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):
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 solid forms of vortioxetine are disclosed in the literature which are capable of being used in pharmaceutical applications.
WO 2014/177491 Al for instance disclose the use of vortioxetine hydrobromide in amorphous form and in association with an adsorbent.
Furthermore, WO 2015/044963 Al describes a stable amorphous vortioxetine hydrobromide that does not convert to any other solid form and contains less than 0.5% (wt/wt) total impurities when stored at a temperature of up to about 40°C and at a relative humidity of about 25% to about 75% for about three months or more. A process for achieving such amorphous form is also described and comprises: (a) providing a solution of vortioxetine hydrobromide in one or more of solvents; and (b) obtaining the amorphous vortioxetine hydrobromide by the removal of the solvent.
Besides the amorphous forms also different crystalline vortioxetine polymorphs are described in patent applications. WO 2015/000833 Al for instance relates to vortioxetine acetate in crystalline form and to methods for the preparation thereof. In addition, this document discloses a solid pharmaceutical composition for oral administration comprising an effective amount of crystalline vortioxetine acetate and the use of the compound for the preparation of pharmaceutical compositions.
In addition to the crystalline acetate salts also a crystalline hydrobromide acid (HBr) salt is known. WO 2014/044721 Al reveals a crystalline compound comprising a hydrobromide acid (HBr) salt of vortioxetine having an XRPD pattern with characteristic peaks (expressed in 20 ± 0,2° 20 (CuKa radiation)) at 5.5°, 14.8°, 16.7° and 20.0°.
Nevertheless, besides the known solid vortioxetine forms and the processes for their production there is still the need for reliable and easy routes of vortioxetine synthesis and the need for further vortioxetine polymorphs comprising an excellent storage stability, low hygroscopicity, pressure stability and fast dissolution kinetics.
BRIEF DESCRIPTION OF THE INVENTION
Above mentioned problem is solved by a process for the preparation of vortioxetine (l-[2-(2,4-dimethyl-phenylsulfanyl)phenyl]piperazine) salts at least comprising the step of forming a salt by addition of a pharmaceutically acceptable acid to the free piperazine base (4),
Η
wherein the free base (4) is prepared via one of the routes a) - c); wherein the routes comprise:
a) Oxidation according to reaction scheme (I) of compound (21), a l-{2-[(2,4dimethylphenyl)sulfanyl]cyclohexyl}piperazine-derivative, wherein the cyclohexylmoiety is mono- or di-unsaturated (dashed-lines) to yield compound (4)
H
b) Reacting according to reaction scheme (II) compound (2) (2-(piperazin-lyl)aniline) in a pharmaceutically acceptable solvent in the presence of tetrafluoroboric acid to yield compound (3) (2-(piperazin-l-yl)benzenediazonium tetrafluoroborate salt), and, in a second step, reacting compound (3) in the presence of alkali 2,4-dimethylbenzenethiolate and a metal catalyst to yield compound (4)
c) Reacting according to reaction scheme (III) 1 -phenylpiperazine in the presence of an oxidizing agent to yield activated compound (10) and further reacting activated compound (10) in a pharmaceutically acceptable solvent in the presence of 2,44 dimethylbenzenesulfenyl chloride to give compound (11), which is further reacted with an reducing agent to yield compound (4)
Surprisingly it has been found that above given routes of synthesis are able to result in compound (4) in high yields, high purity and a small amount of side-products which can easily be separated from compound (4) 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 route of synthesis is easily up-scalable.
Vortioxetine salts in the connotation of the present invention are all pharmaceutically acceptable vortioxetine salts, wherein especially the anionic component can be selected from pharmaceutically acceptable anions. Suitable anions are for instance mentioned in the “Handbook of Pharmaceutical Salts Properties, Selection, and Use” (Wiley, P. Heinrich Stahl (Editor) and Camille G. Wermuth (Editor), May 2008) and may preferably be selected from halides and substituted or unsubstituted acetates. Consequently, for the formation of the vortioxetine salts pharmaceutically acceptable acids can be used in the synthesis. Suitable acids can be selected from pharmaceutically acceptable acids known to the skilled artisan. Preferably the acids are able to result in the above mentioned pharmaceutically acceptable anions by proton exchange.
In reaction scheme (I) an oxidation of the mono- or di-unsaturated cyclohexylmoiety of the piperazine compound (21) is achieved. The cyclohexyl-moiety may comprise one or two double-bonds within the ring structure and the double-bonds can be located at every position in the 6-membered ring. It is also possible to use isomeric mixtures of mono- or isomeric mixtures of mono- and di-unsaturated compounds. In the course of the oxidation an aromatic 6-membered ring structure is formed. The oxidation can be performed by methods known to the skilled artisan, wherein especially Iodine-, Pd- and/or a combination of metal and Lewis-base5 catalysis in an 02 atmosphere has been found to result in high yields and a low amount of unwanted side-products. These oxidation catalysts seem to alter highly selective the double bonds within the cyclohexyl-moiety leaving the other structures of compound (21) unchanged. The oxidation reaction can be performed in a solvent, wherein water-free, dry solvents are preferred. Suitable solvents are for instance DMSO or toluene.
In reaction scheme (II) one of the reaction partners is an alkali 2,4dimethylbenzenethiolate. Suitable alkali salts of the thiolate may be selected from the group comprising Li, Na, K or mixtures thereof. This reaction may be performed in a pharmaceutically acceptable solvent, wherein protic solvents being preferred. A range of suitable pharmaceutically acceptable solvents is given below. Furthermore, a metal catalyst is used in route b) in order to convert compound (3) to compound (4). Suitable metal catalysts can be selected from the group comprising or consisting of complexed or non-complexed zinc, copper, magnesium, aluminum, iron, nickel, manganese, calcium cobalt catalysts or mixtures thereof. Pure zinc catalysts in powder form are preferred, resulting in high yields and the selective formation of the desired compound (4).
Reaction scheme (III) utilizes an oxidation agent to yield activated compound (10). For this reaction any pharmaceutically acceptable oxidation reagent can be used. Especially preferred oxidation agent can be selected from the group consisting of hydrogen peroxide, NaIO4, KIO4, NR4IO4, Ba(IO4)2, Na3H2IO6, orthoiodates (IO(,5), metaperiodates, ozone or mixtures thereof, wherein hydrogen peroxide is preferred. The activated compound (10) is further reacted in a pharmaceutically acceptable solvent to obtain compound (11). Suitable solvents may be selected from the group consisting of acetonitrile, THF, dioxane, pyridine and derivatives thereof, wherein acetonitrile is preferred. In the last step of the reaction route the compound (11) is converted by the use of a reducing agent to yield compound (4). Suitable reducing agents can be selected from the group consisting of magnesium, zinc, copper, aluminium, iron, nickel, manganese, calcium, cobalt, silanes, tin, LiAlH4, LiBH4, boranes or mixtures thereof, wherein a mixture of zinc and magnesium (50:50 molar bases) has been found to give the highest reaction rates and the best selectivity.
In a preferred embodiment the vortiotexine salt can be a hydrobromide or a hydroacetate salt according to compound (5)
Η
Especially bromic and acetic acid can be used to convert compound (4) into compound (5) or the salt, respectively. The salt-form of compound (5) is readily formed by proton transfer from the acid and this form may be isolated from aqueous or alcoholic solution via precipitation.
In another aspect compound (21) can be selected from the group consisting of the compounds (7), (9), (13), (17), (18), (20), (30), (31), (32), (33), (35) and (36):
Especially these cyclohexene/-hexadiene isomeric forms of the piperazinecompound have been found to be readily oxidizable to the desired compound (4) in mild conditions. Therefore, by using these educts within the oxidation reaction it is possible to achieve high yields, good reaction rates and a very low amount of unwanted side-products, rendering this reaction especially suitable for large scale processing.
In a further preferred embodiment in route b) compound (2) is obtainable or obtained via bl) reaction scheme (IV) by reacting l-X-2-nitrobenzene, wherein X is a leaving group, and piperazine to yield compound (1) (l-(2-nitrophenyl)piperazine) and, in a second step, hydrogenation of compound (1) in the presence of a metal catalyst to yield compound (2) (2-(piperazin-l-yl)aniline)
H
H
(IV).
Within this reaction scheme an ortho-substituted nitrobenzene is used, wherein the ortho-substituent X is a leaving group. Suitable leaving groups for this substitution may be selected from -F, -Cl, -Br, -I, -OH, -NH2, mesylate, triflate, tosylate, diazonium salts, alkyl- or aryl sulfonates, phosphates, phosphonic acids, or phosphonic esters and other inorganic esters, the halides being preferred. The metal catalysts used for transforming compound (1) to compound (2) can be either homogeneous or heterogeneous hydrogenation catalysts, wherein heterogeneous catalysts are preferred. Suitable examples are for instance catalysts comprising Pt, Pd, Rh, Ru, Ni, Co, Fe Cu, Cr or Zn. Preferred catalysts comprise platinum, palladium, rhodium, ruthenium or mixtures thereof. The metal catalyst may be mounted on a support, preferably a support such as activated carbon, calcium carbonate, barium sulfate, barium carbonate, silicon dioxide, alumina or may for example be present as a colloid in solution. The hydrogen can be added just at the beginning of the reaction, added repeatedly, generated in situ or being feed continuously into the reactor, wherein a sequential feeding of the hydrogen is preferred. The hydrogen pressure, hydrogenation time and the temperature of conversion is a function of the catalyst and the adaption of these reaction conditions is known to the skilled artisan.
