DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of vortioxetine and pharmaceutically acceptable salts. More particularly, the present invention relates to a preparation and purification process of vortioxetine hydrobromide which is substantially free from impurities.
BACKGROUND OF THE INVENTION
Vortioxetine, namely 1-[2-(2,4-dimethyl-phenylsulfanyl)-phenyl]-piperazine of formula I, is an atypical anti-depressant.

Formula I
It exerts serotonin reuptake inhibition activity combined with an activity on the serotonin receptor 1A (5-HT1a) and the serotonin receptor 3 (5-HT3). Vortioxetine has been approved as hydrobromide salt and is present in the market under the trade name trintellix.
Vortioxetine and its pharmaceutically acceptable salts have been first time disclosed in the US patent 7,144,884 (refer as US’884). The patent describes several synthetic routes for preparing vortioxetine. One of the synthetic routes described in US’ 884 patent, ortho-fluoronitrobenzene and 2,4-dimethyl thiophenol are used as raw materials to synthesize vortioxetine. These intermediates are reacted to form an intermediate 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene. Then the said nitro intermediate has undergone catalytic hydrogenation using palladium/carbon to obtain 2-[(2,4-dimethylphenyl)sulfanyl]aniline. Finally, this amino intermediate is reacted either with bis(2-bromoethyl)amine or bis(2-chloroethyl)amine to obtain the vortioxetine. The process is depicted below:

In the above-mentioned route, the major drawback of this patent is that it does not provide any specific reaction conditions by examples for said process. Moreover, the preparation of vortioxetine and its salts has been exemplified using another process and that too involves use of chromatographic techniques for the purification of vortioxetine which is cumbersome and tedious method for purification to use on an industrial scale.
Another US patent 9,493,409 describes a process for the preparation of vortioxetine consisting of reacting 2-[(2,4-dimethylphenyl)sulfanyl]aniline with bis (2-chloroethyl)amine hydrochloride in the presence of diethylene glycol methyl ether at temperature of 130-160°C for 3 days to provide the product as vortioxetine hydrochloride which is converted to vortioxetine free base by using sodium hydroxide in methyltetrahydrofuran (MeTHF). Thereafter, vortioxetine is treated with 48% hydrobromide in the presence of isopropyl acetate to provide vortioxetine hydrobromide as white powder. However, the process suffers several disadvantages such as poor yield and utilization of longer reaction time i.e., 3 days at 130°C which bounds its industrial perspective. Moreover, it is also silent about the purity of vortioxetine hydrobromide.
An article, namely, Synthesis 2015, 47, 1387-1389, also discloses a process for the preparation of vortioxetine hydrobromide. In the process, cyclization of 2-[(2,4-dimethylphenyl)sulfanyl]aniline with bis(2-chloroethyl)amine hydrochloride is carried out in the presence of 1,2- dichlorobenzene at temperature of 160-170°C for 3-4 hours. After cooling at room temperature, 40% hydrobromic acid is added to the reaction solution to give the final product vortioxetine hydrobromide. In the possession of present inventors, when same process is repeated, it has been observed that at high temperature at 160-170°C, the material turns black and gets charred, need purifications which affects the purity as well as yield of the final product and makes the process uneconomical and industrially unviable.
Another US patent 8,722,684 describes crystalline vortioxetine base and a variety of crystalline salts thereof, comprising vortioxetine hydrobromide. Specifically, examples 4a to 4i of this patent disclose multiple crystalline forms of vortioxetine hydrobromide including a Form, ß Form, ? Form, a hemihydrate, and an ethyl acetate solvate. These crystalline forms are difficult to make in a consistent manner since the production processes are especially critical and sensitive wherein the single crystalline forms are only obtained in pure Form by using same solvent in a quite narrow range of critical parameters i.e., crystallization temperature, the concentration, and the stirring time.
Another US patent 8,598,348 describes a process for the manufacture of vortioxetine hydrobromide by dissolving vortioxetine hydrobromide isopropanol solvate in a non-solvate forming solvent, followed by precipitation. The process is not an attractive option, as it involves an additional step of solvate formation and desolvation.
Another US patent 10,836,730 describes a purification of vortioxetine hydrobromide by using a mixture of 2-butanol and water, wherein a ratio of 2-butanol to water is selected from the group consisting of 1:1, 1:0.75, 1:0.5, 1:0.25 and 1:0.1.
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
In most of the above-mentioned prior arts, when repeated, the purity of vortioxetine hydrobromide obtained after purification is not up to the mark. This may be attributed due to the presence of impurities which originate mainly during the synthetic process from the raw materials, solvents, intermediate and by-products. Moreover, the above mentioned process of vortioxetine involves use of potentially mutagenic (genotoxic) starting materials such as 1-chloro-2-nitrobenzene (CNB) or 1-fluoro-2-nitrobenzene and 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene (DNPSB), 2-[(2,4-dimethylphenyl)sulfanyl]aniline (DPSA) and bis(2-chloroethyl)amine or bis(2-bromoethyl)amine. Due to their use, either these starting materials remain as impurities in the final product or other potential genotoxic impurities can form during the synthesis though genotoxic unreacted by-product that could affect the quality of vortioxetine or its salts.
