WO2016079751A2 - A process for preparation of vortioxetine and polymorphs thereof - Google Patents

A process for preparation of vortioxetine and polymorphs thereof Download PDF

Info

Publication number
WO2016079751A2
WO2016079751A2 PCT/IN2015/000414 IN2015000414W WO2016079751A2 WO 2016079751 A2 WO2016079751 A2 WO 2016079751A2 IN 2015000414 W IN2015000414 W IN 2015000414W WO 2016079751 A2 WO2016079751 A2 WO 2016079751A2
Authority
WO
WIPO (PCT)
Prior art keywords
compound
vortioxetine
less
acid
dimethyl
Prior art date
Application number
PCT/IN2015/000414
Other languages
French (fr)
Other versions
WO2016079751A3 (en
Inventor
Vijayavitthal Thippannachar Mathad
Dattatray Gulabrao Deshmukh
Anil Chaturlal Mali
Mukunda Rajendra PATEKAR
Bhaskar Suresh GADEKAR
Original Assignee
Megafine Pharma (P) Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Megafine Pharma (P) Ltd. filed Critical Megafine Pharma (P) Ltd.
Publication of WO2016079751A2 publication Critical patent/WO2016079751A2/en
Publication of WO2016079751A3 publication Critical patent/WO2016079751A3/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to an improved process for preparation of vortioxetine or pharmaceutically acceptable salts thereof. The present invention also relates to new process for the preparation of vortioxetine or pharmaceutically acceptable salts thereof. The present invention further relates to novel polymorphs of vortioxetine hydrobromide and process for preparation thereof.