Alternatively, compound (2) may be obtained by a reaction scheme (V) (synthesis route b2)) by reacting benzene- 1,2-diamine and bis-(2-chloroethyl)amine to yield compound (2) (2-(piperazin-l-yl)aniline)
H
This reaction can be induced by a thermal treatment at elevated temperatures in the presence of bis-(2-chloroethyl)amine or bis-(2-bromoethyl)amine. A suitable temperature to achieve a sufficient yield is in the range of > 120°C, preferably > 135°C and even > 145°C for reaction times of at least 10 h, preferred 15 h and even more preferred >20 h. A suitable solvent for this reaction can be selected from the group comprising diethylene glycol methyl ether, DMF, DMSO, NMP, sulfolane, ethylene glycol and ethylene glycol ethers or mixtures thereof.
Within another characteristic of the process route bl) (reaction scheme (IV)) can be performed in a one-step synthesis. It is especially preferred to perform this reaction in a one-step synthesis without any separation or purification of the intermediate compound (1). Within this one-step procedure high yields are obtainable. Such reaction reduces the risk of product losses in purification procedures.
In another aspect of the invention the compound (7) can be prepared via:
reaction scheme (Via) at least comprising reacting ortho-functionalized cyclohexanone, wherein the ortho-group X is a leaving group, and alkali 2,4dimethylbenzenethiolate to yield compound (6) (2-(phenylthio)cyclohexanone) and further reacting compound (6) and piperazine to yield compound (7) (l-{6-[(2,4dimethylphenyl)-isulfanyl]-icyclohex-1 -en-1 -yl} piperazine)
H
or reaction scheme (VIb) at least comprising reacting cyclohexanone and N-(2,4dimethyl-ibenzenesulfenyl)caprolactam in the presence of a base to yield compound (6) and further reacting compound (6) and piperazine to yield compound (7) (l-{6[(2,4-dimethylphenyl)sulfanyl]cyclohex-1 -en-1 -yl} piperazine)
In principle it is possible to synthesize compound (7) using two different reaction schemes. Within reaction scheme (Via) an ortho-functionalized cyclohexanone is used, wherein the ortho-group X is a leaving group. Suitable leaving groups in the ortho-position may be selected from -F, -Cl, -Br, -I, -OH, -NH2, mesylate, triflate, tosylate, diazonium salts, alkyl- or aryl sulfonates, phosphates, phosphonic acids, or phosphonic esters and other inorganic esters, the halides being preferred. In addition, within reaction scheme (Via) an alkali 2,4-dimethylbenzenethiolate is used. Suitable thiolate salts may include cations selected from the group comprising Li, Na, K, Ca, Mg or mixtures thereof. In reaction scheme (VIb) the reaction of the cyclohexanone and N-(2,4-dimethylbenzenesulfenyl)caprolactam (or any other S+ source like 2,4dimethylbenzenesulfenyl halogenide, 2-[(2,4-dimethylphenyl)sulfanyl]-lHisoindole-l,3(2H)-dione or any sulfenamide) can preferably be performed in an organic solvent. Suitable solvents may for instance be DMSO, DMF, sulfolane, methylene chloride or others. In addition it has been proven useful to perform this reaction in presence of a base like t-BuOK.
In another embodiment of the invention compound (9) can be prepared via reaction scheme (VII) by reacting a (cyclohexa-1,5-dien-l-yloxyXR’frsilane, wherein R1 is selected from the group consisting of C1-C8 alkyl or aryl, and 2,4dimethylbenzenesulfenyl halogenide solution to yield compound (8) (6-[(2,4dimethylphenyl)sulfanyl]cyclohex-2-en-l-one) and further reacting compound (8) and piperazine to yield compound (9) (l-{2-[(2,4dimethylphenyl)sulfanyl]cyclohexa-l,5-dien-l-yl}piperazine)
Within this reaction the selectivity and reaction rate can inter alia be tailored by the choice of R1. Especially the small alkyl or aryl substituents have been proven useful to achieve a fast and selective reaction to compound (8). Within this group of substituents the C1-C6 alkyl or aryl, and further preferred the C1-C3 alkyl can be used to achieve high yields. Furthermore, within this reaction scheme 2,4dimethylbenzenesulfenyl halogenide (or any other S+ source like N-(2,4dimethyl-ibenzenesulfenyl)caprolactam, 2-[(2,4-dimethylphenyl)sulfanyl]-lHiso-indole-l,3(2H)-dione or any sulfenamide) solutions may be used. Suitable halides may be selected from F, Cl, I or Br.
In another aspect of the invention the compound (13) can be prepared via reaction scheme (IIX) by reacting cyclohexanone and a substituted or unsubstituted piperazine to yield compound (12) (1-(cyclohex-l-en-l-yl)piperazine) and further reacting compound (12) and l-(chlorosulfanyl)-2,4-dimethylbenzene or bis(2,4dimethylphenyl) disulfide to yield compound (13) (l-{2-[(2,4dimethylphenyl)sulfanyl] -cyclohex-1 -en-1 -yi {piperazine)
(IIX)·
Within the reaction scheme (IIX) a substituted or unsubstituted piperazine is used to yield compound (12). Possible piperazine substitutions can be protecting groups like Boc, Bz or Cbz which can be removed afterwards metal or acid catalyzed, wherein unsubstituted piperazine being preferred.
Within a further characteristic compound (17) can be prepared via reaction scheme (IX) by reacting compound (14) (cyclohex-2-en-l-one ) and an oxidizing agent in the presence of a base to yield compound (15) (7-oxabicyclo[4.1.0]heptan-2-one), further reacting compound (15) and 2,4-dimethylbenzenethiol in the presence of a base to yield compound (16) (l-{6-[(2,4-dimethylphenyl)sulfanyl]cyclohex-2-en-lyl}piperazine) and further reacting compound (16) and piperazine in the presence of an acid to yield compound (17) (l-{6-[(2,4-dimethylphenyl)sulfanyl]cyclohexa-l,5dien-1 -yl} piperazine)
H
Within this reaction compound (15) may be synthesized from the starting compound (14) by using standard oxidizing reagents like for instance hydrogen peroxide. Suitable bases in this reaction may be organic or inorganic bases, wherein especially inorganic bases like the bases derived from alkaline or alkaline earth metals, for instance sodium hydroxide, are preferred. Suitable acids for the transformation of compound (16) to compound (17) may be selected form the group comprising organic acids like methansulfonic acid, toluenesulfonic acid and trifluoroacetic acid. This reaction may be further accelerated by the presence of a catalyst like TiCl4 or similar catalysts.
In another general aspect the compound (18) or (34) can be prepared via reaction scheme (X) by reacting 1-phenylpiperazine and a reducing agent in a pharmaceutically acceptable solvent to yield compound (18) (l-{2-[(2,4dimethylphenyl)sulfanyl]cyclohexa-l,4-dien-l-yl}piperazine) or compound (34) (1{2-[(2,4-dimethylphenyl)sulfanyl]cyclohexa-l ,3-dien-1 -yl} piperazine) (X).
Η
Ν.
Η
Ν
Η
Ν
Suitable reducing agents for this reaction may be alkaline or alkaline earth metals, wherein the alkaline metals are preferred. In a special embodiment of the invention the reducing agent can be selected from the groups consisting of Na, Li, K, Mg, Zn, Mg, Ca. These reducing agent have been found to result in high yields and fast reaction times. The pharmaceutically acceptable solvent can be any pharmaceutically acceptable solvent as defined above. Preferably THF or dioxane or any poly ether (glycols) can be used within this reaction. In principle it is also possible to perform this reaction under neat conditions. A suitable temperature range for this neat reaction type may be in between 100 °C and 150°C, preferably between 120 °C and 140°C and process times in between 15 and 24 h.
A preferred embodiment of the inventive process includes that in reaction scheme (Via) the ortho-functionalized cyclohexanone can be selected from the group consisting of 2-bromocyclohexanone, 2-chlorocyclohexanone or 2iodocyclohexanone. It is also possible to achieve the formation of compound (6) by using chloro- or iodo-functionalized cyclohexanone. These reactions yield high yields and nearly no unwanted by-products. The chloro- or iodo-cyclohexanone can easily be prepared by addition of NCS (N-chlorosuccinimide), NBS (Nbromosuccinimide) or NIS (N-iodosuccinimide) to cyclohexanone, respectively.