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
n synthetic organic chemistry, getting
a single end – product with 100% yield is seldom. There is
always a chance of having by-products. Because they can
be formed through variety of side reactions, such as
incomplete reaction, over reaction, isomerization,
dimerization, rearrangement or unwanted reactions
between starting materials or intermediate with chemical
12
reagents or catalysts
Even though, in synthetic organic chemistry getting a single end product with 100% purity is seldom wherein there is always a chance of having by-products. Because by-products or impurities can be formed through variety of side reactions, such as incomplete reaction, over reaction, isomerization, dimerization, rearrangement, or unwanted reactions between starting materials or intermediate with chemical reagents or catalysts. Such impurities that remain within the formulation or active pharmaceutical ingredient (API) even in the small amounts can influence quality, safety and efficacy (QSE) of the product, thereby causing serious health hazards. The regulatory guidelines are evident on the assessment and control of genotoxic impurities associated with API which is usually considered as a very challenging task for pharmaceutical companies who are intended for the quality and safety of the API. As the presence of genotoxic impurities make the use of API incompatible for humans if these contain impurities beyond set exposure limits. Therefore, the limits and threshold values of those impurities should comply with the limits set and specified by ICH guidelines.
Nevertheless, besides the existing routes of preparation as well as purification of vortioxetine hydrobromide, to overcome the aforementioned drawbacks associated in the prior art processes for instance dark brownish color product formation, reaction temperature, solubility, solvent polarity and unacceptable level of impurities specifically genotoxic or mutagenic impurities, there is a continuing need in the art to optimize the purification condition of vortioxetine hydrobromide which will purge the impurities down to the desired level as per ICH guidelines.
OBJECT OF THE INVENTION
The principal object of the present invention is to provide an efficient process for the preparation of vortioxetine hydrobromide wherein level of impurities is controlled as per the prescribed guidelines of ICH.
Another object of the present invention is to provide an efficient process for the purification of vortioxetine hydrobromide wherein level of impurities is controlled as per the prescriptive guidelines of ICH.
Another object of the present invention is to provide pure vortioxetine hydrobromide in a consistent manner by controlling genotoxic impurities as per ICH guidelines.
One another object of the present invention is to provide an effective method of purifying the vortioxetine hydrobromide by using a suitable solvent system.
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation and purification of vortioxetine hydrobromide. The process enables better control of the quality of the product obtained, avoiding the formation of impurities.
In one embodiment, the present invention provides an efficient process for the preparation of vortioxetine hydrobromide, which comprises the steps of,
i. reacting 2-[(2,4-dimethylphenyl)sulfanyl]aniline of formula II

Formula II
with bis (2-haloethyl)amine of formula III or salt thereof

Formula III
wherein X represents Cl, Br
in presence of a solvent at temperature below 160?,
ii. converting vortioxetine or pharmaceutically acceptable salt thereof obtained in step (i) to its hydrobromide salt by reacting with a hydrobromide source,
iii. optionally slurry washing of hydrobromide salt of vortioxetine obtained in step (ii) using a suitable solvent, and
iv. purifying vortioxetine hydrobromide using a suitable solvent system.
In another embodiment, the present invention provides an improved process for the purification of vortioxetine hydrobromide, which comprises the steps of,
i. providing a solution of crude vortioxetine hydrobromide in a first solvent,
ii. concentrating the solution obtained in step (i) by partial recovery of the solvent under vacuum,
iii. adding a second solvent to the concentrated solution obtained in step (ii),
iv. heating the solution of step (iii) to reflux temperature of the solvent,
v. cooling the reaction mixture, and
vi. isolating the pure vortioxetine hydrobromide.
In another embodiment, the present invention provides an efficient process for the preparation of vortioxetine hydrobromide, which comprises the steps of,
i. reacting 2-[(2,4-dimethylphenyl)sulfanyl]aniline of formula II

Formula II
with bis (2-haloethyl)amine of formula III or salt thereof

Formula III
wherein X represents Cl, Br
in presence of a solvent at temperature below 160?,
ii. optionally isolating vortioxetine or a pharmaceutically acceptable salt thereof,
iii. converting vortioxetine or pharmaceutically acceptable salt thereof to its hydrobromide salt by reacting with a hydrobromide source,
iv. adding a suitable solvent to hydrobromide salt of vortioxetine obtained in step (iii), and
v. isolating vortioxetine hydrobromide from step (iv).
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1- represents PXRD pattern of crystalline vortioxetine hydrobromide.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a new and advantageous process for the preparation and purification of vortioxetine hydrobromide wherein impurities are controlled as per prescribed limit of ICH guidelines.
As used herein, the term “ambient temperature” represents a temperature 25? ± 5?.
As used herein, the term “pharmaceutically acceptable salt” refers to acid addition salt selected from the group which may include but not limited to hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, gluconic acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, or maleic acid.
The term “charcoaling” herein refers to carbon or charcoal treatment of vortioxetine hydrobromide solution.
As used herein, the term ‘partial recovery’ represents a removal of solvent from the solution to form concentrated solution.
The term “substantially free” herein means vortioxetine hydrobromide having each known impurity less than about 0.15% by area percentage of HPLC or each unknown impurity less than about 0.10% by area percentage of HPLC. In particular, less than about 0.10% by area percentage of HPLC. More particular, less than about 0.05% by area percentage of HPLC. Most particularly, in the range of about 0.01% to about 0.05% by area percentage of HPLC.
As used herein, the term ‘crude’ represents a compound having impurities greater than the limits specified as per ICH guidelines.
The term “pure” herein refers to purity of vortioxetine hydrobromide, which is substantially free from, one or more impurities and having purity of greater than 99% or more of about 99.5% or more, particularly of about 99.9% or more by area percentage of HPLC.