Description

TITLE OF THE INVENTION
A PROCESS FOR PREPARATION OF VORTIOXETINE AND POLYMORPHS THEREOF
This appclaition claims the priority from our provisional Indian patent application number 3612/mum/2014 which is incorporated herein by reference.
FIELD OF THE INVENTION:
The present invention relates to process for the preparation of l-[2-(2,4- dimethylphenylsulfanyl)phenyl]piperazine compound of formula (I), its pharmaceutically acceptable salts of formula la and ol morphs thereof.
Figure imgf000002_0001
Vortioxetine (I) Vortioxetine salt (la)
The present invention also relates to novel intermediates l-{2-[(2,4- dimethylphenyl)thio]phenyl}piperazin-2-one compound of formula (XIV) and l-(2- bromophenyl) piperazine compound of formula (XV) used for the preparation of compound of formula (I) and (la) and process for preparation thereof.
Figure imgf000002_0002
(XIV) (xv)
Wherein; R = -H, -Boc, -Benzyl etc. The present invention also relates to novel crystalline polymorphs of hydrobromide salt of l-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Vortioxetine hydrobromide)
BACKGROUND OF THE INVENTION:
l-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine (henceforth "Vortioxetine"), and its acid addition salts thereof have affinity to the serotonin transporter and the serotonin receptors 3 and 1A (5-HT3 and 5-HTIA). The vortioxetine hydrobromide having empirical formula Ci8H22N2S.HBr and CAS number of 960203-27-4 was approved by the USFDA and by EMA for the treatment of Major Depressive Disorder (MDD) as antidepressant drug and commercially sold under the brand name BRINTELLIX®
Figure imgf000003_0001
Vortioxetine. HBr
US patents 7,144,884 and 8,476,279 describes process for the preparation of vortioxetine (I) and are presented in Scheme- 1 to Scheme-4
Figure imgf000003_0002
Figure imgf000004_0001
Where G = Br or I Formula-I
Scheme-3
di
Formula - I
Figure imgf000004_0002
Patent application WO 2013102573 discloses the synthesis of vortioxetine as shown in Scheme-5; 2,
Figure imgf000005_0001
Vortioxetine HBr
Scheme-5
US patent US 8,598,348 discloses synthesis of vortioxetine hydrobromide as shown
Figure imgf000005_0002
1 -bromo-2-iodobenzene
Vortioxetine HBr
Scheme-6
The above synthetic Schemes for the preparation of vortioxetine have some draw backs, which limits its scope on an industrial scale and some of the drawbacks are listed below;
a) Scheme 1, 2 and 4 described in patents US 7,144,884 and US 8,476,279 for the synthesis of vortioxetine and its salts are cumbersome, lengthy, tedious to use on an industrial scale and inadvertently affecting on overall atom economy;
b) Schemes 1 to 4 described in US patents 7,144,884 and US 8,476,279 involves use of chromatographic techniques for the purification of vortioxetine, which is industrially not feasible;
c) US patents 7,144,884 and US 8,476,279 involves use of expensive pyrophoric catalyst for the reduction of nitro group and di-keto group are uneconomical; d) Schemes 1 to 4 described in US patents 7,144,884 and US 8,476,279 provides lower yield and purity of the intermediates and final products;
e) Scheme 5 and Scheme 6 of PCT application WO2013102573 and US patent 8,598,348 respectively, involve use of palladium catalyst and ligands like ΒΓΝΑΡ, which are very costly and inadvertently increases the manufacturing cost.
Hence, there is a continuous need to develop simple, commercially advantageous and industrially viable process for the preparation of vortioxetine and its pharmaceutically acceptable salt that reduces the number of reaction steps and in turn increases overall yield of the final product.
The present invention offers an improved, efficient, economic, and production friendly process for preparation of vortioxetine and its pharmaceutically acceptable salts.
Polymorphism is a phenomenon relating to the occurrence of different crystalline forms for one molecule. There may be several different crystalline forms for the same molecule with distinct crystal structures and varying in physical properties like melting point, PXRD pattern and FTIR spectrum. These polymorphs are thus distinct solid forms which share the molecular formula of the compound from which the crystals are made up, however they may have distinct advantageous physical properties such as e.g. chemical stability, physical stability, hygroscopicity, solubility, dissolution rate, morphology or bioavailability. These polymorphic forms of the same drug substance or active pharmaceutical ingredient plays a key role in the development of the final or finished dosage form. Hence, there is a continuing need for new crystalline forms and new processes of preparing crystalline forms. Hence, the present invention provides an improved process for the preparation of vortioxetine or its acid addition salt and a new crystalline form of vortioxetine hydrobromide thereof.
OBJECTS OF THE PRESENT INVENTION
The primary object of the present invention is to provide improved process for the preparation of vortioxetine (I) and/or its pharmaceutically acceptable salts.
Another object of the present invention is to provide new method for the preparation of vortioxetine (I) and/or its pharmaceutically acceptable salts.
Another object of the invention is to provide process for the preparation of vortioxetine and/or its pharmaceutically acceptable salts in a single pot wherein isolation of intermediates is avoided to improve atom economy and reduce the turnaround time.
Yet another object of the present invention is to provide process for preparation of vortioxetine and/or its pharmaceutically acceptable salts, wherein the said process eliminates laborious workup and extensive purifications to make the process simple cost effective, efficient and production friendly.
Yet another object of the present invention is to provide a process for preparation of vortioxetine and/or its pharmaceutically acceptable salts, which is substantially free from impurities.
Yet another object of the invention is to provide a new compound of formula (XIV), which is used as intermediate for the preparation of vortioxetine and/or its pharmaceutically acceptable salts. Yet another object of the present invention is to provide novel crystalline forms of Vortioxetine hydrobromide (I) herein designated as Form Ml and Form M2.
BRIEF DESCRITPION OF DRAWINGS
Figure 1 : X-ray powder diffraction (XRD) pattern of 2,4-dimethyl-l-[(2- nitrophenyl)thio]benzene compound of formula (IV), prepared according to example 1 and 9.
Figure 2:X-ray powder diffraction (XRD) pattern - of 2-[(2,4- dimethylphenyl)thio]aniline hydrochloride, prepared according to example 15.
Figure 3:X-ray powder diffraction (XRD) pattern of vortioxetine hydrobromide, prepared according to example 12.
Figure 4: X-ray powder diffraction (XRD) pattern of vortioxetine hydrobromide, prepared according to example 13.
DETAILED DESCRIPTION OF THE INVENTION
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.
Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having" and the like, means' "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, - but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.
A term herein "reflux temperature" means the temperature at which the solvent or the solvent system refluxes or boils at atmospheric pressure.
The term "substantially free of in reference to a composition, as used herein, means that an absent substance cannot be detected in the composition by methods known to those skilled in the art at the time of the filing of this application.
In one of the embodiments of the present invention there is provided improved process for the preparation of vortioxetine (I) and its pharmaceutically acceptable salt, said process comprising;
a) reacting 1-halo (or l-pseudohalo)-2 -nitrobenzene with 2,4-dimethylbenzenethiol in solvent, base and optionally in presence of catalyst to obtain 2,4-dimethyl-l- [(2-nitrophenyl)thio]benzene compound (IV);
Figure imgf000010_0001
2,4-dimethylbenzenethiol 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene
Wherein X is -CI, -Br, -I, -F, -OTf, -OMs, or -OTs b) reducing 2,4-dimethyl-l-[(2-nitrophenyl)thio]benzene compound (IV) to 2-[(2,4- dimethylphenyl)thio]aniline compound (V) in solvent in presence of reducing agent and catalyst;
Figure imgf000010_0002
2,4-dimet yl-1-[(2-nitrophenyl)thio]benzene 2-[(2,4-dimethylphenyl)thio]aniline c) reacting 2-[(2,4-dimethylphenyl)thio]aniline compound (V) or its salt with dialkyl amine compound (VI) or its acid addition salt in solvent, base and optionally in the presence of phase transfer catalyst to obtain vortioxetine (I) or its salt (la) and optionally purifying vortioxetine (I) or its salt (la);
Figure imgf000010_0003
2-[(2,4-dimethylphenyl)thio]aniline Formula-I Formula-la
Wherein Y is -CI, -Br,-I,-OTf, -OMs, -OTs etc.