Another aspect of the inventive process involves that in reaction scheme (Via) the compound (6) can be prepared by reacting 2-bromocyclohexanone, 2chlorocyclohexanone, or 2-iodocyclohexanone and 2,4-dimethylbenzenethiol in a pharmaceutically acceptable solvent in the presence of a base. The pharmaceutically acceptable solvent can be any pharmaceutically acceptable solvent, wherein aprotic solvents selected from the group consisting of dichloromethane, tetrahydrofuran (THF), ethyl acetate, acetonitrile, dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetone, hexamethylphosphoric triamde (HMPT), dioxane or mixtures thereof are preferred. For the base any pharmaceutically acceptable base can be selected. Surprisingly it has been found that bases comprising no or only low nucleophilic properties are very suitable. A preferred base can be selected from the group of inorganic bases like carbonates, phosphates, hydrogencarbonates, Ca(OH)2,
LiH, NaH, phosphazenes, nitrides or organic bases like for instance amines (triethylamine, Hiinig’s base, LDA, DBU, alcoholates (e.g. t-BuOK), bis(trimethylsilyl)lithiumamid (LHMDS) or NaHMDS and KHMDS, 2,6-di-tertbutylpyridine, LiTMP, amides (NaNH2, KNH2), amidines, guanidines, DABCO, tBuLi, l,8-bis(dimethylamino)naphthalene or mixtures thereof. These bases are able to increase the reaction rate without interfering in the formation of by-products.
In a further embodiment of the inventive process the base can be selected from the group consisting of carbonates, phosphates, hydroxides, hydrides, phosphazenes, nitrides, amines, alcoholates, amides, substituted or unsubstituted pyridines, amidines, guanidines, napthalenes or mixtures thereof. Due to their suitable nucleophilic properties these bases result in the formation of highly pure products in high yields and excellent reaction rates.
Another way of synthesis of compound (6) may include its formation via reaction of 2-hydroxycyclohexanone with p-tosyl chloride (to give 2-oxocyclohexyl 4methylbenzenesulfonate) and subsequent reaction with thiophenol (with or without the presence of a base) according to the following reaction
Within another characteristic of the inventive process in reaction scheme (VIb) the compound (6) can be prepared by reacting equimolar amounts of N-(2,4dimethyl-ibenzenesulfenyl)caprolactam, cyclohexanone and a base. Suitable bases for this reaction path are given above.
In a preferred embodiment of reaction scheme (VIb) the base can be tert-BuOK (potassium tert-butanolate). The tert-BuOK seems particularly suitable to accelerate the reaction yielding compound (6) and reduce the amount of unwanted by-products. Without being bound by the theory this might be caused by the right nucleophilic profile and the steric properties of this base. Highly pure compound (6) is obtainable at high reaction rates via this reaction path.
In another aspect in reaction scheme (Via) the ortho-functionalized cyclohexanone can be a 2-bromocyclohexanone. Particularly the 2-bromo functionalized compound results in a high reaction rate constant at high yields. Therefore, the concentration of by-products is minimized. Preferably the ortho-functionalized cyclohexanone can be prepared by addition of NBS (N-bromosuccinimide) and p-TsOH (p-toluenesulfonic acid) to cyclohexanone. The p-TsOH may be either used in stoichiometric or catalytic amounts.
It is further within the scope of the invention to disclose an intermediate product in the production of a pharmaceutically acceptable vortioxetine salt, comprising compound (7)
H
It is additionally within the scope of the invention to disclose another intermediate product in the production of a pharmaceutically acceptable vortioxetine salt comprising compound (11)
The anion required for obtaining an electrical neutral salt comprising the intermediate cation compound (11) may be any pharmaceutically acceptable anion, for instance a chloride.
Furthermore, also compound (16) (2-[(2,4-dimethylphenyl)sulfanyl]cyclohex-2-en1-one) can be an intermediate product in the production of a pharmaceutically acceptable vortioxetine salt
O
Another intermediate product in the production of vortioxetine hydrobromide can be compound (17) (1 - {6- [(2,4-dimethylphenyl)sulfanyl]cyclohexa-1,5-dien-1 yl} piperazine)
H
Furthermore it is within the scope of the invention to disclose a new vortioxetine hydrobromide polymorph, wherein the X-ray powder diffraction pattern of the polymorph at least comprises the following characteristic peaks at 2 theta (± 0.2° 2theta): 7.9 and 14.8. It is found that this vortioxetine hydrobromide polymorph is freely soluble in water and exhibits an attractive combination of fast solubility and low hygroscopicity compared to the known solid state forms of vortioxetine. Such processing profile renders this vortioxetine hydrobromide polymorph particularly suitable for the preparation of solid pharmaceutical compositions for oral administration.
In another aspect of the invention the X-ray powder diffraction pattern of the inventive polymorph may at least comprise the following characteristic peaks at 2 theta (± 0.2° 2-theta): 7.9 and 14.8, 17.8, 26.8. In addition to the definition of this new vortioxetine hydrobromide polymorph by using 2 characteristic peak positions it is also possible to further define the same polymorph by using 4 characteristic peak position. The polymorphic form exhibiting such diffraction pattern reveals good processing characteristic such as a good compactability, high solubility in aqueous solvents, fast dissolution rate and low hygroscopicity. Therefore, this vortioxetine hydrobromide polymorph is very suitable for pharmaceutical processing.
Within a preferred characteristic of the process for the production of the vortioxetine hydrobromide polymorph the process may comprise the crystallization of the polymorph at least temporarily at a temperature of > 0°C and <10 °C. In contrast to the known polymorphs this new vortioxetine hydrobromide polymorph seem to form only at low temperatures. Without being bound by the theory this polymorph might comprise the highest thermodynamic stability due to the fact that it is formed under equilibrium conditions with low a rate constant, favoring the formation of the thermodynamic most stable polymorph. This behavior can also be attributed to the small diffusion constants of the molecules in solution at low temperatures. The temperature in the cooling step can also be in the range of > 0°C and < 8°C, preferably in between > 0°C and < 6°C.
In another aspect of the process for the production of the vortioxetine hydrobromide polymorph the crystalline product is obtained by cooling crystallization, wherein at least two cooling crystallization cycles are performed and in between the cooling cycles the vortioxetine hydrobromide is heated up to a temperature of > 25 °C and < 80°C. Surprisingly it has been found that repetition of the cooling crystallization step including an in between heating step is able to provide crystalline material comprising a higher thermal stability and even lower hygroscopicity compared to crystalline material achieved by a 1-cycle process only. Without being bound by the theory this might be attributed to a thermodynamically more stable product, which is achievable by repeated crystallization. Higher temperatures at the in between heating step are less favorable, because higher temperatures might destroy all seed crystals of the new polymorph obtained during the cooling crystallization. Lower temperatures in the in between heating step might be not sufficient to dissolve at least in part the obtained vortioxetine hydrobromide polymorph. The temperature in the heating step can also be in the range of > 25°C and < 70°C, preferably in between > 25 °C and < 60°C.
It is further within the scope of the invention to disclose the use of the inventive vortioxetine hydrobromide polymorph for manufacturing of a pharmaceutical composition. These pharmaceutical compositions comprise at least the inventive vortioxetine hydrobromide polymorph as an API (Active Pharmaceutical Ingredient) and optionally further pharmaceutical acceptable excipients. The inventively achievable vortioxetine hydrobromide polymorph is especially suitable for use in a pharmaceutical composition because the vortioxetine hydrobromide polymorph can be processed in a more reproducible way compared to other vortioxetine hydrobromide forms. Hence, pharmaceutical composition are accessible comprising an improved shelf life and more homogeneous characteristics.
In another aspect the pharmaceutical composition comprising the vortioxetine hydrobromide polymorph can be used in the treatment of major depressive and/or generalized anxiety disorder. Within the pharmaceutical composition the vortioxetine hydrobromide polymorph 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.
Within a further aspect of the invention the pharmaceutical composition can be an oral dosage form comprising the vortioxetine hydrobromide polymorph. Especially the inventive vortioxetine hydrobromide polymorph is suitable for being processed into oral dosage forms. This suitability may be addressed caused by the pressure insensitivity, chemical stability and compressibility of this special polymorph. Therefore, the inventive polymorph is easily processable even in harsh tableting steps and comprises a very good storage stability.
In a preferred characteristic the oral dosage form can be a tablet. Based on the physical and chemical characteristics of the new vortioxetine hydrobromide polymorph this polymorph is especially suited for direct compression or granulation processes and results in tablets exhibiting an excellent stability profile and low hygroscopy. Furthermore, it has been found that this vortioxetine hydrobromide polymorph is compatible with a wide range of pharmaceutical excipient used for tableting.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 to 3 show
1. the route of synthesis to vortioxetine free base and vortioxetine hydrobromide;
2. a PXRD-pattern of the new vortioxetine hydrobromide polymorph;
3. an NMR-spectrum of the new vortioxetine hydrobromide polymorph.
Figure 1 depicts the route of synthesis to obtain a pharmaceutically acceptable vortioxetine salts.
Figure 2 exhibits the PXRD-pattern of the new vortioxetine hydrobromide polymorph in comparison to the known vortioxetine a- and β-forms. The pattern with the lowest intensity is a PXRD-pattern of the α-polymorph, followed by the pattern of the β-form and the pattern of the new polymorph is the uppermost pattern. The diffraction patterns are displayed in the 2-theta range from 2° up to 40°. The new polymorph was prepared by subjecting dissolved vortioxetine hydrobromide according to the invention to a cooling precipitation as disclosed in paragraph f) of the experimental section. The PXRD-measurements are performed by placing the sample in a standard glass capillary (0 = 0.7 mm). The patterns were recorded at room temperature with a D8 Bruker Advance Diffractometer (Cu-Καΐ = 1.54059 A, Johansson primary beam monochromator, position sensitive detector) in transmission mode with rotation of the sample. The measurement time is 2 h. It can be clearly seen that the new vortioxetine hydrobromide polymorph exhibits additional peaks at 2 theta (± 0.2° 2-theta): 7.9 and 14.8, 17.8 and 26.8. These peaks are not present in the diffraction patterns of the a- and β-forms.