The term "substantially free of genotoxic impurities", as used herein, refers to the vortioxetine hydrobromide obtained by the process of the present invention wherein genotoxic impurities are not detected. The genotoxic impurities include 1-chloro-2-nitrobenzene (CNB), 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene (DNPSB), 2-[(2,4-dimethylphenyl)sulfanyl]aniline (DPSA) and bis(2-chloroethyl)amine or bis(2-bromoethyl)amine. The amount of the genotoxic impurities in vortioxetine hydrobromide may be determined using high performance liquid chromatography (HPLC), gas chromatography (GC), or liquid chromatography mass spectrometry (LCMS).
In one general aspect there is provided vortioxetine hydrobromide having a purity of about 99.5% or more by area percentage of HPLC.
In another general aspect, there is provided vortioxetine hydrobromide having total impurities less than or equal to 1.0% relative to vortioxetine hydrobromide as measured by area percentage of HPLC. Preferably, total impurities less than or equal to 0.5% relative to vortioxetine hydrobromide as measured by area percentage of HPLC.
Generally, impurities are identified spectroscopically and/or with another physical method, and then are associated with a peak position, such as that in a chromatogram, or with a spot on a TLC plate. Thereafter, the impurity can be identified, e.g., by its relative position in the chromatogram, where the position in a chromatogram is measured in minutes between injection of the sample on the column and elution of the particular component through the detector. The relative position in the chromatogram is known as the “retention time” (RT).
Retention time can vary by a mean value based upon the condition of the instrumentation as well as many other factors. To mitigate the effects such variations, have upon accurate identification of an impurity, those skilled in the art use the “relative retention time” (RRT) to identify impurities. The RRT of an impurity is its retention time divided by the retention time of a reference marker.
Impurities in vortioxetine hydrobromide are undesirable and may be harmful to a patient being treated with a dosage form of the active pharmaceutical ingredient in which abundant impurities are present. Furthermore, the undesired impurities reduce the level of the active pharmaceutical ingredient (API) available in pharmaceutical composition.
As per regulatory guidance for drug manufacturers requires that process impurities be maintained below set limits by specifying the quality of raw materials, controlling process parameters, such as temperature, pressure, time, and stoichiometric ratios, and including purification steps, such as crystallization, distillation, and liquid-liquid extraction, in the manufacturing process. The basic idea of the invention is to specifically develop an improved process of purification of vortioxetine and its pharmaceutically acceptable salt which is free from genotoxic impurities either of mutagenic or non-mutagenic and other known and unknown impurities.
In one embodiment the present invention provides an improved process for the purification of vortioxetine hydrobromide. The process comprises of dissolving crude vortioxetine hydrobromide in the first solvent. The crude vortioxetine hydrobromide can be prepared by the methods reported in the literature or by the process as given in the present specification which may have impurities greater than the limits specified as per ICH guidelines.
The crude vortioxetine hydrobromide has HPLC purity of around 96% and unknown impurities at RRT 2.11, 1.24, 0.32, 1.21 and few known impurities such as DPSA at RRT 0.47, and DNPSB at RRT 0.65 are present in unacceptable amounts.
The dissolution of crude vortioxetine hydrobromide in the first solvent can be achieved by heating the mixture to reflux temperature of the first solvent. After dissolving vortioxetine hydrobromide in a suitable solvent, the solution can be subsequently stirred and then an optional filtration step may be applied, wherein the solution may be treated with charcoal prior to the filtration. In the possession of the present inventors, due to the better solubility of vortioxetine hydrobromide in the first solvent, charcoaling effect is pronounced.
The first solvent used herein can be selected from any suitable organic solvent which is selected form the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene. Preferably, the solvent can be alcohol, more preferably the solvent can be methanol.
Thereafter, the resulting solution can be concentrated by partial recovery of solvent under vacuum till two to four times volume is left. Preferably partial recovery of solvent to obtain concentrated solution can be upto two to three times. After partial recovery of the solvent, the second solvent can be added to the concentrated solution. The second solvent used herein can be selected from any suitable organic solvent which is selected form the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene. Preferably, the solvent can be alcohol, more preferably the solvent can be isopropyl alcohol.
After addition of second solvent, the solution can be heated to reflux temperature and maintained at this temperature for 1-2 hours. Then, the resulting reaction mixture can be cooled to a temperature of 0-20? and kept at same temperature for few minutes to few hours. Preferably, the reaction mixture can be cooled to temperature of 0-10? and stirred for 1-3 hours. After complete crystallization, pure vortioxetine hydrobromide can be isolated by using techniques known in the art such as filtration, centrifugation etc. The resulting solid can then be washed with the suitable solvent used during crystallization. Finally, the solid can be dried at a temperature of 45-65? for 10-20 hours to obtain pure vortioxetine hydrobromide. Preferable drying temperature can be 50-60? and preferably, the solid can be dried for 12-18 hours and more preferably for 16-18 hours.
The pure vortioxetine hydrobromide have HPLC purity [w/w] more than 99.90% and devoid of unknown impurities at RRT 1.24, 0.32 and 1.21 and few known impurities DPSA at RRT 0.47 and DNPSB at RRT 0.65 whereas the individual impurity at RRT 2.13 and is found to be reduced considerably and present within acceptable limit i.e., less than 0.1% w/w by HPLC.
According to the invention it is also unexpectedly found that a good reproducibility of the vortioxetine hydrobromide in terms of purity and yield can be obtained by using a preferable solvent system i.e., mixture of methanol and isopropyl alcohol. The purification process of the present invention can be repeated once or twice if required, when desired purity may not have been achieved.