d) optionally converting compound of formula (I) or its salt (la) to the required acid addition salt and optionally purifying required vortioxetine acid addition salt (la). Further, step (c) of reacting 2-[(2,4-dimethylphenyl)thio]aniline compound (V) or its salt with dialkyl amine compound (VI) or its acid addition salt can be carried out in a solvent with continuous flow of inert gas, wherein the inert gas is nitrogen, argon and the like. Preferably, the inert gas is nitrogen.
Further, the acid addition salt of Vortioxetine can be converted to its free base.
The solvent used in the steps (a), (b), (c) and (d) may be same or different; wherein the said solvent is selected from alcohols such as methanol, ethanol, isopropanol, n- butanol, mono ethylene glycol and the like, aromatic hydrocarbons such as toluene, xylene, mesitylene and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane, chlorobenzene, dichlorobenzene and the like; formamide such as N,N- dimethylformamide, Ν,Ν-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, diglyme and the like, esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ionic liquids; water or a mixture thereof.
Preferably, the solvent used in step (a) is water.
Preferably, the solvent used in step (b) is alcohol. More preferably, the solvent used is isopropanol.
Preferably, the solvent used in step (c) is alcohol. More preferably, the solvent used is n-butanol.
Preferably, the solvent used in step (d) is alcohol, ester, ether, ketone, water or mixtures thereof. The steps (a), (b), (c) and (d) can be carried out at temperature range from about 0°C to 180°C or the boiling points of the solvents used. Usually the reaction may be carried out at temperature up to reflux temperature of the said solvent.
The base used in step (a) and step (c) is selected from organic or inorganic base; organic bases selected from but not limited to l,8-diazabicyclo[5.4.0]undec-7-ene; l,5-diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2-propyl amine, butyl amine and the like; secondary amines such as but not limited to Ν,Ν-diisopropyl amine, dimethyl amine, diethyl amine, N-methyl propyl amine, morpholine and the like; tertiary amines such as but not limited to triethylamine, Ν,Ν-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine and the like; inorganic bases selected from alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as but not limited to sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide, lithium -hydroxide and the like; metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, potassium tert butoxide and the like.
Preferably, the base used in step (a) is alkali metal hydroxides. More preferably, the base used is sodium hydroxide. —
The reduction step (b) can be carried out either by catalytic reduction, metallic reduction, or chemical reduction or enzymatic reduction.
The catalytic reduction of the step (b) can be carried out in presence of a catalyst selected from but not limited to palladium-carbon, palladium hydroxide-carbon, platinum oxide, rhodium on carbon, Raney nickel, nickel chloride, charcoal, graphite and the like; in presence of hydrogen gas or hydrogen generating source such as but not limited to ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid, hydrazinium monoformate, sodium borohydride, lithium aluminium hydride.
Preferably, the reduction step (b) is carried out using Raney nickel in presence of hydrogen gas.
The metallic reduction in the step (b) can be carried out by using metals such as but not limited to iron, zinc, tin, and the like in presence of reagents such as acetic acid, formic acid, calcium chloride, copper sulphate, sodium hydroxide, ammonium chloride, ammonium formate, ammonium acetate, ammonium sulphate, and/or solvent.
The chemical reduction in the step (b) can be carried out using but not limited to sodium dithionate, sodium sulphide, sodium hyposulphite.
Catalyst used in step (a) and (c) is selected from metal halide like sodium iodide, potassium iodide, potassium bromide, sodium bromide and the like; acids like p- toluene sulfonic acid and the like, phase transfer catalyst including quaternary ammonium salts like tetrabutylammonium bromide (TBAB) and the like, amines like 4-Dimethylaminopyridine (DMAP) and the like.
Preferably, the catalyst used in step (a) is quaternary ammonium salts like tetrabutylammonium bromide (TBAB).
Step (c) can be carried out on solid supports like, alumina but not limited to neutral alumina, basic alumina and the like, silica gel and the like, resin and the like. According to embodiment of the present invention, compound of formula (V) and (I) may be further converted into its pharmaceutically acceptable salts by treating with the suitable acid selected from organic acids or inorganic acids in presence of solvent.
The organic acids is selected from but not limited to maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanesulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, Cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, 8-halotheophylline; inorganic acids such as but not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid; preferably hydrobromic acid.
The solvent used for converting compound of formula (V) and (I) to its salt is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N- dimethylformamide, Ν,Ν-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ionic liquids; water or a mixture thereof. Preferably, the solvent used is alcohol, ester, ether, ketones, water or mixtures thereof. According to embodiment of the present invention, process for the preparation of vortioxetine (I) can be performed in a single pot by avoiding the isolation and purification of intermediates of compounds (IV) and (V) obtained in the steps (a), and (b) that improves the overall efficiency of a chemical process and reduces the burden of centrifugation, washing, drying and powder handling.
According to embodiment of the present invention, compound of formula (IV), (V), (I), and (la) may be further purified either by acid-base treatment, or solvent crystallization, or washing with solvent, or converting into its salts. The salts of formula (V) and (I) can be selected from organic salts like but not limited to maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylene salicylic, methanesulfonic, ethanesulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, 8-halotheophylline; and inorganic acjd such as but not limited to hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid.
According to another embodiment the present invention, there is provided a new method for preparation of vortioxetine (I) and its salt (la);
wherein the said process comprising;
e) reacting 1-halo (or l-pseudohalo)-2-nitrobenezene with piperazine in solvent in the presence of base and optionally in presence of catalyst to obtain o- nitrophen l piperazine;
Figure imgf000015_0001
piperazine orthonitrophenylpiperazine
Wherein X is -CI, -Br, -I, -F, -OTf, -OMs, -OTs etc. f) reacting o-nitrophenylpiperazine with 2,4-dimethylbenzenethiol in solvent in the presence of catalyst, and optionally in the presence of base to obtain vortioxetine (I) or its salt of formula (Ia);-
Figure imgf000016_0001
o-nit
g) optionally converting compound of formula (I) or (la) to the required acid addition salt (la), and optionally purifying required acid addition salt (la).
The solvent used in step (e) and (f) may be same or different; wherein the said solvent is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N- dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ionic liquids; water or a mixture thereof.
The step (e), (f) and (g) can be carried out at temperature range from aboutO°C to 180°C or the boiling points of solvents used. Usually the reaction may be carried out at temperature up to reflux temperature of the said solvent. The base used in step (e) and step (f) is selected from organic or inorganic base; organic bases selected from but not limited to l,8-diazabicyclo[5.4.0]undec-7-ene; l,5-diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2-propyl amine, butyl amine and the like; secondary amines such as but not limited to Ν,Ν-diisopropyl amine, dimethyl amine, diethyl amine, N-methyl propyl amine, morpholine and the like; tertiary amines such as but not limited to triethylamine, Ν,Ν-dimethyl aniline, Ν,Ν-diisopropyl ethyl amine, trimethyl amine and the like; inorganic bases selected from alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as but not limited to sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like; metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, potassium tert butoxide and the like.
The catalyst used in step (e) and (f) is selected from but not limited to copper, Cu- halide, Cu-halide-PPh3, palladium catalysts like Pd(OAc)2, Palladium-ligand, PTSA, crown ether, quaternary ammonium salts like tetrabutylammonium bromide (TBAB) and the like, amines like 4-Dimethylaminopyridine (DMAP) and the like.
