A PROCESS FOR THE PREPARATION OF CARIPRAZINE SALT

RELATED APPLICATIONS

This application claims priority to Indian Provisional Patent Application No. 202021041210 filed on September 23, 2020, the contents of which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of trans-N- {4-|2-|4-(2.3-dichlorophcnyl)pipcrazinc- 1 -yl | ethyl |cyclohcxyl A' ^' -dimethyl urea salts such as malate or hydrochloride.

BACKGROUND OF THE INVENTION

The following discussion of the prior art is intended to present the invention in an appropriate technical context, and allows its significance to be properly appreciated. Unless clearly indicated to the contrary, reference to any prior art in this specification should not be construed as an expressed or implied admission that such art is widely known or forms part of common general knowledge in the field.

The present invention relates to development of anti-psychotic drugs. Cariprazine hydrochloride is an atypical antipsychotic drug; indicated for the treatment of schizophrenia in adults, acute treatment of manic or mixed episodes associated with bipolar I disorder in adults and treatment of depressive episodes associated with bipolar I disorder (bipolar depression) in adults.

Cariprazine hydrochloride (hereafter referred to as the compound of Formula I) has the chemical name lrans-N-{4-\ 2- 14-(2.3 -dichlorophcnyl (piperazine- 1 - yl]ethyl]cyclohexyl}-/V’,/V’-dimethylurea hydrochloride, and is structurally represented as,

Formula I Cariprazine hydrochloride being an important drug for treatment and management of schizophrenia and depressive disorder; a number of processes for its preparation are known in the art.

There are a number of patent documents that describe a process for the preparation of cariprazine and similar compounds such as published PCT Application Nos. WO 2019/016828, and WO 2020/042876; similarly Chinese Patent Application No. CN106543039.

There is still a need to develop an industrially viable commercial process for the preparation of cariprazine hydrochloride (Formula I); which is simple, efficient and cost- effective and yet provides the desired compound in improved yield and purity.

The inventors of the present invention have developed an improved process which does not involve the use of any toxic and/or costly solvents, catalysts or reagents. Moreover, the process does not require additional purification steps and critical workup procedures. Accordingly, the present invention provides a process for the preparation of cariprazine and a salt thereof, which is simple, efficient, cost effective, environmentally friendly and commercially scalable for large scale operations.

SUMMARY OF THE INVENTION

In one aspect, the present invention relates to an improved process for the preparation of cariprazine hydrochloride (Formula I),

Formula I comprising the steps of:

(a) reacting trans -4-{2-[4-(2, 3-dichlorophenyl)piperazin- 1-yl] ethyl }cyclohexanamine (Formula II) or its salt

Formula II with A', '-dimcthylcarbamoyl chloride (Formula III)

Formula III in a biphasic solvent system containing an organic solvent phase and an aqueous phase, in the presence of a base;

(b) separating the organic solvent phase and subjecting it to solvent exchange with an alcoholic solvent to get a solution;

(c) treating the solution of step (b) with an organic acid or an inorganic acid to obtain an acid addition salt of cariprazine (Formula V),

Formula V wherein, the acid addition salt of cariprazine (Formula V) is other than a hydrochloric acid salt;

(d) converting the acid addition salt of cariprazine (Formula V) of step (c) to cariprazine hydrochloride (Formula I).

In another aspect, the present invention relates to an improved process for the preparation of cariprazine hydrochloride (Formula I),

Formula I comprising the steps of:

(a) reacting /ram-4- { 2-|4-(2.3-dichlorophcnyl)pipcrazin- 1 -yl |cthyl jcyclohcxanaminc (Formula II) dihydrochloride,

(Formula II).2HC1 with A A'-dimcthylcarbamoyl chloride (Formula III)

Formula III in a biphasic solvent system selected from halogenated hydrocarbon and water, in the presence of triethylamine (TEA);

(b) separating the organic solvent phase and subjecting it to solvent exchange with an alcoholic solvent to get a solution;

(c) treating the solution of step (b) with malic acid to obtain a malate salt of cariprazine (Formula IV);

Formula IV

(d) converting the cariprazine malate salt (Formula IV) of step (c) to cariprazine hydrochloride (Formula I).