Figure 3 displays a NMR spectrum of the new vortioxetine hydrobromide polymorph. The NMR conforms to the theoretical spectrum of vortioxetine hydrobromide and trace amounts of CHC13. Due to the fact that only traces of chloroform are present the compound cannot be classified as solvate.
EXPERIMENTAL EXAMPLES
I) Preparation of the vortioxetine salt
Crude l-{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}piperazine compound (4) was dissolved in ethanol. Water was added, followed by aqueous hydrobromic acid (48%), giving vortioxetine hydrobromide overnight as precipitate. The precipitate was filtered off, washed with water and dried. The powder was washed with EtOAc and dried, giving pure (5) (vortioxetine hydrobromide). The same procedure can be performed using concentrated acetic acid.
II) Synthesis of compound (4) via routes a)-c)
ILA) Synthesis route a)
II. A. 1) Oxidation of compound (21) to the free piperazine base compound (4)
H
The oxidation of compound (21) to compound (4) can be achieved by
II.A.la) Iodine
A mixture of iodine (80 mg, 25 mol%) and compound (21) (for instance compound (7) (373 mg, 1.25 mmol)) in DMSO (5 mL) was stirred at 100 °C for 10 h under nitrogen. The mixture was allowed to cool to room temperature and was quenched by addition of a saturated solution of Na2CO3. Compound (4) was extracted with methylene chloride. The combined organic phase was dried over MgSO4. Evaporation of the solvent gave the crude compound (4).
II.A. lb) Metal catalyzed - Pd
To a solution of compound (21) in dry toluene were added 4 A molecular sieves, dry nitrobenzene, and 10 wt.-% loaded Pd/C. The resulting black mixture was stirred and refluxed for 4 - 12 h under GC/MS monitoring.
II.A.lc) Metal + Lewis base catalyzed
Aromatization of Compound (21) is achieved by using 3 equiv. of a TiCl4/Et3N reagent system or 2 equiv. of a Pd11 complex-system like Pd(OAc)2 or by using SnCl4/Et3N.
II.A.Id) Molecular oxygen: compound (21) in toluene or neat stirred at 80°C overnight under O2 atmosphere.
II.A.2) Synthesis of compound (7) - reaction schemes (Via + VIb)
II.A.2a) Synthesis of compound (6) - reaction scheme (Via)
II.A.2a - 0) Pre-step - Synthesis of ortho-halogenated cyclohexanone
A solution of cyclohexanone (10.4 mL, 100.0 mmol) in methylene chloride (20 mL) was added dropwise to a solution of NBS (18.0 g, 101.0 mmol, 1.01 equiv) and pTsOH (1.9 g, 10.0 mmol, 0.1 equiv) in methylene chloride (80 mL) at 0 °C. The reaction mixture was then brought to reflux for 4 h. After addition of water (100 mL), the organic layer was separated, and the aqueous layer was extracted with methylene chloride (3 x 50 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (100 mL) and brine (100 mL), dried over anhydrous Na2SO4. Methylene chloride was removed using a rotary evaporator. 17.4 g of crude 2-bromocyclohexanone (98.3 mmol, 98% yield) was used without further purification. Analysis: GC/MS: m/z = 176.0 [M+]. The 2-chlorocyclohexanone could be prepared accordingly by using NCS.
II.A.2a - 1) Synthesis of (6) - 2,4-dimethylbenzenethiolate
To a solution of 2.59 g of 2,4-dimethylbenzenethiolate (108.1 mmol) in THF (100 mL) was added a solution of 2-bromocyclohexanone (17.4 g, 98.3 mmol) in THF (50 mL) at 0 °C. The reaction mixture was warmed up to 25 °C. After being stirred at 25 °C for 1.5 h, the reaction mixture was quenched with saturated aqueous NH4C1 (100 mL) and extracted with Et2O (3x100 mL). The organic extracts were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4. The solvents were evaporated. Compound (6) (2-(phenylthio)cyclohexanone) was obtained in a yield of 17.2 g (84%) as yellow oil, which was used without further purification. Analysis: Ή NMR (CD2C12), δ = 1.69 (m, 1H), 1.85 (m, 1H), 2.00 (m, 2H), 2.11 (m, 1H), 2.19 (m, 1H), 2.31 (s, 3H), 2.40 (s, 3H), 2.93 (m, 2H), 3.71 (ddd, J = 1.5, 5.2, 6.0 Hz, 1H), 6.96 (s, 1H), 7.05 (s, 1H), 7.31 (s, 1H). 13C NMR (CD2C12), δ = 20.6,
20.7, 20.9, 27.3, 31.4, 56.08, 127.02, 129.14, 131.3, 133.5, 135.93, 137.95, 140.3,
207.7. GC-MS: m/z = 234.05 [M+],
II.A.2a - 2) Synthesis of (6) - K2CO3 and 2,4-dimethylbenzenethiol
K2CO3 (1.85 g, 13.2 mmol) was placed in a double neck round bottomed flask under a nitrogen atmosphere. Subsequent addition of DMF (20 mL) and 2,4dimethylbenzenethiol (1.92 g, 13.2 mmol) gave a white suspension, which was stirred for 90 minutes at 80°C. 2-bromocyclohexanone (2.34 g, 13.2 mmol) was added to the reaction mixture, which was stirred further for 4 hours at 80°C. Then DMF was evaporated. The residue was dissolved in CH2CI2 (40 mL), dried with Na2SO4 and filtrated. The solid washed with additional CH2CI2 (20 mL). The solvent was evaporated to quantitatively afforded (6) (2.995 g) in form of a yellow oil.
II.A.2b) Synthesis of (6) - reaction scheme (VIb)
II.A.2b - 0) Pre-step - Synthesis of N-(2,4-dimethyl-ibenzenesulfenyl)caprolactam:
A methylene chloride solution (20 mL) of 2,4-dimethylbenzenesulfenyl chloride (0.05 mol) was added dropwise to a solution of caprolactam (0.05 mol) and trimethylamine (0.055 mol) in 30 mL of methylene chloride. After complete addition, the reaction mixture was stirred for 3 hours and then filtered. The filter cake was washed with methylene chloride. The organic phase was poured into water and extracted with methylene chloride. The combined organic extracts were dried with anhydrous MgSO4 and filtered. The filtrate is concentrated on a rotavap to give the crude product, which was used without further purification.
II.A.2b - 1) Synthesis of compound (6)
Compound (6) is prepared in one step process by reacting equimolar amounts (2 mmol) of N-phenylthiocaprolactam, cyclohexanone and tert-BuOK at 25 °C within one hour in anhydrous DMSO (50 mL). In addition, it is also possible to obtain (6) using other S+ sources, such as CISAr.
II.A.2c) Synthesis of (7)
To a stirring solution of piperazine (3.44 g, 40.0 mmol) in anhydrous toluene (50 mL), compound (6) (2.34g, 10.0 mmol) and 10 mol% methanesulfonic acid (trifluoromethanesulfonic acid or p-TsOH) was added. The reaction was refluxed under Dean-Stark conditions for 16 hours. The reaction mixture was cooled to 25°C and decanted. The residue was washed with additional 10 mL of toluene. The organic phases were combined and the solvent was evaporated, giving 2.82 g (93%) of a mixture of l-{(6S)-6-[(2,4-dimethylphenyl)sulfanyl]cyclohex-l-en-lyl Jpiperazine and 1- {(6R)-6-[(2,4-dimethylphenyl)sulfanyl]cyclohex-l -en-1 yl}piperazine, which can directly be used for the next reaction Analysis: 'H NMR (CD2C12), δ = 7.25 (d, 1H); 7.04 (s, 1H); 6.94 (m, 1H); 5.31 (t, 1H); 3.67 (td, 1H); 2.86 (m, 4H), 2.38 (s, 3H); 2.35 (s, 1H), 2.28 (s, 3H); 2.24 (m, 2H); 2.15 (m, 2H), 2.02 (m, 2H), 1.93 (m, 2H), 1.82 (m, 2H), 1.66 (m, 2H); ’^{’Η} NMR (CD2C12), δ = 207.09, 140.44, 138.03, 133.49, 131.20, 130.10, 129.27, 127.19, 56.16, 39.10, 33.79, 27.29, 22.60, 20.71, 20.45. GC/MS: m/z = 231.9 [M+],
II.A.3) Synthesis of compound (9) - reaction scheme (VII)
II.A.3 - 0) Pre-step synthesis of 2,4-dimethylbenzenesulfenyl chloride
In a 50 mL round bottom flask sulfuryl chloride (1.35 g, 10 mmol) was added dropwise to a solution of 2,4-dimethylthiophenol (1.1 g, 10 mmol) in 20 mL dichloromethane at 0°C. The reaction mixture was stirred for 1 h at the same temperature, then concentrated under vacuum to give wine red liquid 2,4dimethyl-ibenzenesulfenyl chloride (1.37 g, 95% yield), which was used immediately in the next step.