In one embodiment the present invention provides the vortioxetine hydrobromide which is substantially free of genotoxic impurities such as 1-chloro-2-nitrobenzene (CNB), 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene (DNPSB) and 2-[(2,4-dimethylphenyl)sulfanyl]aniline (DPSA) and bis(2-chloroethyl)amine or bis(2-bromoethyl)amine and other known and unknown impurities in specified limits. The purification process of vortioxetine hydrobromide of the present invention enables enough to control genotoxic impurities as per ICH guidelines. Based on the daily dose of 20 mg of vortioxetine drug substance and a Threshold of Toxicological Concern (TTC) limit of 1.5 µg/day, the acceptable limit for any mutagenic impurities (MI) present in vortioxetine drug substance is 75 ppm. Further, the presence of genotoxic impurities in a pharmaceutical product is considered to be a serious risk factor due to their potential to damage DNA at any level of exposure which may lead to, or contribute towards, tumor development. Thus, as per the ICH guidelines on the limit of genotoxic impurities in pharmaceutical products, there is a need to control the genotoxic impurities to the lowest possible level in pharmaceutical products. The present invention provides pure vortioxetine hydrobromide wherein genotoxic impurities 1-chloro-2-nitrobenzene (CNB), 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl] benzene (DNPSB) and 2-[(2,4-dimethylphenyl)sulfanyl]aniline (DPSA) of formula II are not detected.
The efficiency of purification process has been checked by spiking the pure vortioxetine hydrobromide with starting materials/intermediates and then subjected the said impure vortioxetine hydrobromide for purification by using a preferable solvent system i.e., mixture of methanol and isopropyl alcohol. The resulting vortioxetine hydrobromide is highly pure wherein any other impurity is not detected.
The process comprises of purification of vortioxetine hydrobromide wherein vortioxetine hydrobromide, having HPLC purity more than 99.99% can be spiked with 0.50% each of 1-chloro-2-nitrobenzene (CNB), 2,4-dimethylbenzene-1-thiol, 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene (DNPSB) and 2-[(2,4-dimethylphenyl)sulfanyl]aniline (DPSA) of formula II. The vortioxetine hydrobromide having spiked material can be subjected for purification by using a preferable solvent system i.e., mixture of methanol and isopropyl alcohol as per the present invention which provides pure vortioxetine hydrobromide having purity more than 99.99 % and any other impurity is not detected i.e., vortioxetine hydrobromide is free from each spiked product.
In specified manner, vortioxetine hydrobromide (98g) having HPLC purity=100%, have been spiked with, 500mg each of all four genotoxic impurities [CNB, 2,4-dimethylbenzene-1-thiol, DNPSB and DPSA], can be taken in methanol (100ml) and heated to 60-70°C. The reaction mass can be concentrated under vacuum to get residue. The residue is then subjected to purification step of present invention and of the resulting vortioxetine hydrobromide have HPLC purity [w/w] = 100%; and any other impurity is not detected.
The pure vortioxetine hydrobromide prepared by using process of present invention have purity of greater than 99.5%, preferably 99.93% and more preferably greater than 99.99% and all impurities have been reduced to less than 0.1% w/w by HPLC. Vortioxetine hydrobromide is crystalline in nature and has XRD pattern as depicted in Figure-1. Preferably, the crystalline form is ß form of vortioxetine hydrobromide.
In another embodiment the present invention provides an efficient process for the preparation of vortioxetine hydrobromide starting from 2-[(2,4-dimethylphenyl) sulfanyl]aniline of formula II. The process comprises of condensing the compound 2-[(2,4-dimethylphenyl)sulfanyl]aniline [having HPLC purity[w/w]=99.49% and unknown impurity = 0.24% and known impurity DNPSB=0.17%] with bis (2-haloethyl)amine of formula III or its pharmaceutically acceptable salt thereof in the presence of solvent at temperature below 160? followed by stirring of the reaction mixture to obtain vortioxetine or its salt. The compound bis (2-haloethyl)amine of formula III or pharmaceutically acceptable salt can be selected from the compound either 2-chloro-N-(2-chloroethyl)ethan-1-amine or bis(2-chloroethyl)amine of formula IIIa or bis(2-bromoethyl)amine of formula IIIb.
Formula IIIa
Formula IIIb

Preferably, pharmaceutically acceptable salt of bis (2-haloethyl)amine of formula III can be selected from its hydrochloride or hydrobromide salt. The solvent used herein can be selected from the group consisting of 1,2-dichlorobenzene, 1,3-dichlorobenzene and 1,4-dichlorobenzene or mixture thereof. Preferably, the solvent can be 1,2-dichlorobenzene. The solvents used herein may include but not limited to 1,2-dichlorobenzene. The reaction mixture can be heated to 140-160?, preferably heated to 150-160?. The reaction mixture can be stirred for 18-30 hours at same temperature and preferable stirring can be 24-30 hours, more preferably 28-30 hours. It is beneficial to perform the reaction below 160? to avoid the formation of black colour and charring of reaction mass. After reaction completion, the reaction mass can be cooled at 80-110°C, preferably at 90-100°C. Thereafter, charcoal or carbon treatment can be given to the reaction mass, then the resulting reaction solution can be cooled to ambient temperature and maintained at same temperature for further 1-2 hours. The resulting mixture can be filtered and washed with a suitable solvent. The solvent used for washing herein can be selected from the group consisting of 1,2-dichlorobenzene, 1,3-dichlorobenzene and 1,4-dichlorobenzene or mixture thereof. Vortioxetine and its salt can be isolated by using techniques known in the art such as filtration, centrifugation or can be used as such for the next step without isolation.