According to embodiment of the present invention, process for the preparation of vortioxetine (I) can be performed in a single pot by avoiding the isolation and purification of intermediates of compounds (IV) and (V) obtained in the steps (a), and (b) that improves the overall efficiency of a chemical process and reduces the burden of centrifugation, washing, drying and powder handling. According to embodiment of the present invention, o-nitrophenylpiperazine, vortioxetine (I) and its salt (la) may be further converted into its pharmaceutically acceptable salts, and purified as per method mentioned in first embodiment.
According to yet another embodiment there is provided a new method for preparation of vortioxetine (I) and its pharmaceutically acceptable salts (la);
wherein the said process comprising;
h) reacting 2-[(2, 4-dimethylphenyl) thio] aniline (V) or its salt with compound (XIII) or its salt in solvent, in the presence of base and reagent and/or catalyst to obtain compound (XIV);
Figure imgf000018_0001
2-[(2,4-dimethylphenyl)thio]aniline Formula - XIV
Wherein; X is-OH, -O-alkyl, -O-aryl, -halogen etc.,
Y is -halogen, -OTf, -OMs, and -OTs etc., and
R is-H, -Boc, -Benzyl etc., i) reducing compound of formula-(XlV), in solvent in the presence of reducing agent to obtain vortioxetine (I) or its salt (la).
Figure imgf000018_0002
Formula - XIV Formula - 1 Formula - la The solvent used in step (h) and (i) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as N,N-dimethylformamide, Ν,Ν-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N- Methylpyrrolidinone and the like; nitriles such as aceton.itrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ionic liquids; water or a mixture thereof.
The base used in step (h) is selected from organic or inorganic base; the organic base is selected from but not limited to l,8-diazabicyclo[5.4.0]undec-7-ene; 1,5- diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2-propyl amine, butyl amine and the like; secondary amines such as but not limited to Ν,Ν-diisopropyl amine, dimethyl amine, diethyl amine, N-methyl propyl amine, morpholine and the like; tertiary amines such as but not limited to triethylamine, N,N-dimethyl aniline, Ν,Ν-diisopropyl -ethyl amine, trimethyl amine and the like; inorganic bases selected from alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as but not limited to sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like; metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, potassium tert butoxide and the like. The reagent used in steps (h) are selected from but not limited to borane reagents such as boric acid, phenyl boronic acid, trimethyl borate and the like;- carbodiimide reagents such as Ν,Ν'-dicyclohexylcarbodiimide (DCC) and l-ethyl-3-(3- dimethylaminoprpyl)carbodiimide (EDC) or its salt; or imidazole reagents such as Ι,Γ-carbonyldiimidazole (CDI) and the like, chlorinating reagents selected from but not limited to thionyl chloride, oxalyl chloride, cynuric chloride, phosphorus oxychloride and the like.
The catalyst used in step (h) of the present invention is selected from organic or inorganic catalyst or phase transfer catalyst.
The reduction step (i) can be carried out by using reducing agents such as but not limited to lithium aluminium hydride, sodium borohydride in presence of Iodine; or sodium borohydride in presence of acids, wherein acids are selected from but not limited sulfuric acid, acetic acid, trifluoroacetic acid, sodium borohydride and BF3etherate; diborane solutions like BH3:THF, BH3:SMe2, vitride, sodium acyloxyborohydrides, lithium aminoborohydrides, and the like.
According to another embodiment of the present invention, compound of formula (XIV), (I) and (la) may be further converted into its pharmaceutically acceptable salts, and purified as per method mentioned in first embodiment.
According to the invention there is provided a new compound having a formula
(XIV);
Figure imgf000020_0001
Formula - XIV Wherein R is -H, -BOC, -Benzyl, etc.is an intermediate of vortioxetine (I) or its salt (la).
A process for the preparation of new compound of formula (XIV) is described in the foregoing embodiment of the present invention.
According to yet another embodiment the present invention, there is provided new method for the preparation of vortioxetine (I) or its pharmaceutically acceptable salts (la);
wherein the said process comprising:
j) reacting 1 -halo (or l-pseudohalo)2-phenylpiperazine of formula (XV) or its acid addition salt with2, 4-dimethylbenzenethiol in a solvent and in the presence of base, and optionally in presence of catalyst to produce vortioxetine (I) or its salt (la);
Figure imgf000021_0001
Formula - XV 2,4-dimethylbenzenethiol
Wherein X is -CI, -Br, -I, -OTf, -OMs, -OTs etc.
R= -H, -Boc, -Benzyl etc.
The solvent used in step (j) is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as Ν,Ν-dimethylformamide, N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic . amides such as N- Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ionic liquids; water or a mixture thereof.
The base used in step (j) is selected from organic or inorganic base; the organic base is selected from but not limited to l,8-diazabicyclo[5.4.0]undec-7-ene; 1,5- diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2-propyl amine, butyl amine and the like; secondary amines such as but not limited to N,N-diisopropyl amine, dimethyl amine, diethyl amine, N-methyl propyl amine, morpholine and the like; tertiary amines such as but not limited to triethylamine, Ν,Ν-dimethyl aniline, Ν,Ν-diisopropyl ethyl amine, trimethyl amine and the like; inorganic bases selected from alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as but not limited to sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like; metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, potassium tert butoxide and the like.
The catalyst used in step (j) is selected from but not limited to copper, Cu-halide, Cu- halide-PPh3, palladium catalysts like Pd(OAc)2, Palladium-ligand, PTSA, crown ether, quaternary ammonium salts like tetrabutylammonium bromide (TBAB) and the like, amines like 4-Dimethylaminopyridine (DMAP) and the like. According to another embodiment of the present invention, compound of formula (XV), (I) and (la) may be further converted into its pharmaceutically acceptable salts, and purified as per method mentioned in first embodiment.
According to yet another embodiment of the present invention, the invention provides a novel crystalline form of vortioxetine hydrobromide, herein defined as Form Ml, characterized by PXRD peaks at 2-theta (Θ) = 4.50, 9.06, 1 1.84, 13.09, 14.22, 15.12, 15.96, 17.07, 18.15, 18.71, 19.90, 20.32, 21.28, 23.32, 23.62, 24.4, 24.93, 25.36, 27.06, 27.98 29.60, 32.53, 34.09, 35.30, 36.32±0.2 Θ, with characteristic peak being at about 4.50, 9.06, 1 1.84, 15.96, 17.07, 18.15, 18.71, 23.32, 23.62, 24.93, 25.36+ 0.2 Θ. Crystalline form of vortioxetine hydrobromide may also be characterized by PXRD pattern as depicted by Figure 3. The X-ray diffractogram was measured on Bruker Axe; DS advance Powder X-ray Diffractometer with Cu K alpha- 1 Radiation source having the wavelength 1.54 A°.
According to yet another embodiment of the present invention , the application provides a novel crystalline form of vortioxetine hydrobromide, herein defined as Form M2, characterized by PXRD peaks at 2-theta (Θ) = 3.79, 7.60, 11.41, 13.17, 13.60, 15.12, 16.61, 17.10, 17.57, 18.34, 19.10, 20.25, 22.76, 23.17, 24.23, 27.41, 28.53±0.2, with characteristic peak being at about 3.79, 11.41, 13.17, 13.60, 17.57, 18.34, 20.25, 23.17, 27.41, 28.53±0.2Θ. Crystalline form of vortioxetine hydrobromide may also be characterized by PXRD pattern as depicted by Figure 4. The X-ray diffractogram was measured on Bruker Axe, DS advance Powder X-ray Diffractometer with Cu K alpha- 1 Radiation source having the wavelength 1.54 A°.
The vortioxetine (I) or its salt (la) used in the preparation of form Ml and M2 may be obtained as per any of the above mentioned embodiment. Form Ml and M2 of vortioxetine hydrobromide may be prepared from vortioxetine free base (I) or from its salt (la).
Form Ml and M2 of vortioxetine hydrobromide may be prepared from alpha, beta, gamma, delta or any other polymorphic form.
According to yet another embodiment of the present invention, the application provides a crystalline form of 2,4-dimethyl-l-[(2-nitrophenyl)thio]benzene (IV), characterized by PXRD peaks at 2-theta (θ)=7.51, 13.76, 14.41, 15.04, 17.80, 18.13, 22.59, 24.18, 25.66, 27.72, 31.57±0.2Θ, with characteristic peak being at about 7.51, 13.76, 14.41, 15.04, 17.80, 18.13, 24.18, 25.66, 27.72±0.2Θ. Crystalline form of compound (IV) may also be characterized by PXRD pattern as depicted by Figure 1. The X-ray diffractogram was measured on Bruker Axe, DS advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source having the wavelength 1.54 A°.