II.A.3a) Synthesis of (8)
A THF solution (5mL) of (cyclohexa-l,5-dien-l-yloxy)(trimethyl)silane (5 mmol) was added dropwise to a THF solution (lOmL) of 2,4-dimethylbenzenesulfenyl chloride solution (0.76g, 5 mmol) at -78°C and stirred for 30 minutes. The reaction mixture was poured into water. The crude product was extracted with Et2O, dried over MgSO4, concentrated under reduced pressure to give 0.65 g (76%) of crude compound (8) (6-[(2,4-dimethylphenyl)sulfanyl]cyclohex-2-en-l-one), which was directly used for the next reaction. Analysis: 'H-NMR (CDC13) 7.35 (d, 1 arom. H); 7.04 (s, 1 arom. H); 6.97-6.92 (m, 2 H); 6.02 (d, 1 H); 3.75-3.73 (m, 1 H); 2.69-2.62 (m, 1 H); 2.41 (s, 3 H, CH3); 2.35-2.30 (m, 2 H); 2.29 (s, 3 H, CH3); 2.21-2.15 (m, 1H). 13C-NMR (CDC13) 194.94, 149.59, 141.43, 138.68, 134.98, 131.98, 129.80, 128.45, 127.59, 52.63, 28.89, 23.73, 21.31, 21.04. GC/MS: m/z = 232.15 [M+],
II.A.3b) Preparation of (9)
To a stirring solution of piperazine (168.9 mg, 1.95 mmol) in anhydrous toluene (10 mL), compound (8) (113.5 mg, 0.49 mmol) and 10 mol% trifluoromethanesulfonic acid (or p-TsOH) were added. The reaction was refluxed under Dean-Stark conditions for 23 hours. The reaction mixture was cooled to 25 °C and decanted. The residue was washed with additional 1 mL of toluene. The organic phases were combined and the solvent was evaporated. The crude product was directly used for the next reaction. Analysis: GC-MS m/z = 300.01 [M+].
II.A.4) Synthesis of compound (13)- reaction scheme (IIX)
13
II.A.4a) Synthesis of compound (12)
To a stirring solution of cyclohexanone (5.2 mL, 50.0 mmol) and piperazine (17.2 g, 200.0 mmol) in anhydrous toluene (20 mL) 10 mol% trifluoromethanesulfonic acid was added. It is also possible to use p-TsOH instead. The reaction was refluxed under Dean-Stark conditions for 4 hours. The reaction mixture was cooled to 25 °C and the solvent evaporated. The crude product was extracted with Et2O, washed with NaHCO3 and brine, dried over MgSO4, concentrated under reduced pressure, which can directly be used for the next reaction.
Alternatively also substituted piperazine can be used for the reaction. One example is the reaction of cyclohexanone and benzylpiperazine. Suitable piperazinesubstituents can be selected from the group comprising Cl-Cl5 alkyl or aryl substituents. A suitable example for using substituted piperazine can be: In a 50 mL double neck round bottomed flask under nitrogen was added toluene (10 mL) and 124 benzylpiperazine (3.67 g, 20.18 mmol), cyclohexanone (2.00 g, 20.18 mmol) and methanesulfonic acid (0.195 g, 2.02 mmol, 10% mol). The reaction was refluxed under Dean-Stark conditions for 4 hours. The solvent was evaporated. The crude product was extracted with methylene chloride, washed with NaHCO3 and brine, dried over MgSO4, concentrated under reduced pressure to give 3.93 g (76%) of (12)-benzyl as a dark-yellow oil. Analysis: 'H NMR (CDC13), δ = 7.30 (m, 5H); 3.49 (m, 2H); 2.95 (m, 4H); 2.44 (m, 4H); 2.33 (m, 4H); 1.86 (m, 3H); 1.69 (m, 2H); 13C{’H} NMR (CDC13), δ = 137.94, 129.16, 128.20, 127.05, 63.52, 53.77, 45.75, 41.98, 27.01, 25.00. GC/MS: m/z = 256.00 [M+],
II.A.4b) Synthesis of compound (13) l-(chlorosulfanyl)-2,4-dimethylbenzene or bis(2,4-dimethylphenyl) disulfide
To a stirring toluene solution (5mL) of compound (12) (5 mmol) was added 2,4dimethylbenzenesulfenyl chloride solution (0.76g, 5 mmol) at 0-5 °C. The reaction mixture was stirred at 25 °C for 12 hours. The crude product was extracted with Et2O, dried over MgSO4 and concentrated under reduced pressure.
II.A.5) Synthesis of compound (17) - reaction scheme (IX)
H
N.
Cyclohex-2-en-l-one (1.00 g, 10.4 mmol) and 2 M NaOH (1.3 mL) were dissolved in H2O (8.4 ml) at 0 °C. After stirring at this temperature for 10 minutes H2O2 (E77 g, 15.6 mmol, 30 wt %) was added. The mixture was allowed to warm to room temperature. The mixture was then extracted with diethyl ether. The organic phase was dried over MgSO4 and evaporated under reduced pressure to give 0.6 g (-50%) of 7-oxabicyclo[4.E0]heptan-2-one with 99% purity.
II.A.5b) Synthesis of compound (16)
0.276 g of 2,4-dimethylbenzenethiol (2 mmol) was added to 3.75 mL of water and 0.25 mL of NaOH 0.1 M aqueous solution to obtain a resulting pH of approx. 9.0. After 5 min, 224 mg (2.0 mmol) of 7-oxabicyclo[4.1.0]heptan-2-one (compound (15)) was added, and after an additional 0.5 h under vigorous stirring at 30 °C, 0.4 mL of concentrated HC1 was added and the reaction mixture warmed to 70 °C. After 18 h, the reaction mixture was extracted with Et2O (3x5 mL). The combined organic layers were washed with brine (1x5 mL), dried over Na2SO4, and evaporated under vacuum to give 0.438 g (93%) of compound (16).
Compound (16) may also be synthesized by a direct route from cyclohex-2-en-lone. 0.192 g of cyclohex-2-en-l-one (2 mmol) and 0.25 mL (0.5 molar equiv.) of 2 M NaOH were dissolved in 1.62 mL of water at 0-2 °C. After stirring at this temperature for 10 minutes, 0.340 g of 30 wt% aqueous hydrogen peroxide solution (1.5 molar equiv.) was added. After 30 minutes, 0.290 g (1.05 molar equiv.) of 2,4dimethylthiophenol was added at 30 °C and the stirring was continued for 30 minutes at this temperature before it was heated to 70°C for 16 hours. The reaction mixture was extracted with diethyl ether and the organic phase dried over MgSO4 and evaporated under reduced pressure, giving 0.445 g (96%) of compound (16).
II.A.5b) Synthesis of compound (17)
To a stirring solution of compound (16) (200 mg, 0.86 mmol) in anhydrous toluene (10 mL), methanesulfonic acid (104.3 mg, 1.08 mmol) and piperazine (296.6 mg, 3.4 mmol) were added. The reaction was refluxed under Dean-Stark conditions for 21 hours. The reaction mixture was cooled to 25 °C followed by decantation. The residue was washed with additional 1 mL of toluene. The organic phases were combined and the solvent was evaporated. The crude product (containing 15-20% of compound (17)) was directly used for the next reaction. Analysis: GC-MS m/z = 297.99 [M+],
II.A.6) Synthesis of compound (18) (besides (20), (34), (35) or (36)) - reaction scheme (X)
II.A.6 - 0) Pre-Step: Synthesis of 2,4-dimethyl-ibenzenesulfenyl chloride
In a 50 ml round bottom flask sulfuryl chloride (1.35 g, 10 mmol) was added dropwise to a solution of 2,4-dimethylthiophenol (1.1 g, 10 mmol) in 20 mL dichloromethane at 0°C. The reaction mixture was stirred for 1 h at the same temperature, then concentrated under vacuum to give wine red liquid 2,4dimethyl-ibenzenesulfenyl chloride (1.37 g, 95% yield), which was used immediately in the next step.
II.A.6 - 1) Synthesis of compound (18)
In a 100 mL double necked round bottomed flask under a nitrogen atmosphere was placed metallic sodium (78 mg, 3.39 mmol), followed by the addition of 40 mL of THF (or Dioxane) and 1-phenylpiperazine (250 mg, 1.54 mmol). The mixture was vigorously stirred under for 15 hours. The solution was transferred using a cannula to another 100 mL double necked round bottomed flask under nitrogen to eliminate residual sodium. Then absolute ethanol (121 mg, 1.54 mmol) was added to the solution, which was stirred for 15 minutes at 80°C. Thereafter, a solution of 2,4dimethyl-ibenzenesulfenyl chloride (266 mg, 1.54 mmol in 3 mL of THF) was added dropwise. The resulting suspension was then stirred at 80°C for 30 minutes and then filtrated. The solvent was evaporated to afford a semisolid yellow compound (317 mg). The addition of cyclohexane (10 mL) led to the precipitation of a brown solid, which was filtered off. The solvent of the filtrate was evaporated and dried under vacuum for 5 hours. The dried oil was then stirred in open air for 20 hours to afford a semisolid that was triturated in cold Et2O (-4°C) and filtrated the white solid was then crystallized in THF/Et2O. Crystallization gave white crystals, which were dried and analyzed. The GC-MS analysis gave evidence of a compound with a mass of
298 g/mol. The 'H and NMR spectra were compatible with the structure of
Vortioxetine.