In one another embodiment, the present invention provides a process for the preparation of vortioxetine hydrobromide comprises of condensing 2-[(2,4-dimethylphenyl) sulfanyl]aniline of formula II with bis (2-haloethyl)amine of formula III or its pharmaceutically acceptable salt thereof, optionally in the presence of a base, in a suitable solvent at temperature below 160? to obtain vortioxetine or its salt thereof.
Optionally, the reaction can be performed in the presence of base, which can be selected from the group comprising one or more inorganic base. The inorganic base can be selected from the group comprising one or more of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, potassium t-butoxide, preferably potassium carbonate.
The suitable solvent used herein can be selected from alcoholic solvent which may be selected from the C1 to C8 alcohol, which includes but not limited to methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 2-methylbutan-1-ol, 3-methylbutan-2-ol, 1-pentanol, 3-methyl-3-pentanol; The solvents used herein may include but not limited to 1-butanol.
The reaction mixture can be heated below 160?, preferably can be heated below 140?, most preferably heated to 110-120?. The reaction mixture can be stirred for 60-95 hours at same temperature and preferable stirring can be for 70-90 hours.
After completion of the reaction, the reaction mass can be cooled to 40-70?, preferably can be cooled to 50-60?, and then filtered. The solvent can be recovered, and the resulting residue can be dissolved in a first solvent as defined above. Preferably toluene can be use and stirred for 10-20 minutes at ambient temperature. Thereafter, water and ammonia solution can be added and then stirred at 20-30? for 20-30 minutes. The resulting layers can be separated, and the organic layer can be used for the next step either in situ or after isolating from the same layer.
The conversion of vortioxetine or its pharmaceutically acceptable salt [isolated or not, from the reaction] to vortioxetine hydrobromide salt can be achieved by treating with hydrobromide source. The hydrobromide source can be selected from hydrobromic acid or its aqueous solution. The hydrobromic acid solution can be added to the resulting reaction mixture and stirred for 19-25 hours, preferably for 22-24 hours.
Thereafter, the resulting reaction mixture can be cooled at a temperature less than or equal to 10°C and can be maintained at the same temperature for a further 1-2 hours. Preferably, the reaction mixture can be cooled to temperature of less than or equal 5?.
Optionally, hydrobromide source can be added to organic layer and stirred for 10-50 minutes, preferably 20-30 minutes. Thereafter, solvent can be recovered from the organic layer to obtain the crude product.
The reaction mass can be filtered and washed with a suitable solvent. The resulting wet material is a dark colored compound. The solvent used for washing herein can be selected from the group consisting of 1,2-dichlorobenzene, 1,3-dichlorobenzene and 1,4-dichlorobenzene or mixture thereof. In hands of the present inventors, it is observed that removal of solvent 1,2-dichlorobenzene from vortioxetine hydrobromide is very difficult and affect the nature as well as quality since the material remains sticky and on drying it becomes blackish. The nature of material and colour can be improved by treating vortioxetine hydrobromide with suitable solvent. The suitable solvent used herein can be selected from any suitable organic solvent which is selected from the group consisting of hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene. Preferably, the solvent can be n-hexane, cyclohexane, more preferably the solvent can be cyclohexane. The solvent can be added to vortioxetine hydrobromide to form a suspension or slurry based on solubility of solvent used. Finally, the slurry or suspension can be stirred at an ambient temperature for 1- 2 hours followed by filtering and washing with the solvent to obtain the vortioxetine hydrobromide as solid mass, which is not sticky and does not turn black on drying. It is advantageous to slurry wash the resulting vortioxetine hydrobromide with a suitable solvent to remove colour impurities and stickiness and is an inventive part of the invention. The solid mass obtained from the above process can be further subjected for one or more purifications as given in the present specification to achieve the desired purity of greater than 99.5%.
The starting compound 2-[(2,4-dimethylphenyl)sulfanyl]aniline of formula II can be prepared by the methods reported in the literature or by the process as given in the present specification. The 1-chloro-2-nitrobenzene (CNB) and 2,4-dimethyl thiophenol are condensed in the presence of a solvent and base to obtain an intermediate 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene (DNPSB). Then, the nitro intermediate is further reduced by catalytic hydrogenation with Raney nickel in the presence of an alcoholic solvent. Finally, a brown oily residue i.e., 2-[(2,4-dimethylphenyl)sulfanyl]aniline (DPSA) of formula II is isolated which can be utilized for the preparation of vortioxetine and its pharmaceutically acceptable salts.
The process of the present invention provides highly pure vortioxetine hydrobromide wherein the level of individual specified, and unspecified impurities is controlled at a level of equal to or less than 0.15% and 0.10% respectively and total impurities at a level of less than 1.0 % as per regulatory guidelines.
It is advantageous to use purified compound of vortioxetine hydrobromide to avoid the contamination and degradation during final pharmaceutical composition.
Although the following examples illustrate the practice of the present invention in some of its embodiments, the examples should not be construed as limiting the scope of invention. Other embodiments will be apparent to one skilled in the art from consideration of the specification and examples.