In another aspect, the present invention provides an improved process for the preparation of cariprazine malate salt (Formula IV),

comprising the steps of:

(a) reacting /ram-4- { 2-|4-(2.3-dichlorophenyl)piperazin- 1 -yl |ethyl jcyclohcxanaminc (Formula II) or its salt

Formula II with V, V'-dimethylcarbamoyl chloride (Formula III)

Formula III in a biphasic solvent system containing an organic solvent phase and an aqueous phase, in the presence of a base;

(b) separating the organic solvent phase and subjecting it to solvent exchange with an alcoholic solvent to get a solution;

(c) treating the solution of step (b) with malic acid to obtain the malate salt of cariprazine (Formula IV).

DETAILED DESCRIPTION OF THE INVENTION

Accordingly, the present invention relates to an improved process for the preparation of cariprazine hydrochloride (Formula I) represented by the following formula,

Formula I comprising the steps of:

(a) reacting /ram-4- { 2-|4-(2.3-dichlorophenyl)piperazin- 1 -yl |ethyl jcyclohcxanaminc (Formula II) or its salt

Formula II with A '-dimethylcarbamoyl chloride (Formula III)

Formula III in a biphasic solvent system containing an organic solvent phase and an aqueous phase, in the presence of a base; (b) separating the organic solvent phase and subjecting it to solvent exchange with an alcoholic solvent to get a solution;

(c) treating the solution of step (b) with an organic acid or an inorganic acid to obtain an acid addition salt of cariprazine (Formula V),

Formula V wherein, the acid addition salt of cariprazine (Formula V) is other than a hydrochloric acid salt;

(d) converting the acid addition salt of cariprazine (Formula V) of step (c) to cariprazine hydrochloride (Formula I).

The process according to the one aspect of the present invention, wherein the compound trans -4-{2-[4-(2,3-dichlorophenyl)piperazin-l-yl]ethyl}cyclohexan amine

(Formula II) used in step (a) is in the form of free base or alternatively, its salt is selected from hydrochloric acid.

The term‘biphasic solvent system’ as used herein, refers to the reaction solvent, wherein it consists of a two phase solvent system containing an organic solvent phase and an aqueous phase. In the context, the‘organic solvent phase’ is selected from a halogenated hydrocarbon, aromatic hydrocarbon, an ether, a ketone and an ester, or a mixture thereof; and the‘aqueous phase’ is water.

In an embodiment, the organic solvent phase used in step (a) is selected from a halogenated solvent such as dichloromethane, chloroform, tetrachloromethane, 4- bromotoluene, diiodomethane and chlorobenzene, or a mixture thereof; an aromatic solvent such as toluene, benzene and xylene, or a mixture thereof; an ether solvent such as di -tert- butyl ether, di -butyl ether, di-isopropyl ether, di-methoxyethane, di-methoxymethane, 1,4- dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, or a mixture thereof; a ketone such as methyl isobutyl ketone; an ester such as ethyl acetate, methyl acetate, «-butyl acetate, isobutyl acetate, sec-butyl acetate and isopropyl acetate, or a mixture thereof. In a preferred embodiment, the organic solvent phase used in step (a) is a halogenated hydrocarbon.

In an embodiment, the aqueous phase used in step (a) represents water.

According to one aspect of the present invention, the‘base’ used in the step (a) is selected from an organic base and an inorganic base.

In an embodiment, the inorganic base used in the step (a) is selected from a group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide.

In a preferred embodiment, the inorganic base used in the step (a) is sodium hydroxide.

In an embodiment, the organic base used in the step (a) is selected from a group consisting of methylamine, ethylamine, diethylamine, benzylamine, triethylamine (TEA), diisopropyl amine, diisopropylethylamine, tri-n-butylamine, tert-butylamine, A-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine and dimethylaminopyridine.

In a preferred embodiment, the organic base used in the step (a) is triethylamine

(TEA).

The term‘separating’ the organic solvent phase as used herein in step (b) represents that, after completion of the reaction according to step (a), the biphasic solvent system is subjected to physical separation from the reaction mixture, and collected into different flasks as organic solvent phase and aqueous phase.