According to yet another embodiment of the present invention, the application provides a crystalline form of 2-[(2,4-dimethylphenyl)thio]aniline) hydrochloride (HC1 salt of V), characterized by PXRD peaks at 2-theta (Θ) - 7.1 1, 9.12, 11.03, 14.30, 16.60, 16.86, 17.27, 18.81, 19.62, 19.80, 20.03, 21.50, 23.12, 23.62, 23.90, 24.36, 24.70, 25.72, 30.17, 31.36, 32.16±0.2, with characteristic peak being at about 7.1 1, 9.12, 11.03, 14.30, 16.86, 19.62,19.80, 23.12, 23.62, 23.90, 24.36, 25.72, 30.17±0.2Θ. Crystalline form of compound (V) may also be characterized by PXRD pattern as depicted by Figure 2. The X-ray diffractogram was measured on Bruker Axe; DS advance Powder X-ray Diffractometer with Cu K alpha-1 Radiation source having the wavelength 1.54 A°.
According to yet another embodiment of the present invention provides a compound (A), (B), (C), (D), (E) (F), (G), (H), (I), (J), (K), (L), (M), (N) and (O);
Figure imgf000025_0001
Compound - A Compound - B . Compound-C
Figure imgf000025_0002
Compound - Nl Compound- N Compound- O
According to the present invention vortioxetine (I) or its pharmaceutically acceptable salt (la) prepared by foregoing process, having less than about 0.2% of compound (A), has less than about 0.2% of compound (B), has less than about 0.2% of compound (C), having less than about 0.2% of compound (D), has less than about 0.2% of compound (E), has less than about 0.2% of compound (F), having less than about 0.2%) of compound (G), has less than about 0.2% of compound (H), has less than about 0.2% of compound (I), having less than about 0.2% of compound (J), has less than about 0.2% of compound (K), has less than about 0.2% of compound (L), haying less than about 0.2% of compound (M), has less than about 0.2% of compound (N), and has less than about 0.2% of compound (O) by HPLC.
BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
EXAMPLE - 1
Preparation of 2,4-dimethyl-l-[(2-nitrophenyl) thio] benzene (IV)
To the solution of 2,4-dimethylbenzenethiol (100.0 g; 0.7246 moles) and l-fluoro-2- nitrobenzene (102.0 g; 0.7246 moles)in THF (600mL) was added KOH (5% solution in water, 800mL)at room temperature, reaction mixture was stirred at room temperature for 12 h. Product was extracted in methylene dichloride (800mL), extract was dried, filtered and evaporated to give residue, residue was crystallized in n-heptane to get yellow crystalline solid of 2,4-dimethyl-l-[(2- nitrophenyl)thio]benzene. [Yield: 160.0 g (85.0%); Purity (HPLC) = 99.95%]
EXAMPLE - 2
Preparation of2-f(2,4-dimethylphenyl)thiolaniline (V)
2,4-dimethyl-l-[(2-nitrophenyl)thio]benzene (180 g; 0.6949 moles) in IPA (1500mL) was reduced using Ra/Ni (40 g) at 63±3 °C in autoclave under 5-7 kg of hydrogen pressure for 3-5 h, catalyst was filtered through celite bed, IPA was evaporated to obtain oil of 2-[(2,4-dimethylphenyl)thio]aniline.[Yield: 146.0 g (91.0%); Purity (HPLC) = 99.0%]
EXAMPLE - 3
Preparation of l-[2-(2, 4-dimethyl-phenylsulfanvD-phenvn-piperazine hydrochloridefVortioxetine Hydrochloride!
The solution of 2-[(2,4-dimethylphenyl)thio]aniline (100 g; 0.4347 moles) and bis- (2-chloroethyl)amine hydrochloride (77.6 g; 0.4347 moles) in n-butanol (500mL) was heated to reflux temperature for 24 h, cool the reaction mass to 70±2°C, anhydrous potassium carbonate (30 g; 0.2170 moles) was added and again heated the reaction mass to reflux temperature and maintained for 42 h, reaction mixture was filtered to remove undissolved solid, filtrate was evaporated to give syrup. The obtained syrup crystallized in acetone (500mL) at room temperature, solid was filtered and washed with acetone (lOOmL) to obtain white to off white colored crystalline solid of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloride (vortioxetine hydrochloride). [Yield: 70.0 g (53.8%); Purity (HPLC) = 99.0%]
EXAMPLE -
Preparation of l-[2-(2,4-dimethyI-phenylsulfanyl)-phenyll-piperazine (I)
To the mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine
hydrochloride (100 g; 0.2980 moles) and water (500mL),aqueous ammonia solution was added to adjust the pH to 8-9, reaction mixture was stirred for 1 h at room temperature, solid was filtered and washed with water (lOOmL) to obtain white to off white crystalline solid of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine (vortioxetine free base).[Yield: 85.0 g (95.5%)]
EXAMPLE - 5 Preparation of l-i2-(2,4-dimethyl-phenylsulfanyl)-phenyl1piperazine hydrobro mide (I)
To the mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine (100 g; 0.3344 moles) and ethyl acetate (500mL)was added aqueous hydrobromic acid at room temperature, pH of reaction mass adjusted to 1-3, obtained white solid was filtered and wash with ethyl acetate (lOOmL), dried the solid to obtain crystalline solid Of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (vortioxetine hydrobromide). [Yield: 100.0 g (79.3%); Purity (HPLC) = 99.5%]
EXAMPLE - 6
Preparation of beta polymorphic form of l-\2-(2, 4-Dimethyl-phenylsulfanvD- phenyll-piperazine hydrobromide (I)
To the mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine (100 g; 0.3344 moles) and acetone (500 mL) was added aqueous hydrobromic acid at room temperature, pH of reaction mass adjusted to 1-3, obtained white solid was filtered and washed with acetone (100 mL), dried the solid to obtain beta polymorphic formofl-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (Vortioxetine hydrobromide). [Yield: 100.0 g (79.3%); Purity (HPLC) = 99.9%]
EXAMPLE - 7
Preparation of beta polymorphic form of l-f2-(2, 4-dimethvl-phenylsulfanvD- phenyll-piperazine hydrobromide (I)
To the mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (100 g; 0.3344 moles) and methanol (500 mL) was added MTBE at room temperature to precipitate solid, filtered the solid and wash with MTBE (100 mL), dried the solid to obtain beta polymorphic form of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide (Vortioxetine hydrobromide). [Yield: 95.0 g (95.0%); Purity (HPLC) = 99.85%] EXAMPLE - 8
Preparation novel crystalline formMl of l-[2-(2, 4-dimethyl-phenylsulfanyl)- phenyll-piperazine hydrobromide (I)
l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (100 g; 0.3344 moles) was added in methylene dichloride (500 mL), mixture was heated to reflux temperature to get clear solution, methylene dichloride was dried under vacuum at 38±2°Coverrota-evaporator to obtain solid of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenylj-piperazine hydrobromide (Vortioxetine hydrobromide).
[Yield: 95.0 g (95.0%); Purity (HPLC) = 99.80%, melting point; 85-90°C]
EXAMPLE -9
Preparation of 2,4-dimethyl-l-[(2-nitrophenyI)thio1benzene (IV)
To the solution of 2,4-dimethylbenzenethiol (10 g; 0.07246 moles) and l-fluoro-2- nitrobenzene ( 10.2 g; 0.07246 ) in water (40mL), 5% aqueous KOH solution (80 mL) was added at room temperature, reaction mixture was stirred at room temperature for 12 h. n-heptane was added to the reaction mass, stirred for 30 minutes, solid was filtered and washed with n-heptane (50 mL) to get yellow crystalline solid of 2,4-dimethyl-l-[(2-nitrophenyl)thio]benzene. [Yield: 14.0 g (77.0%); Purity (HPLC) = 99.9%]
EXAMPLE -11
Preparation of 2,4-dimethyl-l-[(2-nitrophenyl)thiolbenzene (IV)
To the solution of 2,4-dimethylbenzenethiol (100 g;0.7246 moles), l-fluoro-2- nitrobenzene (102 g; 0.7246 moles) and tetrabutylammonium bromide (4g) in water (600.0 ml) was added 5% aqueous KOH solution (800mL) at room temperature, reaction mixture was stirred at room temperature for 10 h, and n-heptane was added to the stirred reaction mass. Solid was filtered and washed with n-heptane (100 mL) to get yellow crystalline solid of 2,4-dimethyl-l-[(2-nitrophehyl)thio]benzene. [Yield: 180.0 g (96.0%); Purity (HPLC) = 99.63%]
EXAMPLE -12
Preparation of novel crystalline form Ml of l-[2-(2, 4-Dimethyl- phenylsulfanvD-phenyll-piperazine hvdrobromide (I)
l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (10 g; 0.0334 moles)was dissolved in mixture of methanol and methylene dichloride in the ratio of 8:2 at room temperature to obtained clear solution. The obtained clear solution spray dried using spray dryer to obtain novel form (Ml) of l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide (Vortioxetine hydrobromide). [Yield: 7.50 g (75.0%); Purity (HPLC) = 99.80%]
EXAMPLE -13
Preparation of novel crystalline form M2 of l-[2-(2, 4-Dimethyl- phenylsulfanvD-phenyll-piperazine hvdrobromide (I)
l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloride (5.0 g) prepared as per example no 3 was heated in water (100.0 mL) to 83±2°C, maintained till turbid solution observed. One drop of aqueous hydrobromic acid was added to obtain clear solution. Aqueous hydrobromic acid' was added till turbid solution was observed, solution was cooled to room temperature, maintained at room temperature for 30-45 min. solid was filtered, washed with water and dried under vacuum at 53±2°C to obtain novel form (M2) of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]- piperazine hydrobromide (Vortioxetine hydrobromide).
[Yield: 3.5 g (70.0%); Purity (HPLC) = 99.80%]
EXAMPLE - 14
Preparation of l-[2-(2, 4-Dimethyl-phenylsulfanyl)-phenyll-piperazine (I)