EXAMPLES:
Example 1: Preparation of vortioxetine hydrobromide
2-Chloro-N-(2-chloroethyl)ethan-1-amine hydrochloride (100g) was added into the solution of 2-[(2,4-dimethylphenyl)sulfanyl]aniline (100g) [HPLC purity[w/w]=99.49%; having one impurity=0.24% and DNPSB=0.17%], in 1,2-dichlorobenzene (850ml) at ambient temperature. The resulting reaction mixture was heated to 150-160°C and stirred for 24 hours. After reaction completion, the reaction mass was then cooled at 90-100°C followed by addition of carbon (5g), cooled at ambient temperature, and stirred for 1-2 hours. The resulting mixture was filtered and washed with 1,2-dichlorobenzene (25ml). The hydrobromic acid solution (370g) was added to the filtrate and stirred for 24 hours. The resulting reaction mixture was cooled at =5°C and further stirred for 1-2 hours, filtered, and washed with 1,2-dichlorobenzene (25ml). The cyclohexane (500ml) was added to the resulting wet cake and stirred at ambient temperature for 1-2 hours. The resulting mass was filtered and washed with cyclohexane (25ml). The wet material was dissolved in methanol (100ml) and heated to 60-70°C. The reaction mass was concentrated under vacuum to get residue. The residue was dissolved in methanol (600ml) and heated at 60-70°C and stirred. Afterward, the resulting solution subjected for charcoalization. After charcoaling, the resulting reaction mass was concentrated under vacuum till 2 times volume was left and then isopropyl alcohol (300ml) was added. The resulting mass was heated to 70-80°C and stirred for 1-2 hours. The reaction mass was cooled to 0-10°C and stirred for 1-2 hours. After complete crystallization, the resulting mass was filtered, washed with chilled isopropyl alcohol (25ml) and dried at 50-60°C for 18 hours to obtain 58g of vortioxetine hydrobromide having HPLC purity [w/w] = 99.91%; one impurity at RRT 2.15 = 0.09% and any other impurity was not detected.
Example 2: Preparation of vortioxetine hydrobromide
2-Chloro-N-(2-chloroethyl)ethan-1-amine hydrochloride (100g) was added into the solution of 2-[(2,4-dimethylphenyl)sulfanyl]aniline (100g) [HPLC purity[w/w] =99.20%; having one impurity=0.46% and DNPSB=0.25%], in 1,2-dichlorobenzene (850ml) at ambient temperature. The resulting reaction mixture was heated to 150-160°C and stirred for 24 hours. After reaction completion, the reaction mass was then cooled at 90-100°C followed by addition of carbon (5g), cooled at ambient temperature, and stirred for 1-2 hours. The resulting mixture was filtered and washed with 1,2-dichlorobenzene (25ml). The hydrobromic acid solution (370g) was added to the filtrate and stirred for 24 hours. The resulting reaction mixture was cooled at =5°C and further stirred for 1-2 hours, filtered, and washed with 1,2-dichlorobenzene (25ml). The cyclohexane (500ml) was added to the resulting wet cake to form suspension and stirred at ambient temperature for 1-2 hours. The resulting mass was filtered and washed with cyclohexane (25ml). The wet material was dissolved in methanol (100ml) and heated to 60-70°C. The reaction mass was concentrated under vacuum to get residue. The residue was dissolved in methanol (600ml) and heated at 60-70°C and stirred. The carbon (5g) was added to the reaction mass and stirred for 1-2 hours. The resulting mass was hyflo filtered and washed with hot methanol (25ml). The resulting mass was concentrated under vacuum till 2 times volume was left and then isopropyl alcohol (300ml) was added. The resulting mass was heated to 70-80°C and stirred for 1-2 hours. The reaction mass was cooled to 0-10°C and stirred for 1-2 hours. After complete crystallization, the resulting mass was filtered, washed with chilled isopropyl alcohol (25ml) and dried at 50-60°C for 18 hours to obtain 62g of vortioxetine hydrobromide having HPLC purity [w/w] = 99.93%; one impurity at RRT 2.15 = 0.07% and any other impurity was not detected.
Example 3: Purification of vortioxetine hydrobromide
Vortioxetine hydrobromide (100g) [having HPLC purity [w/w] = 96.48%; and having one impurity= 1.41% at RRT 2.11 and other impurities 0.78% at RRT 1.24; 0.61% at RRT 0.32; 0.16% at RRT 0.47 (DPSA); 0.14% at RRT 1.21 and 0.05% at RRT 0.65 (DNPSB)], was dissolved in methanol (100ml) and heated to 60-70°C. The reaction mass was concentrated under vacuum to get residue. The residue was dissolved in methanol (600ml) and heated at 60-70°C and stirred. The carbon (5g) was added to the reaction mass and stirred for 1-2 hours. The resulting mass was hyflo filtered and washed with methanol (25ml). The resulting mass was concentrated under vacuum till 2 times volume was left and then isopropyl alcohol (300ml) was added. The resulting mass was heated to 70-80°C and stirred for 1-2 hours. The reaction mass was cooled to 0-10°C and stirred for 1-2 hours. After complete crystallization, the resulting mass was filtered, washed with chilled isopropyl alcohol (25ml) and dried at 50-60°C for 12-18 hours to obtain 58g of vortioxetine hydrobromide having HPLC purity [w/w] = 99.93%; one impurity at RRT 2.13 = 0.05% and any other impurity was not detected.