According to one aspect of the present invention, the‘solvent exchange’ with an alcoholic solvent as in step (b) can be performed by concentrating the organic solvent phase obtained from step (a) and adding an alcoholic solvent to the concentrate to get a solution. In this context, an appropriate alcoholic solvent for the purpose of solvent exchange is selected from methanol, ethanol, isopropanol, or a mixture thereof.

In an embodiment, the alcoholic solvent used for the purpose of solvent exchange is ethanol.

The term‘treating’ as used herein in step (c) refers to a process wherein an organic acid or an inorganic acid other than hydrochloric acid is added to the solution of step (b) to obtain an acid addition salt of cariprazine (Formula V), wherein the acid addition salt of cariprazine (Formula V) is other than a hydrochloric acid salt

In an embodiment, the organic acid used in step (c) is selected from a group consisting of formic acid, acetic acid, propionic acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, tartaric acid, mandeiic acid, benzoic acid, salicylic acid, methane sulfonic acid, naphthalenesulfonic acid, ethanesulfbnic acid, benzenesulibnic acid and p-toluenesulfonic acid.

In a preferred embodiment, the solution of step (b) is treated with an organic acid.

In another preferred embodiment, the organic acid used in step (c) is malic acid. In an embodiment, the inorganic acid used in step (c) is selected from a group consisting of hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid.

According to one aspect of the present invention, the term‘converting’ used herein represents the process step wherein the acid addition salt of cariprazine (Formula V) is transformed into cariprazine hydrochloride (Formula I).

In a specific embodiment, the process for preparation of cariprazine hydrochloride

(Formula I) comprises the steps of:

(1) dissolving an inorganic base in water to obtain an aqueous solution of the inorganic base;

(2) adding an organic solvent, /ra -4- {2-|4-(2.3-dichlorophcnyl)pipcrazin- 1 - yl] ethyl }cyclohexanamine (Formula II) or its salt, A, A-di methyl carbamoyl chloride

(Formula III) and an organic base to a stirring solution of step (1) to form a biphasic solvent system consisting of an organic solvent phase and an aqueous phase;

(3) heating the reaction mixture at a temperature of about 35-40 °C for 5 hours;

(4) separating the organic phase from reaction mixture of step (3) and subjecting it to solvent exchange with an alcoholic solvent;

(5) adding an organic acid or an inorganic acid (other than hydrochloric acid) to the alcoholic solution of step (4);

(6) isolating an acid addition salt of cariprazine (Formula V) from the reaction mixture of step (5); (7) converting the acid addition salt of cariprazine (Formula V) of step (6) to cariprazine hydrochloride (I); and

(8) isolating cariprazine hydrochloride (I).

The process of the present invention as per the specific embodiment described above is illustrated in following Scheme-I,

Cl

Biphasic Solvent System

Organic solvent/water

ry

.acid

inorganic acid N NH

Formula II Formula III I

Formula V

Scheme-I

The inorganic base used in the step (1) of the above process (as depicted in the Scheme I) is selected from a group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide.

The organic base used in the step (2) of the above process (as depicted in the Scheme I) is selected from the group consisting of methylamine, ethylamine, diethylamine, benzylamine, triethylamine (TEA), diisopropyl amine, diisopropylethylamine, tri-n- butylamine, tert-butylamine, A-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine and dimethylaminopyridine.

The organic solvent used in the step (2) of above process (as depicted in the Scheme I) in forming the organic solvent phase is selected from a halogenated solvent such as dichloromethane, chloroform, tetrachloromethane, 4-bromotoluene, diiodomethane and chlorobenzene, or a mixture thereof; an aromatic solvent such as toluene, benzene and xylene, or a mixture thereof; an ether solvent such as diethyl ether, di-/ -butyl ether, di butyl ether, di -isopropyl ether, di-methoxy ethane, di-methoxymethane, 1,4-dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, or a mixture thereof; a ketone such as methyl isobutyl ketone; an ester such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate and isopropyl acetate, or a mixture thereof; and water, or a mixture thereof.