Mixture of 2-[(2,4-dimethylphenyl)thio]aniline (10 g; 0.0434 moles), b'is-(2- chloroethyl)amine hydrochloride (15.5g; 0.0868 moles) and basic alumina (lOOg) was heated 140±2°Cfor 5-10 h, cooled the mixture to room temperature and methylene dichloride (500 ml) was added, stirred the mixture and filtered to separate the inorganic solid. Evaporated the methylene dichloride to obtain l-[2-(2, 4- dimethyl-phenylsulfanyl)-phenyl]-piperazine (I) (Vortioxetine free base).
[Yield: 5.0 g (34.24%)]
EXAMPLE - 15
Preparation of 2-f(2, 4-dimethylphenyI) thiol aniline hydrochloride
To the stirred solution of 2-[(2,4-dimethylphenyl)thio]aniline (V) benzene (25.0 g) (prepared as per example-2) in ethyl acetate (150.0 ml), aqueous solution of hydrochloric acid was added to adjust the pH in the range of 1-3, precipitated solid was filtered, washed with ethyl acetate (10 ml) and dried to obtain crystalline solid of 2-[(2, 4-dimethylphenyl) thio] aniline hydrochloride. [Yield: 25.0 g (84.7%); Purity (HPLC) - 99.05%]
EXAMPLE -16
Preparation of 2, 4-dimethyl-l-f(2-nitrophenyi) thiol benzene (IV)
To the solution of 2,4-dimethylbenzenethiol (50 g; 0.3615 moles), l-chloro-2- nitrobenzene ( 57 g; 0.3615 moles ) and TBAB (2 g) in water (400mL), was added 5% aqueous KOH solution (800 mL) at room temperature, reaction mixture was stirred at room temperature for 12 h. n-heptane was added to the reaction mass, stirred for 30 minutes, solid was filtered and washed with n-heptane (50 mL) to get yellow crystalline solid of 2,4-dimethyl-l -[(2-nitrophenyl)thio]benzene.
[Yield: 85.0 g (90.0%); Purity (HPLC) = 99.6%]
EXAMPLE -17
Purification of l-[2-(2, 4-dimethyl-phenylsulfanyl)-phenyll-piperazine hydrochloride (IV l-[2-(2, 4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloride (10 g) was added to the mixture of isopropanol (100 mL) and water (20 mL), resulting mixture heated to 83±2°C and maintained till clear solution was observed, cooled the mixture to 28±2°C and maintained for 1-2 h, solid was filtered and washed with isopropanol (20 mL), solid was dried to get crystalline solid of l-[2-(2, 4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrochloride. [Yield: 9.0 g (90.0%); Purity (HPLC) = 99.9%]
EXAMPLE -18
Preparation of 2, 4-dimethyl-l-[(2-nitrophenvD thiol benzene (IV)
To the mixture of 2,4-dimethylbenzenethiol (100 g; 0.7234 moles), l-chloro-2- nitrobenzene (1 14 g; 0.7236 moles ) and TBAB (1 g) in water (250 mL) was added aqueous NaOH solution (36.2 g, 0.905 moles of NaOH in 250 mL of water) at 25-35 °C, and stirred for 6 h, after completion of reaction n-heptane (200 mL) was added to the reaction mass,. stirred for 30 minutes, solid was filtered and washed with n-heptane (200 mL) to get yellow crystalline solid of 2,4-dimethyl-l-[(2- nitrophenyl)thio]benzene. [Yield: 175.0 g (93.5%); Purity (HPLC) = 99.6%]
EXAMPLE -19
Preparation of 2, 4-dimethvI-l-f(2-nitrophenvD thiol benzene (IV)
To the mixture of 2,4-dimethylbenzenethiol (10 g; 0.0723 moles), l-chloro-2- nitrobenzene ( 1 1.4 g; 0.0723 moles ) and TBAB (0.5 g) in water (50 mL) was added aqueous ammonia (10 mL) at 25-35 °C, and stirred for 6 h. after completion of reaction n-heptane (20 mL) was added to the reaction mass, stirred for 30 minutes, solid was filtered and washed with n-heptane (10 mL) to get yellow crystalline solid of 2,4-dimethyl-l-[(2-nitrophenyl)thio]benzene.
[Yield: 15.0 g (79.95%); Purity (HPLC) = 99.2%]
EXAMPLE -20 Purification of 2, 4-dimethyl-l-f(2-nitrophenyl) thiol benzene (IV)
The mixture of 2, 4-dimethyl-l-[(2-nitrophenyl) thio] benzene (100 g), n-heptane (500 mL) and water (500 mL) was stirred at 35-40 °C for 1 h, solid was filtered and washed with n-heptane (50 mL) to get highly pure yellow crystalline solid of 2,4- dimethyl-l-[(2-nitrophenyl)thio]benzene.
[Yield: 98.0 g (98.0%); Purity (HPLC) = 99.9%]
EXAMPLE - 21
Preparation of 2-[(2,4-dimethylphenyl)thio1aniline (V)
2,4-dimethyl-l-[(2-nitrophenyl)thio]benzene (100 g; 0.3856 moles) in IPA (500 mL) was reduced using Ra/Ni (10 g) at 30-35 °C in autoclave under 5-7 kg of hydrogen pressure, catalyst was filtered through celite bed, filtrate was concentrated to obtain oil of 2-[(2,4-dimethylphenyl)thio]aniline (V).
[Yield: 85.0 g (96.1%); Purity (HPLC) = 99.0%]
EXAMPLE - 22
Preparation of l-[2-(2, 4-Dimethyl-phenylsulfanyl)-phenvn-piperazine [Vortioxetine (1)1
2,4-dimethyl-l-[(2-nitrophenyl)thio]benzene (IV) (100 g; 0.3856 moles) in IPA (500 mL) was reduced using Ra/Ni (10 g) at 30-35 °C in autoclave under 5-7 kg of hydrogen pressure, catalyst was filtered through celite bed, filtrate was concentrated to obtain oil of 2-[(2,4-dimethylphenyl)thio]aniline (V).
To the obtained oil of (V), n-butanol (100 mL) and bis-(2-chloroethyl)amine hydrochloride (VI) (103.5 g; 0.5797 moles) was added, continuous flow of nitrogen gas was adjusted during heating and reaction mass was maintained at 1 12-1 16 °C, second lot of n-butanol (50 mL) was added after 50 h of maintaince, again maintained the reaction mass at same temperature for another 50 h. Temperature of reaction mass was lowered to 100 °C, third lot of n-butanol (50 mL) was added, reaction mass was further cooled to 35-55 °C and ethyl acetate (1000 mL) was added. The obtained slurry was cooled to 25-35 °C and then was aged for 2 h, solid was filtered and washed with ethyl acetate (200 mL) to obtain l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrochloride (la).
The obtained 1 -[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloride (la) and water (1000 mL) was heated to 80-85 °C to get clear solution, the solution was cooled to 25-30 °C and agitated for 2 h, solid was filtered, washed with water (200 mL) and dried under vacuum at 55-60 °C for 5 h to obtain l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine hydrochloride (la) free from unreacted bis-(2- chloroethyl)amine hydrochloride.
The mixture of l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloride (la), isopropanol (100 mL) and water (20 mL) was heated to 80-85 °C to get clear solution, solution was cooled to 55-60 °C and ethyl acetate was added, the mixture was further cooled to 25-30 °C and aged for 2 h, , solid was filtered and washed with ethyl acetate to obtain pure crystalline solid of l-[2-(2,4-dimethyl-phenylsulfanyl)- phenyl]-piperazine hydrochloride (la).
To the solution of pure l-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrochloride (la) in methanol (600 mL), 10% aqueous solution of sodium hydroxide (150 mL) was added at 25-30 °C, mixture was heated to 45-50 °C and filtered to get clear solution, to this clear solution water (500 mL) was added, Obtained slurry was cooled to 15-20 °C and aged for 2 h. Solid was filtered, washed with water (200 mL) and dried to obtain highly pure l-[2-(2,4-dimethyl- phenylsulfanyl)-phenyl]-piperazine (I). [Yield: 100 g (86.9%) Purity (HPLC) = 99.9%] EXAMPLE - 23
Preparation of l-f2-(2,4-Dimethyl-phenylsulfanyl)-phenyll-piperazine hydrobromide (la)
The mixture of l-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine (100 g; 0.3350 moles) and methanol (500 mL) was heated to 45-50 °C and filtered to get clear solution, the solution was cooled to 20-25 °C, aqueous hydrobromic acid (47 mL) was added, slurry was cooled to 15-20 °C and stirred for 2 h. Solid was filtered, washed with methanol (100 mL) and dried to obtain crystalline l-[2-(2,4-Dirnethyl- phenylsulfanyl)-phenyl]-piperazine hydrobromide (vortioxetine hydrobromide). [Yield: 105.0 g (82.6%); Purity (HPLC) = 99.9%]
EXAMPLE -24
Purification of l-f2-(2, 4-Dimethyl-phenylsulfanvD-phenvU-piperazine hydrobromide (la)
The mixture of l-[2-(2, 4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (10 g; 0.0264) and methanol (100 mL) was heated to 60 °C to get clear solution, solution was filtered, the filtrate was cooled to 20-25 °C and maintained for 1 h, obtained solid was filtered, washed with methanol (10 mL) and dried to obtain pure l-[2-(2, 4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide. [Yield: 9.0 g (90.0%); Purity (HPLC) = 99.9%]
EXAMPLE -25
Preparation of l-[2-(2, 4-DimethvI-phenylsulfanvD-phenyll-piperazine (I)
To the mixture of l-[2-(2, 4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (10 g; 0.0264) and methanol (200 mL), 10% aqueous solution of sodium hydroxide (10 mL) was added. The mixture was heated to 60 °C, filtered to get clear solution, to the obtained solution, water (50 mL) was added at 20-25 °C and stirred for 1 h. Solid was filtered, washed with methanol (10 mL) and dried to obtain pure crystalline solid of l-[2-(2, 4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine (I). [Yield: 7.0 g (90.0%); Purity (HPLC) = 99.9%]
EXAMPLE -26
Preparation of novel crystalline form Ml of l-[2-(2, 4-Dimethyl- phenylsulfanvO-phenyll-piperazine hydrobromide (la)
l-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide (10 g; 0.0264 moles) was dissolved in methylene dichloride (100 mL) at room temperature to obtained clear solution. The obtained clear solution spray dried using spray dryer to obtain Ml crystalline form of l-[2-(2,4-Dimethyl-phenylsulfanyl)-phenyl]- piperazine hydrobromide (Vortioxetine hydrobromide).
[Yield: 7.50 g (75.0%); Purity (HPLC) = 99.80%]