Example 4: Purification of vortioxetine hydrobromide
Vortioxetine hydrobromide (100g) [having HPLC purity [w/w] = 98%, wherein impurities present are observed 0.74% at RRT 2.20; 0.61% at RRT 0.52; 0.24% at RRT 1.29 and 0.22% at RRT 1.26], was dissolved in methanol (100ml) and heated to 60-70°C. The reaction mass was concentrated under vacuum to get residue. The residue was dissolved in methanol (600ml) and heated at 60-70°C and stirred. Afterward, the resulting solution subjected for charcoalization. After charcoaling, the resulting reaction mass was concentrated under vacuum till 2 times volume was left and then isopropyl alcohol (300ml) was added. The resulting mass was heated to 70-80°C and stirred for 1-2 hours. The resulting mass was filtered, washed with isopropyl alcohol (25ml) and dried at 50-60°C for 4-6 hours. Methanol (600ml) was added to dried mass followed by refluxing to get clarity. The carbon (5g) was added to the reaction mass and stirred for 1-2 hours. The resulting mass was hyflo filtered and washed with hot methanol (25ml). The resulting mass was concentrated under vacuum till 2 times volume was left and then isopropyl alcohol (300ml) was added. The resulting mass was heated to 70-80°C and stirred for 1-2 hours. The reaction mass was cooled to 0-10°C and stirred for 1-2 hours. After complete crystallization, the resulting mass was filtered, washed with chilled isopropyl alcohol (25ml) and dried at 50-60°C for 12-18 hours to obtain 62g of vortioxetine hydrobromide having HPLC purity [w/w] = 99.94%; one impurity at RRT 2.20 = 0.03% and any other impurity was not detected.
Example 5: Preparation of vortioxetine hydrobromide
2-[(2,4-Dimethylphenyl)sulfanyl]aniline (2.00 Kg) [HPLC purity[w/w]=99.49%; having one impurity=0.24% and DNPSB=0.17%], was taken in 1-butanol (9.0 L). To this. 2-chloro-N-(2-chloroethyl)ethan-1-amine hydrochloride (2.32 Kg) and potassium carbonate (1.80 kg) were added at 20-30°C. The resulting reaction mixture was heated to 110-120°C and stirred for 70-90 hours. After reaction completion, the reaction mass was cooled to 50-60°C followed by filtration. Thereafter, solvent was recovered, and the resulting residue was dissolved in toluene (10 L) followed by addition of water (10 L) and ammonia solution (2.4 L; 15-20%) and stirred at 20-30° and thereafter, layers were separated. Hydrobromic acid (2.0 L; 47%) was added to the toluene layer and stirred for 20-30 min. The toluene was recovered the resulting crude product was dissolved in acetone (4.0 L) and isopropyl alcohol (6.0 L) followed by stirring for 20-24 hours at 20-30°C. Thereafter, the reaction mass was cooled to 0-10°C and stirred further for 1-2 hours. The product was filtered and dried under vacuum for 8-12 hours at 50-60°C. The dried material was dissolved in methanol (12 L) and heated at 60-70°C and charcoalized. After charcoaling, the resulting reaction mass was filtered and resulting filtrate was concentrated under vacuum till 2 times volume was left and then isopropyl alcohol (6.0 L) was added. The resulting mass was heated to 70-80°C and stirred for 1-2 hours. The reaction mass was cooled to 0-10°C and stirred. After complete crystallization, the resulting mass was filtered, washed with chilled isopropyl alcohol (500 ml) and dried at 50-60°C for 18 hours to obtain 1.40 Kg of vortioxetine hydrobromide having HPLC purity [w/w] = 99.93%; one impurity at RRT 0.15 = 0.03%, another at RRT 1.41 = 0.03% and 0.01% impurity at RRT 0.52.
Comparative example 1: Preparation of vortioxetine hydrobromide
2-Chloro-N-(2-chloroethyl)ethan-1-amine hydrochloride (100g) was added into the solution of 2-[(2,4-dimethylphenyl)sulfanyl]aniline [100g, having purity=98.67%; one impurity= 0.40% and DNPSB=0.68%], in 1,2-dichlorobenzene (850ml) at ambient temperature. The resulting reaction mixture was heated to 150-160°C and stirred for 24 hours. After reaction completion, the reaction mass was then cooled at ambient temperature and stirred for 1-2 hours. The resulting mixture was filtered and washed with 1,2-dichlorobenzene (25ml). The hydrobromic acid solution (370g) was added to the filtrate and stirred for 24 hours. The resulting reaction mixture was cooled at =5°C and further stirred for 1-2 hours, filtered, and washed with 1,2-dichlorobenzene (25ml). The suspension of wet cake and cyclohexane (500ml) was stirred at ambient temperature for 1-2 hours. The resulting mass was filtered and washed with cyclohexane (25ml). The wet material was dissolved in methanol (100ml) and heated to 60-70°C. The reaction mass was concentrated under vacuum to get residue. The residue was dissolved in methanol (600ml) and heated at 60-70°C to get clarity. The reaction mass was cooled to 0-10°C and stirred for 1-2 hours. After reaction completion, the resulting mass was filtered, washed with chilled methanol (25ml) and dried at 50-60°C for 12-18 hours to obtain 30g of vortioxetine hydrobromide as light brownish solid having HPLC purity [w/w] = 99.61%; and impurities present are: 0.22% at RRT 0.33 & other impurity= 0.10% at RRT 0.51 (DPSA).