The alcoholic solvent used in step (4) of the above process (as depicted in the

Scheme I) is selected from methanol, ethanol, isopropanol, or a mixture thereof.

The organic acid used in step (5) of above process (as depicted in the Scheme I) in forming the acid addition is selected from formic acid, acetic acid, propionic acid, valeric acid, capric acid, oxalic acid, malonic acid, maleic acid, fumaric acid, malic acid, succinic acid, citric acid, tartaric acid, mandelic acid, benzoic acid, salicylic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or p- toluenesulfonic acid.

The inorganic acid used in step (5) of above process (as depicted in the Scheme I) in forming the acid addition is selected from hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid.

The term‘isolating’ the compound referred to in step (6) and step (8) corresponds to any of the general isolation steps comprising separation of organic phase, fdtration, decantation, extraction, distillation, evaporation of solvent, cooling and precipitation, concentration, crystallization, centrifugation, recry stallization, washing and drying.

In a preferred embodiment, the compound trans- 4-{2-[4-(2,3- dichlorophenyl)piperazin-l-yl] ethyl }cyclohexanamine (Formula II) is in the form of its dihydrochloride salt.

In a preferred embodiment, the acid addition salt of cariprazine is cariprazine malate (Formula IV) represented as,

According to another aspect, the present invention relates to an improved process for the preparation of cariprazine hydrochloride (Formula I),

Formula I comprising the steps of:

(a) reacting /ram-4- { 2-|4-(2.3-dichlorophcnyl)pipcrazin- 1 -yl |cthyl [cyclohcxanaminc

(Formula II) dihydrochloride,

(Formula II).2HC1 with A, '-dimcthylcarbamoyl chloride (Formula III)

Formula III in a biphasic solvent system selected from a halogenated hydrocarbon and water, in the presence of triethylamine (TEA);

(b) separating the organic solvent phase and subjecting it to solvent exchange with an alcoholic solvent to get a solution;

(c) treating the solution of step (b) with malic acid to obtain a malate salt of cariprazine (Formula IV);

Formula IV

(d) converting the cariprazine malate salt (Formula IV) of step (c) to cariprazine hydrochloride (Formula I).

According to another aspect of the present invention, the halogenated hydrocarbon used in step (a) is selected from dichloromethane, chloroform, tetrachloromethane, 4- bromotoluene, diiodomethane, chlorobenzene, or a mixture thereof.

In preferred embodiment, the halogenated hydrocarbon used in step (a) is dichloromethane .

According to another aspect of the present invention, the alcoholic solvent used in step (b) for the purpose of solvent exchange is selected from methanol, ethanol, isopropanol, or a mixture thereof.

The process of the present invention involving preparation of cariprazine hydrochloride (Formula I) via formation of malic acid salt of cariprazine (Formula IV) is illustrated in the following Scheme-II:

Scheme-II

The process illustrated in the above Scheme-II comprises the steps of adding N,N- dimethyl carbamoyl chloride (Formula III), triethylamine (TEA) and trans- 4-{2-[4-(2,3- dichlorophenyl)piperazin-l-yl] ethyl }cyclohexanamine dihydrochloride (II) in dichloromethane to a stirring aqueous solution of sodium hydroxide. The reaction mixture was further heated to temperature ranging from 35-40 °C for 5 hours. The separated dichloromethane layer (organic phase) was subjecting to solvent exchange with ethanol (alcoholic solvent), followed by the addition of malic acid. The malate salt of cariprazine (Formula IV) was isolated by precipitation at lower temperature of about 0 to 5 °C and fdtration. Further, the cariprazine malate (Formula IV) was suspended in water and methanol, and heated to the temperature of about 65 to 75 °C. To the reaction mixture was added dilute hydrochloric acid solution at the same temperature and continued stirring for 10 min to obtain a clear solution. The cariprazine hydrochloride (I) was isolated by precipitation and filtration of the solution by cooling at temperature of about 0 to 5 °C.

Advantageously, the improved process of the present invention for the preparation of cariprazine hydrochloride (Formula I) as described herein, requires a shorter reaction time of about 5 hours.