Claims

We claim:
1. A process for preparation of Vortioxetine of formula (I) or its acid addition salt thereof, comprising:
a) reacting l-halo-2 -nitrobenzene with 2,4-dimethylbenzenethiol in a solvent, a base and optionally in presence of a catalyst to obtain 2,4-dimethyl-l-[(2-
Figure imgf000037_0001
2,4-dimethylbenzenethiol 2,4-dimethyl-1-[(2-nitrophenyl)thio]benzene wherein X is -CI, -Br, -I, or -F.
b) reducing 2,4-dimethyl-l-[(2-nitrophenyl)thio]benzene compound (IV) to 2-[(2,4- dimethylphenyl)thio]aniline compound (V) in a solvent in presence of a reducing
Figure imgf000037_0002
io]aniline
c) reacting 2-[(2,4-dimethylphenyl)thio] aniline compound (V) or its salt with dialkyl amine compound (VI) or its acid addition salt in a solvent, a base to obtain vortioxetine (I) or its salt (la) and optionally purifying vortioxetine (I) or its salt (la); and
Figure imgf000038_0001
2-[(2,4-dimethylphenyl)thio]aniline Formula-I Formula-la wherein Y is -CI, -Br, or -I. d) optionally converting compound of formula (I) or its salt (la) to a required acid addition salt and optionally purifying required vortioxetine acid addition salt (la).
2. The process as claimed in claim 1, wherein the catalyst used in step (a) is selected from metal halides such as sodium iodide, potassium iodide, potassium bromide, sodium bromide, p-toluene sulfonic acid, phase transfer catalyst like quaternary ammonium salts such as tetra-butyl ammonium bromide (TBAB), or amines such as 47dimethylaminopyridine (DMAP); and the catalyst used in step (b) is selected from palladium-carbon, palladium hydroxide-carbon, platinum oxide, rhodium on carbon, Raney nickel, nickel chloride, charcoal, or graphite.
3. The process as claimed in claim 1, wherein the solvent used in steps (a), (b), (c) and (d) is either same or different and is selected from alcohols such as methanol, ethanol, isopropanol, n-butanol and mono ethylene glycol; aromatic hydrocarbons such as toluene, xylene and mesitylene; aliphatic hydrocarbons such as hexane and heptane; halogenated hydrocarbon such as dichloromethane, dichloroethane, chlorobenzene and dichlorobenzene; formamide such as N,N- dimethylformamide and Ν,Ν-dimethylacetamide; sulfoxides such as dimethylsulfoxide; cyclic amides such as N-Methylpyrrolidinone; nitriles such as acetonitrile; ketones such as acetone and methyl isobutyl ketone; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert:butyl ether and diglyme; esters such as ethyl acetate, methyl acetate and isopropyl acetate; ionic liquids; water or mixture thereof.
4. The process as claimed in claim 1, wherein the base used in step (a) and (c) is selected from organic or inorganic base; organic bases selected from 1,8- diazabicyclo[5.4.0]undec-7-ene; l,5-diazabicyclo[4.3.0]non-5-ene; primary amines such as methylamine, propyl amine, 2-propyl amine and butyl amine; secondary amines such as Ν,Ν-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, and morpholine; tertiary amines such as triethylamine, Ν,Ν-dimethyl aniline, N,N-di isopropyl ethyl amine, and trimethyl amine; inorganic bases selected from alkali metal carbonates such as potassium carbonate, sodium carbonate, and cesium carbonate; alkali metal bicarbonates such as sodium bicarbonate-and potassium bicarbonate; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide; metal alkoxides such as sodium methoxide, sodium ethoxide and potassium tert butoxide.
5. The process as claimed in claim 1 , wherein the reducing agent used in step (b) is hydrogen gas or hydrogen generating source such as ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid, hydrazinium monoformate, sodium borohydride, lithium aluminium hydride.
6. The process as claimed in claim 1, wherein step (c) can also be carried out in a solvent and with continuous flow of inert gas, wherein the inert gas is selected from nitrogen or argon.
7. The process as claimed in claim 1, wherein the acid used for preparation of acid addition salts of vortioxetine (I) in step (d) is selected from maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanesulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, Cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p- aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, 8- halotheophylline, hydrochloric acid, hydrobromic acid, nitric acid or sulfuric acid.
8. The process as claimed in any of the preceding claims wherein compound of formula (V) and (I) is further converted into its pharmaceutically acceptable salts by treatment with an acid in a suitable solvent.
9. The process as claimed in claim 8, wherein acid is selected from organic acids selected from maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis- methylenesalicylic, methanesulfonic, ethanesulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, Cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene sulfonic and theophylline acetic acids, 8-halotheophyllineor inorganic acids, or wherein inorganic acids is selected from hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid.
10. Crystalline vortioxetine hydrobromide Form Ml characterized by an x-ray diffraction pattern (XRD) as shown in FIG. 3.
1 1. A process for preparation of crystalline vortioxetine hydrobromide Form Ml, comprises the steps of:
a) dissolving vortioxetine hydrobromide in a mixture of methanol and methylene dichloride; and b) subjecting the resulting solution to spray drying to obtain crystalline vortioxetine hydrobromide Form ML
12. The process as claimed in any of the preceding claims, wherein vortioxetine (I) or its pharmaceutically acceptable salt (la), has less than about 0.2% of compound (A), has less than about 0.2% of compound (B), has less than about 0.2% of compound (C), having less than about 0.2% of compound (D), has less than about 0.2% of compound (E), has less than about 0.2% of compound (F), having less than about 0.2% of compound (G), has less than about 0.2% of compound (H), has less than about 0.2% of compound (I), having less than about 0.2% of compound (J), has less than about 0.2% of compound (K), has less than about 0.2% of compound (L), having less than about 0.2% of compound (M), has less than about 0.2% of compound (N), and has less than about 0.2% of compound (O) by HPLC.
Figure imgf000041_0001
ompoun - Compound - E ompoun -
Figure imgf000042_0001
41
PCT/IN2015/000414 2014-11-17 2015-11-10 A process for preparation of vortioxetine and polymorphs thereof WO2016079751A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN3612/MUM/2014 2014-11-17
IN3612MU2014 2014-11-17

Publications (2)

Publication Number Publication Date
WO2016079751A2 true WO2016079751A2 (en) 2016-05-26
WO2016079751A3 WO2016079751A3 (en) 2016-07-14

Family

ID=55305032

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2015/000414 WO2016079751A2 (en) 2014-11-17 2015-11-10 A process for preparation of vortioxetine and polymorphs thereof

Country Status (1)

Country Link
WO (1) WO2016079751A2 (en)

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106349132A (en) * 2016-08-30 2017-01-25 重庆植恩药业有限公司 Vortioxetine intermediate impurities and preparing method and use thereof
CN106518807A (en) * 2016-09-17 2017-03-22 北京万全德众医药生物技术有限公司 Preparation method of lactic acid vortioxetine crystal form
WO2017154016A1 (en) * 2016-03-07 2017-09-14 Msn Laboratories Private Limited Novel crystalline polymorphs of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and process for preparation thereof
WO2017215636A1 (en) * 2016-06-16 2017-12-21 广东东阳光药业有限公司 Diaryl sulphide piperazine compound and preparation method and use thereof
CN107843656A (en) * 2016-09-21 2018-03-27 成都弘达药业有限公司 A kind of detection method of 2,4 thiophenol dimethyl benzene about material
CN107915694A (en) * 2016-10-09 2018-04-17 北京阜康仁生物制药科技有限公司 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof
CN107954947A (en) * 2016-10-14 2018-04-24 北京莱瑞森医药科技有限公司 Vortioxetine hydrobromate crystal form C and preparation method thereof
CN108017595A (en) * 2017-12-20 2018-05-11 安徽源久源科技有限公司 A kind of preparation method of 1- [2- (2,5- dimethyl benzenes sulfenyl) phenyl] piperazine
WO2018154451A1 (en) * 2017-02-23 2018-08-30 Unichem Laboratories Ltd An improved process for preparation and purification of vortioxetine hydrobromide
CN108929287A (en) * 2017-05-26 2018-12-04 万全万特制药江苏有限公司 The purification of Vortioxetine
KR20190005679A (en) 2017-07-07 2019-01-16 영진약품 주식회사 Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same
US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts
CN110790727A (en) * 2019-09-30 2020-02-14 杭州和康药业有限公司 Preparation method of vortioxetine hydrobromide α type crystal
WO2021115372A1 (en) * 2019-12-10 2021-06-17 江苏恩华药业股份有限公司 Vortioxetine prodrug and use thereof
CN115160258A (en) * 2022-06-24 2022-10-11 辰欣药业股份有限公司 Preparation method of vortioxetine hydrobromide gamma crystal form
CN115181077A (en) * 2022-07-27 2022-10-14 安徽峆一药业股份有限公司 Synthetic method of vortioxetine with low impurity content
CN115894314A (en) * 2022-12-20 2023-04-04 苏州敬业医药化工有限公司 Preparation process of 2' -amino- (2,4-dimethyl) diphenyl sulfide

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7144884B2 (en) 2001-10-04 2006-12-05 H. Lundbeck A/S Phenyl-piperazine derivatives as serotonin reuptake inhibitors
WO2013102573A1 (en) 2012-01-03 2013-07-11 H. Lundbeck A/S Process for the manufacture of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine
US8598348B2 (en) 2009-02-17 2013-12-03 H. Lundbeck A/S Purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014161976A1 (en) * 2013-04-04 2014-10-09 Lek Pharmaceuticals D.D. New process for the synthesis of 1-(2-((2,4-dimethylphenyl)thio)phenyl)piperazine
CN104628676A (en) * 2013-11-08 2015-05-20 上海医药工业研究院 Preparation method of Vortioxetine
CN103788019B (en) * 2014-01-22 2015-10-07 苏州明锐医药科技有限公司 The fertile preparation method for Xi Ting
CN103788020B (en) * 2014-01-22 2015-11-04 苏州明锐医药科技有限公司 The fertile preparation method for Xi Ting
CN106103418A (en) * 2014-01-31 2016-11-09 埃吉斯药物私人有限公司 The fertile preparation method for western spit of fland salt
CN103936694A (en) * 2014-04-23 2014-07-23 中国药科大学 Preparation method of antidepressant vortioxetine
WO2015166379A2 (en) * 2014-04-28 2015-11-05 Alembic Pharmaceuticals Limited Novel polymorphic forms of vortioxetine and its pharmaceutically acceptable salts
CZ2014471A3 (en) * 2014-07-08 2016-01-20 Zentiva, K.S. Process for preparing vortioxetine
CN104230852B (en) * 2014-08-29 2017-03-29 桑迪亚医药技术（上海）有限责任公司 The fertile synthetic method for Xi Ting