Comparative example 2: Preparation of vortioxetine hydrobromide
2-Chloro-N-(2-chloroethyl)ethan-1-amine hydrochloride (100g) was added into the solution of 2-[(2,4-dimethylphenyl)sulfanyl]aniline [100g, having purity=99.39%; an impurity= 0.28% and DNPSB=0.19%], in 1,2-dichlorobenzene (850ml) at ambient temperature. The resulting reaction mixture was heated to 150-160°C and stirred for 24 hours. After reaction completion, the reaction mass was then cooled at ambient temperature and stirred for 1-2 hours. The resulting mixture was filtered and washed with 1,2-dichlorobenzene (25ml). The hydrobromic acid solution (370g) was added to the filtrate and stirred for 24 hours. The resulting reaction mixture was cooled at =5°C and stirred for 1-2 hours, filtered and washed with 1,2-dichlorobenzene (25ml). The wet material was dissolved in ethanol (700ml) and heated to 75-85°C for dissolution. The reaction mass was cooled to 0-10°C and stirred for 1-2 hours. After reaction completion, the resulting mass was filtered, washed with chilled ethanol (25ml) and dried at 45-55°C for 12-18 hours to obtain 30g of vortioxetine hydrobromide as dark brownish solid having HPLC purity [w/w] = 99.12%; and impurities present are: 0.40% at RRT 1.18, 0.26% at RRT 0.52 (DPSA), and 0.22% at RRT 2.67.
Comparative example 3: Preparation of vortioxetine hydrobromide
2-Chloro-N-(2-chloroethyl)ethan-1-amine hydrochloride (100g) was added into the solution of 2-[(2,4-dimethylphenyl)sulfanyl]aniline (100g) [having HPLC purity=99.35%; having one impurity= 0.32% and DNPSB=0.27%], in 1,2-dichlorobenzene (850ml) at ambient temperature. The resulting reaction mixture was heated to 150-160°C and stirred for 24 hours. After reaction completion, the reaction mass was then cooled at ambient temperature and stirred for 1-2 hours. The resulting mixture was filtered and washed with 1,2-dichlorobenzene (25ml). The hydrobromic acid solution (370g) was added to the filtrate and stirred for 24 hours. The resulting reaction mixture was cooled at =5°C and further stirred for 1-2 hours, filtered, and washed with 1,2-dichlorobenzene (25ml). The suspension of wet cake and cyclohexane (500ml) was stirred at ambient temperature for 1-2 hours. The resulting mass was filtered and washed with cyclohexane (25ml). The wet material was taken in acetone (500ml) and heated to 60-65°C then water was added for dissolution or clarity. The reaction mass was cooled to 0-10°C and stirred for 1-2 hours. After reaction completion, the resulting mass was filtered, washed with chilled acetone (25ml) and dried at 45-55°C for 12-18 hours to obtain 25.2g of vortioxetine hydrobromide as dark brownish solid having HPLC purity [w/w] = 98.83%; and one impurity at RRT 2.19= 0.43%.
It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:We Claim:
1. A process for the preparation of vortioxetine hydrobromide of formula I,

Formula I
which comprises the steps of,
i. reacting 2-[(2,4-dimethylphenyl)sulfanyl]aniline of formula II

Formula II
with bis (2-haloethyl)amine of formula III or salt thereof

Formula III
wherein X represents Cl, Br
in presence of a solvent at temperature below 160?,
ii. converting vortioxetine or pharmaceutically acceptable salt thereof obtained in step (i) to its hydrobromide salt by reacting with a hydrobromide source,
iii. optionally slurry washing of hydrobromide salt of vortioxetine obtained in step (ii) using a suitable solvent, and
iv. purifying vortioxetine hydrobromide using a suitable solvent system.
2. The process as claimed in claim 1, wherein solvent in step (i) is selected from 1,2-dichlorobenzene, 1,3-dichlorobenzene and 1,4-dichlorobenzene or mixture thereof; hydrobromide source in step (ii) is selected from hydrobromic acid or its aqueous solution; and solvent in step (iii) is selected from the group consisting of hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene.
3. The process as claimed in claim 1, wherein suitable solvent system in step (iv) is selected from first and second solvent; wherein first solvent is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene, and second solvent is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene.
4. A process for the purification of vortioxetine hydrobromide, which comprises the steps of,
i. providing a solution of crude vortioxetine hydrobromide in a first solvent,
ii. concentrating the solution obtained in step (i) by partial recovery of the solvent under vacuum,
iii. adding a second solvent to the concentrated solution obtained in step (ii),
iv. heating the solution of step (iii) to reflux temperature of the solvent,
v. cooling the reaction mixture, and
vi. isolating the pure vortioxetine hydrobromide.
5. The process as claimed in claim 4, wherein first solvent is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane.
6. The process as claimed in claim 4, wherein second solvent is selected from the group consisting of C1-C8 alcohols such as methanol, ethanol, 1-propanol, isopropyl alcohol, 1-butanol, 2-butanol, 1-pentanol; hydrocarbons such as n-hexane, n-heptane, cyclohexane, petroleum ether, toluene, pentane, methylcyclohexane, ethyl benzene.
7. The process as claimed in claim 4, wherein partial recovery of solvent in step (ii) is carried out under vacuum till two to four times volume is left.
8. The process as claimed in claim 4, wherein pure vortioxetine hydrobromide in step (vi) is free of genotoxic impurities such as 1-chloro-2-nitrobenzene (CNB), 2,4-dimethyl-1-[(2-nitrophenyl)sulfanyl]benzene (DNPSB) and 2-[(2,4-dimethylphenyl)sulfanyl] aniline (DPSA) and bis(2-chloroethyl)amine or bis(2-bromoethyl)amine, and having purity greater than 99.91% by HPLC.
9. The process as claimed in claim 1, wherein reaction is performed optionally in the presence of base.
10. The process as claimed in claim 1, wherein optionally vortioxetine or a pharmaceutically acceptable salt is isolated.