The inventors of the present invention have also observed by in-process reaction monitoring that the quantity of the organic base also affect the product formation. For instance, the conversion of the reactant /ram-4-{2-|4-(2.3-dichlorophenyl)piperazin- 1 - yl] ethyl jcyclohexanamine (Formula II) to the product was experimented using triethylamine (TEA) at different molar concentrations with respect to the compound of Formula II and monitored. The following Table- A, refers to the results obtained by the use of triethylamine at different molar ratio, wherein the higher % of the product formation (about 99.03%) was observed with minimal % (about 0.07%) of total impurity formation using 1.27 mole equivalents of TEA.

Table-A:

Accordingly, the improved process of the present invention for the preparation of cariprazine hydrochloride (Formula I) as described herein involves the use of organic base at 1.27 mole equivalent with respect to the compound trans- 4-{2-[4-(2,3- dichlorophenyl)piperazin-l-yl]ethyl}cyclohexanamine (Formula II).

In an embodiment, the process of the present invention involves formation of a salt represented as cariprazine malate (Formula IV),

Formula IV

In an embodiment, there is provided a compound represented as cariprazine malate (Formula IV)

Formula IV

In another aspect, the cariprazine malate (Formula IV) of the following formula,

Formula IV is prepared by the process comprising the steps of:

(a) reacting trans -4-{2-[4-(2, 3-dichlorophenyl)piperazin- 1-yl] ethyl }cyclohexanamine (Formula II) or its salt,

Formula II with A', '-dimcthylcarbamoyl chloride (Formula III)

Formula III in a biphasic solvent system containing an organic solvent phase and an aqueous phase, in the presence of a base;

(b) separating the organic solvent phase and subjecting it to solvent exchange with an alcoholic solvent to get a solution;

(c) treating the solution of step (b) with malic acid to obtain a malate salt of cariprazine (Formula IV).

The term‘biphasic solvent system’ as used herein, refers to the reaction solvent, wherein the system consists of a two phase solvent system containing an organic solvent phase and an aqueous phase. In the context, the‘organic solvent phase’ is selected from a halogenated hydrocarbon, aromatic hydrocarbon, an ether, a ketone and an ester, or a mixture thereof; and the‘aqueous phase’ is water.

In an embodiment, the organic solvent phase used in step (a) is selected from a halogenated solvent such as dichloromethane, chloroform, tetrachloromethane, 4- bromotoluene, diiodomethane and chlorobenzene, or a mixture thereof; an aromatic solvent such as toluene, benzene and xylene, or a mixture thereof; an ether solvent such as di -tert- butyl ether, di -butyl ether, di-isopropyl ether, di-methoxyethane, di-methoxymethane, 1,4- dioxane, tetrahydrofuran and 2-methyltetrahydrofuran, or a mixture thereof; a ketone such as methyl isobutyl ketone; an ester such as ethyl acetate, methyl acetate, «-butyl acetate, isobutyl acetate, .sec-butyl acetate and isopropyl acetate, or a mixture thereof.

In a preferred embodiment, the organic solvent phase used in step (a) is a halogenated hydrocarbon. In an embodiment, the aqueous phase used in step (a) represents water.

According to one aspect of the present invention, the‘base’ used in the step (a) is selected from an organic base and an inorganic base.

In an embodiment, the inorganic base used in the step (a) is selected from a group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, cesium carbonate, calcium carbonate, sodium hydroxide and potassium hydroxide.

In a preferred embodiment, the inorganic base used in the step (a) is sodium hydroxide.

In an embodiment, the organic base used in the step (a) is selected from a group consisting of methylamine, ethylamine, diethylamine, benzylamine, triethylamine (TEA), diisopropyl amine, diisopropylethylamine, tri-n-butylamine, tert-butylamine, A-methyl morpholine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), pyridine and dimethylaminopyridine.

In a preferred embodiment, the organic base used in the step (a) is triethylamine (TEA).