II.B) Synthesis route b)
II.B) Synthesis of compound (4) - reaction scheme (II)
II.B.l) Synthesis of compound (4)
II.B.la) Synthesis of compound (3)
Tert-butyl nitrite (582mg, 5.6 mmol) was slowly added (40 min) to a mixture of 500mg (2.8 mmol) of compound (2) dissolved in a mixture of 9mL ethanol and aqueous HBF4 (48%, 0.74mL, 5.6 mmol) at 0°C. The reaction was stirred at room temperature for 1 hour and diethyl ether (30 mL) was added to precipitate compound (3) that was filtered off and washed with diethyl ether. Compound (3) was dried in vacuo for 10 minutes and then directly used without further purification. Compound (3) was isolated as a dark brown solid. Analysis: 'H-NMR (D2O) 8.28-8.26 (m, 1 arom. H); 8.12-8.09 (m, 1 arom. H); 7.60-7.58 (m, 1 arom. H); 7.44-7.40 (m, 1 arom. H); 3.83-3.81 (m, arom-N-CH2, 4H); 3.56-3.54 (m, N-CH2, 4H). ^Cl’Hl-NMR (D2O) 155.62 (1C, arom C), 143.07 (1C, aromC), 132.19 (1C, aromC), 124.89 (1C, arom C), 121.96 (1C, arom C), 101.31(lC, arom C), 47.79 (2C, piperazine C), 42.86 (2C, piperazine C). In addition, treatment of the dark brown solid with Cul exclusively yielded l-(2-iodophenyl)piperazine, which confirms the iodination of (3).
II.B. lb) Synthesis of compound (4)
To a DMSO solution of sodium 2,4-dimethylbenzenethiolate (290mg, 1.8mmol) and zinc (118mg, 1.8mmol) was added (portionwise) compound (3) 2-(piperazine-lyl)benzenediazonium tetrafluoroborate (500mg, 1.8mmol) over a period of 1 hour.
After stirring for 2 hours at room temperature, the mixture was basified, extracted with ethyl acetate, washed with brine and the solvent was evaporated. The compound was precipitated with ethyl acetate and filtered off. The crude product (1{2-[(2,4-dimethylphenyl)-isulfanyl]phenyl}piperazine compound (4)) contained some phenylpiperazine (Conversion is between 50 and 60%). Analysis: 'H-NMR (CDC13) 7.33 (d, 1 arom. H); 7.16 (m, 1 arom. H); 7.09-7.07 (m, 2 arom. H); 7.047.04 (m, 1 arom. H); 6.55-6.53 (m, 1 arom. H); 3.44-3.40 (m, 8 H, piperazine H); 2.36 (s, 3 H, CH3); 2.30 (s, 3 H). 13C-NMR (CDC13) 147.58 (1C, arom. C); 142.39 (1C, arom. C); 139.70 (1C, arom. C); 136.16 (1C, arom. C); 134.92 (1C, arom. C); 132.03 (1C, arom. C); 128.12 (1C, arom. C); 127.40 (1C, arom. C); 126.72 (1C, arom. C); 126.00 (1C, arom. C); 125.79 (1C, arom. C); 120.57 (1C, arom. C); 48.86 (2C, piperazine C); 44.32 (2C, piperazine C); 21.39 (1C, CH3); 20.28 (1C, CH3). MS (m/z) = 297.94.
Synthesis of 2,4-dimethylbenzenethiolate (for the reaction above):
To a cooled (0 °C) THF solution of 2,4-dimethylbenzenethiol (3.0g, 21.7mmol) was slowly added sodium hydride (510.2mg, 21.3mmol). After being stirred overnight, the reaction mixture was evaporated to dryness. The obtained solid was washed with diethyl ether and dried to afford 2,4-dimethylbenzenethiolate (2.5g, 15.5mmol, 71%) as an off-white solid.
II.B.2) Synthesis of compound (2) - reaction scheme (IV)
2
II.B.2a) Synthesis of (1)
To a solution of l-fluoro-2-nitrobenzene (2g, 14mmol) or l-chloro-2-nitrobenzene (2g, 12.7 mmol), in Ethanol (95%) was added 4 equiv. of piperazine (4.8g, 56mmol) and the mixture was refluxed (90°C). After 12 hours the solvent was evaporated and the residue was partitioned between H2O and CH2C12. The organic phase was separated, dried over MgSO4 and evaporated. Compound (1) was obtained quantitatively (2.7g; >98%) as bright orange amorphous solid, which was used without further purification. Analysis: MS (m/z) = 208.14
II.B.2b) Synthesis of (2)
Hydrogenation (5 bar, 25°C) of 2.7g (19mmol) of compound (1) with 300mg (10 mol%) of Pd/C (10%) in Methanol, yielded (2) after 4 hours. Filtration of the reaction mixture over celite and evaporation of Methanol yielded 2.1 lg (>99%) of (2) as off-white solid.
Alternatively: Direct Synthesis of (2)
To a solution of l-fluoro-2-nrtrobenzene (2g, 14mmol) or l-chloro-2-nitrobenzene (2g, 12.7 mmol), in Ethanol (95%) was added 4 equiv. of piperazine (4.8g, 56mmol). The mixture was refluxed (90°C) for 12 hours. Thereafter, the reaction mixture was subjected in an autoclave. Hydrogenation (5 bar, 25°C) of the reaction mixture with 225mg (10 mol%) of Pd/C (10%), quantitatively yielded 2 after 4 hours. Filtration of the reaction mixture over celite and evaporation of Ethanol and piperazine yielded
I. 65g (>99%) of 2 as off-white solid. Therefore, there is no need to evaporate the solvent in between the reaction and hydrogenation step and a highly pure product is also obtained in the direct synthesis.
II. B.3) Synthesis of compound (2) - reaction scheme (V)
H
Compound (2) was obtained by treatment of benzene- 1,2-diamine (0.5 g, 4.6 mmol) with bis(2-chloroethyl)amine hydrochloride (1.07 g, 6.0 mmol) in sulfolane at 150 °C for 15 hours. The reaction mixture consisted of 85% of 2, 7.5% of benzene-1,2diamine and 7.5 % of l,l'-benzene-l,2-diyldi-piperazine. Analysis: MS (m/z) = 177.09; Ή-NMR (DMSO) 6.87-6.85 (m, 1 arom. H); 6.79-6.77 (m, 1 arom. H); 6.67-6.65 (m, 1 arom. H); 6.56-6.52 (m, 1 arom. H); 4.71 (s, NH2, 2 H); 2.87-2.85 (m, arom-N-CH2, 4H); 2.72-2.7 (m, N-CH2, 4H).
II.C) Synthesis route c)
II.C) Synthesis of compound (4) - reaction scheme (III)
HO OH
11
II.C.l) Synthesis of compound (10)
In a 250 mL one neck round bottom flask 1-phenyliperazine (2.0 g; 12.20 mmol) was added dropwise to NaIO4.and stirred for 40 minutes. The reaction product was extracted with methylene chloride. The combined organic phases were dried with MgSO4, the solvent was evaporated and the brownish solid was dried under vacuum to yield 1.4 g of a dark solid. (Mw=194.24; 7.32 mmol; Yield= 60%).
II. C.2) Synthesis of compound (11)
In a double neck round bottom flask equipped with a stirring bar was dissolved compound (10) (7.32 mmol, 1422 mg) in acetonitrile. Then 2,4dimethyl-ibenzenesulfenyl chloride (1264 mg; 7.32 mmol) was added at once using a syringe. The dark solution was then stirred under reflux for 3 hours to give compound (11).
III. C.3) Synthesis of compound (4)
Mg and Zn were added portionwise to the solution obtained in D.2 under vigorous stirring. The reaction was refluxed until the dark red solution became a light red. Then the suspension was filtered, the acetonitrile evaporated and the dark solid was dissolved in EtOAc (60 mL). The solvent was evaporated and then again AcOEt was added. After the last addition of solvent compound (4) was separated as a light brown solid.
II.D) Preparation of the piperazine salt
The crude l-{2-[(2,4-dimethylphenyl)sulfanyl]phenyl}piperazine (4) was dissolved in Ethanol. Water was added, followed by aqueous hydrobromic acid (48%), giving vortioxetine hydrobromide overnight as precipitate. The precipitate was filtered off, washed with water and dried. The powder was washed with EtOAc and dried, giving pure (5) (vortioxetine hydrobromide).