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7144884B2 (en) 2001-10-04 2006-12-05 H. Lundbeck A/S Phenyl-piperazine derivatives as serotonin reuptake inhibitors
US8476279B2 (en) 2001-10-04 2013-07-02 H. Lundbeck A/S Phenyl-piperazine derivatives as serotonin reuptake inhibitors
US8598348B2 (en) 2009-02-17 2013-12-03 H. Lundbeck A/S Purification of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine
WO2013102573A1 (en) 2012-01-03 2013-07-11 H. Lundbeck A/S Process for the manufacture of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine

Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017154016A1 (en) * 2016-03-07 2017-09-14 Msn Laboratories Private Limited Novel crystalline polymorphs of 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine hydrobromide and process for preparation thereof
US10927089B2 (en) 2016-06-16 2021-02-23 Sunshine Lake Pharma Co., Ltd. Diaryl thioether piperazine compounds, preparation methods and uses thereof
WO2017215636A1 (en) * 2016-06-16 2017-12-21 广东东阳光药业有限公司 Diaryl sulphide piperazine compound and preparation method and use thereof
JP2019525900A (en) * 2016-06-16 2019-09-12 サンシャイン・レイク・ファーマ・カンパニー・リミテッドＳｕｎｓｈｉｎｅ Ｌａｋｅ Ｐｈａｒｍａ Ｃｏ．，Ｌｔｄ． Diarylthioether piperazine compounds, their preparation and use
CN109311833A (en) * 2016-06-16 2019-02-05 广东东阳光药业有限公司 Diaryl sulfide piperazine compounds and its preparation method and application
CN106349132A (en) * 2016-08-30 2017-01-25 重庆植恩药业有限公司 Vortioxetine intermediate impurities and preparing method and use thereof
CN106349132B (en) * 2016-08-30 2018-02-02 重庆植恩药业有限公司 Vortioxetine intermediate impurities and its production and use
CN106518807A (en) * 2016-09-17 2017-03-22 北京万全德众医药生物技术有限公司 Preparation method of lactic acid vortioxetine crystal form
CN107843656A (en) * 2016-09-21 2018-03-27 成都弘达药业有限公司 A kind of detection method of 2,4 thiophenol dimethyl benzene about material
CN107915694A (en) * 2016-10-09 2018-04-17 北京阜康仁生物制药科技有限公司 1 [2 (2,4 3,5-dimethylphenyl sulfydryl) phenyl] piperazine hydrochloride and preparation method thereof
CN107954947A (en) * 2016-10-14 2018-04-24 北京莱瑞森医药科技有限公司 Vortioxetine hydrobromate crystal form C and preparation method thereof
US10519121B2 (en) 2016-12-30 2019-12-31 Apicore Us Llc Process and novel polymorphic form of vortioxetine and its pharmaceutically acceptable salts
WO2018154451A1 (en) * 2017-02-23 2018-08-30 Unichem Laboratories Ltd An improved process for preparation and purification of vortioxetine hydrobromide
US10836730B2 (en) 2017-02-23 2020-11-17 Unichem Laboratories Ltd. Process for preparation and purification of vortioxetine hydrobromide
US20200010429A1 (en) * 2017-02-23 2020-01-09 Unichem Laboratories Ltd An improved process for preparation and purification of vortioxetine hydrobromide
CN108929287A (en) * 2017-05-26 2018-12-04 万全万特制药江苏有限公司 The purification of Vortioxetine
KR20190005679A (en) 2017-07-07 2019-01-16 영진약품 주식회사 Novel 1-[2-(2,4-Dimethylphenylsulfanyl)phenyl]piperazine salt and method for preparing the same
CN108017595A (en) * 2017-12-20 2018-05-11 安徽源久源科技有限公司 A kind of preparation method of 1- [2- (2,5- dimethyl benzenes sulfenyl) phenyl] piperazine
CN110790727A (en) * 2019-09-30 2020-02-14 杭州和康药业有限公司 Preparation method of vortioxetine hydrobromide α type crystal
WO2021115372A1 (en) * 2019-12-10 2021-06-17 江苏恩华药业股份有限公司 Vortioxetine prodrug and use thereof
CN114728920A (en) * 2019-12-10 2022-07-08 苏州恩华生物医药科技有限公司 Vortioxetine prodrug and application thereof
CN114728920B (en) * 2019-12-10 2023-07-21 苏州恩华生物医药科技有限公司 Vortioxetine prodrug and application thereof
CN115160258A (en) * 2022-06-24 2022-10-11 辰欣药业股份有限公司 Preparation method of vortioxetine hydrobromide gamma crystal form
CN115160258B (en) * 2022-06-24 2023-11-17 辰欣药业股份有限公司 Preparation method of vortioxetine hydrobromide gamma crystal form
CN115181077A (en) * 2022-07-27 2022-10-14 安徽峆一药业股份有限公司 Synthetic method of vortioxetine with low impurity content
CN115181077B (en) * 2022-07-27 2024-03-29 安徽峆一药业股份有限公司 Synthesis method of vortioxetine with low impurity content
CN115894314A (en) * 2022-12-20 2023-04-04 苏州敬业医药化工有限公司 Preparation process of 2' -amino- (2,4-dimethyl) diphenyl sulfide

Also Published As

Publication number Publication date
WO2016079751A3 (en) 2016-07-14

Similar Documents

Publication Publication Date Title
WO2016079751A2 (en) A process for preparation of vortioxetine and polymorphs thereof
US8871942B2 (en) Process for producing 1-triazole-2-butanol derivatives
US8877931B2 (en) Process and intermediates for preparing integrase inhibitors
WO2015044965A1 (en) A process for preparation of mirabegron and alpha crystalline form thereof
US10836730B2 (en) Process for preparation and purification of vortioxetine hydrobromide
JP6873053B2 (en) Method for Producing Protein Deacetylation Inhibitor
JPS6214540B2 (en)
WO2016125191A2 (en) Processes for the preparation of vortioxetine hydrobromide
MX2015004764A (en) Compounds useful in the synthesis of benzamide compounds.
KR102396059B1 (en) Novel compound and method for preparing same
JP4953822B2 (en) Method for producing muscarinic receptor antagonist and intermediate thereof
EP2070899A1 (en) Deprotection of N-BOC compounds
CA2930089C (en) Fingolimod hydrochloride process
JPH0510354B2 (en)
KR100850558B1 (en) Process for preparing useful in synthesis of atorvastatin
CN113493385B (en) Method for synthesizing butenafine hydrochloride
AU2009356897A1 (en) Process for the preparation of O-desmethyl-venlafaxine and salts thereof
EP1918276A1 (en) Production method of optically active 2- [ (N-Benzylprolyl) Amino ] Benzophenone compound
US20120259116A1 (en) Novel Process for the Preparation of Paliperidone
CA2507587A1 (en) Process for preparing terbinafine by using platinum as catalyst
WO2022241188A1 (en) Enantioselective synthesis of aminotropane compound
WO2024023012A1 (en) Process for preparation of 2-chloro-3-fluoro-4-alkoxy-anilines and 2-fluoro-3-chlorophenol
JP2003113153A (en) METHOD FOR PRODUCING beta-OXONITRILE DERIVATIVE OR ALKALI METAL SALT THEREOF
CN113880773A (en) Preparation method of oxalagogri intermediate
US20140228582A1 (en) Process for preparation of zolmitriptan

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 15832699

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15832699

Country of ref document: EP

Kind code of ref document: A2