In an embodiment, the cariprazine malate salt (Formula IV) is converted to cariprazine hydrochloride (Formula I) by the process steps comprising of:

(w) suspending the cariprazine malate salt (Formula IV) in water and an alcoholic solvent, and heating the reaction mixture to a temperature ranging from 65 to 75 °C;

(x) adding dilute hydrochloric acid solution to a stirring solution of step (w) at a temperature ranging from 65-75 °C;

(y) adding activated carbon to the stirring solution of step (x) at a temperature ranging from 65 to 75 °C, and filtering the reaction mixture; and

(z) cooling the filtrate of step (y) to a temperature ranging from 0 to 5 °C and isolating the precipitated cariprazine hydrochloride (Formula I).

In an embodiment, the alcoholic solvent used in the step (w) is selected from methanol, ethanol, isopropanol, or a mixture thereof.

Accordingly, the improved process of the present invention for the preparation of cariprazine hydrochloride (Formula I) as described herein provides the product cariprazine hydrochloride (Formula I) with purity of about > 99.73 % as determined by high- performance liquid chromatography (HPLC).

HPLC method and analysis:

HPLC purity was determined using Agilent 1200 HPLC instrument, having other parameters as:

Column: X Bridge C18, 3.5 pm (150 mm X 4.6 mm)

Flow rate: LO mL/min

Detection: UV at 215 nm

Diluent: dil. hydrochloric acid + Methanol

Mobile Phase: Orthophosphoric acid + Acetonitrile

The invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES

Example 1: Preparation of Cariprazine malate salt (Formula IV)

Charged sodium hydroxide (51.2 g) and water (100 mL) in a flask at 20-25 °C and stirred for 10 min. To the stirring reaction mixture was added dichloromethane (200 mL), triethylamine (6.0 g), A, A-di methyl carbamoyl chloride (10 g, Formula III) and trans- 4-{2- [4-(2,3-dichlorophenyl)piperazin-l-yl]ethyl}cyclohexanamine dihydrochloride (20 g, Formula II). The reaction mixture was heated to a temperature of about 38 to 40 °C for 5.0 hrs. The reaction mixture was cooled to room temperature and the organic solvent layer was separated, concentrated and ethanol (100 mL) was added. Malic acid (6.33 g) was added in to the alcoholic solution and the reaction mixture was heated to a temperature of about 70 to 75 °C to obtain a clear solution. The reaction mixture was cooled to a temperature of about 0 to 5 °C and the precipitated solid was fdtered and dried to provide cariprazine malate salt (Formula IV).

Yield - 17.5 g (0.87 w/w) Example 2: Preparation of Cariprazine malate salt (Formula IV)

Charged sodium hydroxide (256 g) and water (500 mL) in a flask at 20-25 °C and stirred for 10 min. To the stirring reaction mixture was added dichloromethane (1000 mL), triethylamine (30.0 g), A' A'-dimcthylcarbamoyl chloride (50 g, Formula III) and trans-4-{2- [4-(2,3-dichlorophenyl)piperazin-l-yl]ethyl}cyclohexanamine dihydrochloride (100 g, Formula II). The reaction mixture was heated to a temperature of about 38 to 40 °C for 5.0 hrs. The reaction mixture was cooled to room temperature and the organic solvent layer was separated, concentrated and ethanol (500 mL) was added. Malic acid (31.23 g) was added in to the alcoholic solution and the reaction mixture was heated to a temperature of about 70 to 75 °C to obtain a clear solution. The reaction mixture was cooled to a temperature of about 0 to 5 °C and the precipitated solid was filtered and dried to provide cariprazine malate salt (Formula IV).

Yield - 87 g (0.87 w/w)

Example 3: Preparation of Cariprazine hydrochloride (Formula I)

Charged cariprazine malate (12 g, Formula IV), water (96 mL) and methanol (24 mL) in a flask, followed by heating the reaction mixture to a temperature about 72° C. To the reaction mixture was added dilute hydrochloric acid (5.89 mL) and continued stirring at temperature of about 68 to 72 °C to obtain clear solution. To the stirring solution was added activated carbon ( 1.2 g) and the hot solution was filtered through Hyflo bed. The filtrate was cooled to 0 to 5°C and stirred for 3 hrs. at 0-5°C. The precipitated solid was filtered and dried to provide pure cariprazine hydrochloride (Formula I).

Yield: 9.2 g (0.76 w/w), HPLC purity: 99.73%.