Direct Synthesis of (5) from (3)
To a DMSO solution of sodium 2,4-dimethylbenzenethiolate (289.8mg, 1.81mmol) and zinc (118.5mg, 1.81mmol) was added (portionwise) 2-(piperazine-lyl)benzenediazonium tetrafluoroborate (500mg, 1.38mmol) over a period of 1 hour. After stirring for 2 hours at room temperature, the crude mixture was added drop wise into water and stirred for 10 minutes. The formed precipitate was filtered off. The filtrate was basified with NaOH, extracted with dichloromethane, washed with brine and the solvent was evaporated. The obtained brown syrup was dissolved in little chloroform, concentrated HBr was added and it was stirred for 3 hours. The mixture was extracted with chloroform and the solvent was evaporated to afford 5 (155.4-mg, 0.41mmol, 30%). Analysis: 'H-NMR (DMSO-d6) 8.71 (br s, 2 H); 7.32 (d, J = 8 Hz, 1 arom. H); 7.24 (m, 1 arom. H); 7.16-7.08 (m, 3 arom. H); 6.98-6.95 (m, 1 arom. H); 6.42 (d, J = 8 Hz, 1 arom. H); 3.25-3.18 (m, 8 H, piperazine H); 2.32 (s, 3 H, CH3); 2.24 (s, 3 H, CH3).
Ill) Cooling Crystallization of (5)
Compound (5) prepared according to any of the above given routes a)-d) is placed in a round bottom flask and dissolved under gentle shaking in chloroform, heated to 50°C and subjected to a cooling crystallization at ambient pressure. The cooling crystallization profile is
1. 50 °C cooling down to 5 °C at a rate of 0.1°C/min
2. 5°C for 2 h
3. Heating up to 40°C at 0.1 °C/min
4. 40°C for 2 h
5. 40°C cooling down to 4°C at a rate of 0.1 °C/min
6. 4°C for 2 h
7. Heating up to 30°C at 04°C/min
8. 30°C for 2 h
9. 30°C cooling down to 3°C at a rate of 0.1 °C/min
10. 3°C for 2 h
11. Heating up to 5 °C at 0.1°C/min
12. 5°C for 6 Month
In the last cycle step clear colorless needles are obtained exhibiting the PXRD pattern of Figure 1. The peak table of the new polymorph is:
2 theta [°] | d value [A] | Int. [Counts] | Int [%] |
6,304 | 14,00997 | 1138 | 10,3 |
6,686 | 13,20895 | 5318 | 48,0 |
7,931 | 11,13837 | 2175 | 19,6 |
8,313 | 10,62738 | 1550 | 14,0 |
10,206 | 8,66047 | 764 | 6,9 |
11,819 | 7,48173 | 792 | 7,2 |
12,184 | 7,25827 | 6478 | 58,5 |
12,570 | 7,03634 | 714 | 6,4 |
12,885 | 6,86528 | 883 | 8,0 |
12,957 | 6,82720 | 854 | 7,7 |
13,277 | 6,66305 | 1129 | 10,2 |
13,436 | 6,58468 | 1139 | 10,3 |
14,178 | 6,24182 | 973 | 8,8 |
14,851 | 5,96031 | 1148 | 10,4 |
15,931 | 5,55870 | 5828 | 52,6 |
16,014 | 5,52996 | 4981 | 45,0 |
16,703 | 5,30344 | 2735 | 24,7 |
17,004 | 5,21036 | 934 | 8,4 |
17,278 | 5,12823 | 4314 | 38,9 |
17,761 | 4,98975 | 4630 | 41,8 |
17,973 | 4,93145 | 1377 | 12,4 |
18,787 | 4,71957 | 1105 | 10,0 |
19,451 | 4,55995 | 11076 | 100,0 |
19,568 | 4,53302 | 4697 | 42,4 |
20,233 | 4,38547 | 2077 | 18,7 |
20,320 | 4,36682 | 3709 | 33,5 |
20,716 | 4,28427 | 760 | 6,9 |
22,074 | 4,02359 | 3605 | 32,5 |
22,228 | 3,99607 | 1694 | 15,3 |
22,634 | 3,92541 | 1454 | 13,1 |
22,849 | 3,88889 | 1322 | 11,9 |
23,040 | 3,85710 | 2121 | 19,1 |
23,313 | 3,81256 | 946 | 8,5 |
23,749 | 3,74357 | 2575 | 23,2 |
23,849 | 3,72808 | 7436 | 67,1 |
24,411 | 3,64351 | 2079 | 18,8 |
24,927 | 3,56917 | 1406 | 12,7 |
25,118 | 3,54250 | 1719 | 15,5 |
25,253 | 3,52390 | 1406 | 12,7 |
25,638 | 3,47187 | 911 | 8,2 |
25,959 | 3,42963 | 968 | 8,7 |
26,111 | 3,40998 | 2483 | 22,4 |
26,308 | 3,38487 | 1758 | 15,9 |
26,812 | 3,32237 | 3232 | 29,2 |
27,014 | 3,29807 | 719 | 6,5 |
27,257 | 3,26922 | 789 | 7,1 |
27,535 | 3,23674 | 1111 | 10,0 |
27,956 | 3,18902 | 1386 | 12,5 |
28,124 | 3,17032 | 1669 | 15,1 |
28,461 | 3,13358 | 1213 | 11,0 |
28,609 | 3,11769 | 1474 | 13,3 |
29,003 | 3,07624 | 860 | 7,8 |
29,425 | 3,03300 | 1875 | 16,9 |
29,657 | 3,00982 | 908 | 8,2 |
29,826 | 2,99315 | 1150 | 10,4 |
29,991 | 2,97706 | 1199 | 10,8 |
30,180 | 2,95885 | 1472 | 13,3 |
30,346 | 2,94302 | 1962 | 17,7 |
30,848 | 2,89629 | 981 | 8,9 |
31,024 | 2,88028 | 615 | 5,6 |
31,210 | 2,86351 | 581 | 5,2 |
31,716 | 2,81896 | 1113 | 10,0 |
31,942 | 2,79952 | 864 | 7,8 |
32,222 | 2,77587 | 619 | 5,6 |
32,692 | 2,73703 | 608 | 5,5 |
32,829 | 2,72594 | 726 | 6,6 |
33,176 | 2,69815 | 574 | 5,2 |
33,356 | 2,68405 | 675 | 6,1 |
33,815 | 2,64863 | 656 | 5,9 |
34,421 | 2,60342 | 699 | 6,3 |
34,978 | 2,56318 | 580 | 5,2 |
35,122 | 2,55302 | 1102 | 9,9 |
35,331 | 2,53842 | 642 | 5,8 |
35,553 | 2,52304 | 1179 | 10,6 |
35,821 | 2,50476 | 855 | 7,7 |
35,902 | 2,49932 | 798 | 7,2 |
36,421 | 2,46487 | 463 | 4,2 |
36,727 | 2,44506 | 536 | 4,8 |
36,913 | 2,43316 | 896 | 8,1 |
37,057 | 2,42406 | 1294 | 11,7 |
37,333 | 2,40676 | 647 | 5,8 |
37,538 | 2,39409 | 650 | 5,9 |
37,763 | 2,38031 | 642 | 5,8 |
37,859 | 2,37451 | 581 | 5,2 |
38,110 | 2,35944 | 843 | 7,6 |
38,315 | 2,34727 | 528 | 4,8 |
38,538 | 2,33419 | 893 | 8,1 |
38,715 | 2,32396 | 548 | 4,9 |
38,872 | 2,31494 | 434 | 3,9 |
39,163 | 2,29839 | 448 | 4,0 |
39,387 | 2,28582 | 495 | 4,5 |
39,774 | 2,26446 | 923 | 8,3 |
39,941 | 2,25538 | 812 | 7,3 |
40,248 | 2,23888 | 658 | 5,9 |
40,658 | 2,21727 | 392 | 3,5 |
40,869 | 2,20628 | 589 | 5,3 |
41,042 | 2,19738 | 607 | 5,5 |
41,306 | 2,18397 | 586 | 5,3 |
41,501 | 2,17416 | 426 | 3,8 |
42,115 | 2,14387 | 717 | 6,5 |
43,037 | 2,10003 | 561 | 5,1 |
43,471 | 2,08008 | 578 | 5,2 |
44,709 | 2,02530 | 520 | 4,7 |
45,293 | 2,00055 | 501 | 4,5 |
45,455 | 1,99380 | 507 | 4,6 |
45,893 | 1,97576 | 525 | 4,7 |
46,371 | 1,95650 | 436 | 3,9 |
46,960 | 1,93335 | 440 | 4,0 |
47,357 | 1,91806 | 528 | 4,8 |
47,467 | 1,91388 | 485 | 4,4 |
47,851 | 1,89941 | 510 | 4,6 |
48,047 | 1,89213 | 496 | 4,5 |
48,207 | 1,88621 | 541 | 4,9 |
48,752 | 1,86637 | 416 | 3,8 |
48,931 | 1,85997 | 526 | 4,7 |
49,195 | 1,85059 | 538 | 4,9 |
49,417 | 1,84283 | 433 | 3,9 |
49,696 | 1,83311 | 459 | 4,1 |
49,920 | 1,82540 | 505 | 4,6 |
Claims (27)
1) Process for the preparation of vortioxetine (1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine) salts at least comprising the step of forming a salt by addition of a pharmaceutically acceptable acid to the free piperazine base compound (4),
H characterized in that the free base compound (4) is prepared via one of the routes a) - c); wherein the routes at least comprise:
a) Oxidation according to reaction scheme (I) of compound (21), a l-{2-[(2,4dimethylphenyl)sulfanyl]cyclohexyl}piperazine-derivative, wherein the cyclohexyl-moiety is mono- or di-unsaturated (dashed-lines) to yield compound (4)
H (I)
b) Reacting according to reaction scheme (II) compound (2) (2-(piperazin-l-yl) aniline) in a pharmaceutically acceptable solvent in the presence of tetrafluoroboric acid to yield compound (3) (2-(piperazin-l-yl)benzenediazonium tetrafluoroborate salt), and, in a second step, reacting compound (3) in the presence of alkali 2,4-dimethylbenzenethiolate and a metal catalyst to yield compound (4)
Η (Π);
c) Reacting according to reaction scheme (III) 1 -phenylpiperazine in the presence of an oxidizing agent to yield activated compound (10) and further reacting activated compound (10) in a pharmaceutically acceptable solvent in the presence of 2,4-dimethylbenzenesulfenyl chloride to give compound (11), which is further reacted with an reducing agent to yield compound (4) (III).
2) Process according to claim 1, wherein the vortiotexine salt is a hydrobromide or a hydroacetate salt according to compound (5)
H
3) Process according to any of the preceding claims, wherein compound (21) is selected from the group consisting of the compounds (7), (9), (13), (17), (18), (20), (30), (31), (32), (33), (35) and (36):
4) Process according to claim 1 or 2, wherein in route b) compound (2) is obtainable via bl) reaction scheme (IV) by reacting 1-X-2-nitrobenzene, wherein X is a leaving group, and piperazine to yield compound (1) (l-(2-nitrophenyl)piperazine) and, in a second step, hydrogenation of compound (1) in the presence of a metal catalyst to yield compound (2) (2(piperazin-1 -yl)aniline)
Η
Η
ΝΗ;
(IV);
or via b2) reaction scheme (V) by reacting benzene-1,2-diamine and bis-(2-chloroethyl)amine to yield compound (2) (2-(piperazin-l-yl)aniline)
H (V).
5) Process according to claim 4, wherein the route bl) is performed in a one-step synthesis.
6) Process according to claim 3, wherein compound (7) is prepared via:
reaction scheme (Via) at least comprising reacting ortho-functionalized cyclohexanone, wherein the ortho-group X is a leaving group, and alkali 2,4-dimethylbenzenethiolate to yield compound (6) (2-(phenylthio)cyclohexanone) and further reacting compound (6) and piperazine to yield compound (7) (l-{6-[(2,4-dimethylphenyl)-isulfanyl]-icyclohex-l-en-lyl} piperazine)
H or reaction scheme (VIb) at least comprising reacting cyclohexanone and N-(2,4dimethylbenzenesulfenyl)caprolactam in the presence of a base to yield compound (6) and further reacting compound (6) and piperazine to yield compound (7) (1-(6-((2,4dimethylphenyl) sulfanyl] cyclohex-1 -en-1 -yl} piperazine)
7) Process according to claim 3, wherein compound (9) is prepared via reaction scheme (VII) by reacting a (cyclohexa-1 .S-dien-l-yloxyXR'bsilane, wherein R1 is selected from the group consisting of C1-C8 alkyl or aryl, and 2,4-dimethylbenzenesulfenyl halogenide solution to yield compound (8) (6-[(2,4-dimethylphenyl)sulfanyl]cyclohex-2-en-l-one) and further reacting compound (8) and piperazine to yield compound (9) (1-(2-((2,4dimethylphenyl)sulfanyl]cyclohexa-l,5-dien-l-yl}piperazine)
8) Process according to claim 3, wherein compound (13) is prepared via reaction scheme (IIX) by reacting cyclohexanone and a substituted or unsubstituted piperazine to yield compound (12) (1-(cyclohex-l-en-l-yl)piperazine) and further reacting compound (12) and 1(chlorosulfanyl)-2,4-dimethylbenzene or bis(2,4-dimethylphenyl) disulfide to yield compound (13) (1-( 2-[(2,4-dimethylphenyl)sulfanyl] -cyclohex-1 -en-1 -yl (piperazine)
9) Process according to claim 3, wherein compound (17) is prepared via reaction scheme (IX) by reacting compound (14) (cyclohex-2-en-l-one ) and an oxidizing agent in the presence of a base to yield compound (15) (7-oxabicyclo[4.1.0]heptan-2-one), further reacting compound (15) and 2,4-dimethylbenzenethiol in the presence of a base to yield compound (16) (l-{6[(2,4-dimethylphenyl)sulfanyl]cyclohex-2-en-l-yl}piperazine) and further reacting compound (16) and piperazine in the presence of an acid to yield compound (17) (l-{6-[(2,4dimethylphenyl)sulfanyl]cyclohexa-l,5-dien-l-yl}piperazine)
H
10) Process according to claim 3, wherein compound (18), compound (20), compound (35) or compound (34) is prepared via reaction scheme (X) by reacting 1-phenylpiperazine and a reducing agent in a pharmaceutically acceptable solvent to yield compound (18) (l-{2-[(2,4dimethylphenyl)sulfanyl]cyclohexa-l,4-dien-l-yl}piperazine) or compound (34) (l-{2-[(2,4dimethylphenyl)sulfanyl]cyclohexa-l,3-dien-l-yl}piperazine)
11) Process according to claim 6, wherein in reaction scheme (Via) the ortho-functionalized cyclohexanone is selected from the group consisting of 2-bromocyclohexanone, 2chlorocyclohexanone or 2-iodocyclohexanone.
12) Process according to claim 6, wherein in reaction scheme (Via) the compound (6) is prepared by reacting 2-bromocyclohexanone, 2-chlorocyclohexanone, or 2-iodocyclohexanone and 2,4dimethylbenzenethiol in a pharmaceutically acceptable solvent in the presence of a base.
13) Process according to claim 12, wherein the base is selected from the group consisting of carbonates, phosphates, hydroxides, hydrides, phosphazenes, nitrides, amines, alcoholates, amides, substituted or unsubstituted pyridines , amidines, guanidines, napthalenes or mixtures thereof.
14) Process according to claim 6, wherein in reaction scheme (VIb) the compound (6) is prepared by reacting equimolar amounts of N-(2,4-dimethyl-ibenzenesulfenyl)caprolactam, cyclohexanone and a base.
15) Process according to claim 14, wherein the base is tert-BuOK (potassium tert-butanolate).
16) Intermediate product in the production of a pharmaceutically acceptable vortioxetine salt, comprising compound (7)
Η
17) Intermediate product in the production comprising compound (11) of a pharmaceutically acceptable vortioxetine salt
18) Intermediate product in the production of a pharmaceutically acceptable vortioxetine salt comprising compound (16) (2-[(2,4-dimethylphenyl)sulfanyl]cyclohex-2-en-l-one)
19) Intermediate product in the production of a pharmaceutically acceptable vortioxetine salt comprising compound (17) (l-{6-[(2,4-dimethylphenyl)sulfanyl]cyclohexa-l,5-dien-lyl} piperazine)
H
20) Vortioxetine hydrobromide polymorph, characterized in that the X-ray powder diffraction pattern of the polymorph at least comprises the following characteristic peaks at 2 theta (± 0.2° 2-theta): 7.9 and 14.8.
21) Vortioxetine hydrobromide polymorph according to claim 20, wherein the X-ray powder diffraction pattern of the polymorph at least comprises the following characteristic peaks at 2 theta (+ 0.2° 2-theta): 7.9 and 14.8, 17.8, 26.8.
22) A process for the production of the vortioxetine hydrobromide polymorph according to claim 20 or 21, wherein the process comprises the crystallization of the polymorph at least temporarily at a temperature of > 0°C and <10 °C.
23) Process according to claim 22, wherein the crystalline product is obtained by cooling crystallization, wherein at least two cooling crystallization cycles are performed and in between the cooling cycles the vortioxetine hydrobromide is heated up to a temperature of > 25°C and < 80°C.
24) Use of vortioxetine hydrobromide polymorph according to claims 20 or 21 for manufacturing of a pharmaceutical composition.
25) A pharmaceutical composition comprising the vortioxetine hydrobromide polymorph according to claims 20 or 21 for use in the treatment of major depressive and/or generalized anxiety disorder.
26) Oral dosage form comprising a vortioxetine hydrobromide polymorph according to claim 20 or 21.
27) Oral dosage form according to claim 26, wherein the oral dosage form is a tablet.
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CN112250642A (en) * | 2020-10-28 | 2021-01-22 | 合肥亿帆生物制药有限公司 | Preparation method of hydrobromic acid vortioxetine impurity standard substance |
US11707461B2 (en) * | 2017-09-20 | 2023-07-25 | Zhejiang Huahai Pharmaceutical Co., Ltd | N-formyl vortioxetine and preparation method thereof and solid preparation of vortioxetine |
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EP2975032A1 (en) * | 2014-07-18 | 2016-01-20 | Dipharma Francis S.r.l. | Crystalline forms of an antidepressant drug |
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WO2007144005A1 (en) * | 2006-06-16 | 2007-12-21 | H. Lundbeck A/S | 1- [2- (2, 4-dimethylphenylsulfanyl) -phenyl] piperazine as a compound with combined serotonin reuptake, 5-ht3 and 5-ht1a activity for the treatment of cognitive impairment |
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