FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Cariprazine hydrochloride (1). It further provides Cariprazine hydrochloride (1) with purity more than 99.0% by High-performance liquid chromatography (HPLC).
BACKGROUND OF THE INVENTION
Cariprazine hydrochloride (1) is an antipsychotic drug and is indicated for the treatment of schizophrenia and acute treatment of manic or mixed episodes associated with bipolar I disorder. It is also potentially useful as an add-on therapy in major depressive disorder. Chemically, it is known as trans-N-{4-[2-[4-(2,3-dichlorophenyl) piperazine-1-yl] ethyl] cyclohexyl}-N', N'-dimethylurea hydrochloride. It is marketed by Actavis under the trade name Vraylar and was approved by the FDA in September 2015.
The following patents and non-patents describe the synthesis of Cariprazine hydrochloride (1). The contents of which are hereby incorporated as reference in their entirety.
US9718795 patent discloses the process for the synthesis of Cariprazine, by treating tert-butyl (lR,4R)-4-(2-hydroxyethyl) cyclohexylcarbamate with l-(2,3-dichlorophenyl) piperazine with triruthenium dodecacarbonyl (Ru3(CO)i2) and xantophos to form trans-4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclohexylamine. It was further treated with l,l'-Carbonyldiimidazole and dimethylamine hydrochloride in presence of triethylamine to form N-trans-4-2-4-(2,3-dichlorophenyl)-l-piperazinylethylcyclohexyl)-N', N'-dimethyl urea. It uses flash chromatography for the purification of the intermediates and the said compound. Flash chromatography reservoirs are susceptible to explode due to over pressurization and fluctuations in pressure which is inconvenient and unsafe at industrial scales. Also, the purity of the final product and intermediates are not disclosed.

US7943621 patent discloses the synthesis of Cariprazine hydrochloride (1) by adding trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-l-yl]-ethyl}-N, N-dimethylcarbamoyl cyclohexyl amine to a mixture of water and methanol and treating with ammonium chloride or aqueous hydrogen chloride solution and isolating Cariprazine hydrochloride (1) as crystalline form I and anhydrous forms but does not disclose the purity of the intermediates or the final compound.
Synthesis 2016, 48, A-G discloses a process for the synthesis of Cariprazine hydrochloride by reacting 2-[trans-4-(3,3-dimethylureido) cyclohexyl] ethylmethanesulfonate with l-(2,3-dichloro phenyl) piperazine, sodium carbonate, potassium iodide and acetonitrile. The reaction mixture on treatment with hydrochloric acid and ethyl acetate formed Cariprazine hydrochloride. This process leads to the formation of an impurity ethyl 2-(4-(ethoxycarbonylamino)cyclohexyl) acetate which is very difficult to remove from the final active pharmaceutical ingredient (API), further the prior art does not disclose the purity of the intermediates.
Drawbacks associated with the above said prior arts include purification of intermediates and Cariprazine using column chromatography which is not feasible for industrial scale, lack of desired yield and purity of Active Pharmaceutical Ingredient (API)B and impurities associated with final API. Hence, the present invention aims at providing an improved process for the preparation and purification of Cariprazine hydrochloride (1) limiting the formation of impurities and yield enhancement of the final compound by using safe and commercially viable reagents under mild reaction conditions and in short time which are applicable at large scales.
OBJECTIVE OF THE INVENTION
Accordingly, one objective of the invention is to provide an improved process for the preparation of Cariprazine hydrochloride (1).

Another objective of the invention is to provide Cariprazine hydrochloride (1) with purity greater than 99.0% by High-performance liquid chromatography (HPLC).
Yet, another objective of the invention is to provide a process for the removal of a dimer impurity identified as 4-(2,3-dichlorophenyl)-N-((trans)-4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclohexyl) piperazine-1-carboxamide from the Cariprazine hydrochloride (1).
SUMMARY OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of Cariprazine hydrochloride (1) following steps as depicted in scheme-1 comprising:
a) Converting tert-butyl 4-oxocyclohexylcarbamate (9) to ethyl 2-(4-((tert-butoxy carbonyl) amino) cyclo hexylidene) acetate (8) using Wittig reagent;
b) hydrogenating intermediate (8) to obtain ethyl 2-(4-((tert-butoxy carbonyl) amino) cyclo hexyl) acetate (7);
c) deprotecting the amino protecting group followed by amidation of intermediate (7) to afford ethyl 2-(4-(3,3-dimethylureido) cyclohexyl) acetate (6);
d) hydrolysis of intermediate (6) to form 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) acetic acid (5);
e) reducing intermediate (5) to obtain 3-((trans)-4-(2-hydroxyethyl) cyclohexyl)-1,1-dimethylurea (4);
f) protecting intermediate (4) by using suitable hydroxyl protecting group to yield 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) ethyl 4-methylbenzenesulfonate
(3);
g) coupling of intermediate (3) with l-(2,3-dichlorophenyl) piperazine
hydrochloride (10) to form Cariprazine free base (2); and
h) converting Cariprazine free base (2) to Cariprazine hydrochloride (1).

In another aspect, the present invention provides an alternative process for the preparation of Cariprazine hydrochloride (1) by coupling intermediate (3) and intermediate (10) without isolating Cariprazine free base (2) as described in scheme-2.
Another aspect of the present invention is to provide process for the preparation of solid form of Cariprazine hydrochloride (1) comprising:
I. providing a mixture of Cariprazine hydrochloride (1) in a suitable protic
solvent; II. stirring the reaction mixture at 25-30 °C; and III. isolating Cariprazine hydrochloride (1)
In another aspect, the present invention provides Cariprazine hydrochloride (I), having purity greater than 99.0% by HPLC.
In another aspect, the present invention provides pure trans isomer of intermediate (5) having purity greater than 99.0% which is advantageous over prior arts as it is commercially applicable at industrial scale.
Yet in another aspect the present invention provides intermediate 3-((trans)-4-(2-hydroxyethyl) cyclohexyl)-l,l-dimethylurea (4) without any impurity, which makes another part of the embodiment.
Further, in another aspect , the present invention provides process for the control of dimer impurity 4-(2,3-dichlorophenyl)-N-((trans)-4-(2-(4-(2,3-dichloro phenyl) piperazin-1-yl) ethyl) cyclohexyl) piperazine-1-carboxamide (11) in the final Cariprazine, which provides Cariprazine hydrochloride with dimer impurity less than 0.2%, preferably less than 0.15% (w/w), still more preferably less than 0.1% (w/w).

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, in one embodiment the present invention provides an improved process for the preparation of Cariprazine hydrochloride (1) with purity greater than 99.0% by HPLC.

In one embodiment, step a) proceeds with reacting tert-butyl 4-oxocyclohexylcarbamate (9) with a suitable Wittig reagent in presence of base in aprotic solvent to obtain ethyl 2-(4-((tert-butoxy carbonyl) amino) cyclohexylidene) acetate (8).
In another embodiment, the suitable Wittig reagent used in step a) may be selected from the group comprising of triethyl phosphonoacetate, trimethyl phosphonoacetate, triphenyl phosphonoacetate, ethyl (triphenylphosphoranylidene)acetate, methyl (triphenylphosphoranylidene) acetate or the like. Preferably triethyl phosphonoacetate was used in the present invention.
In some embodiment, step b) proceeds with hydrogenation of ethyl 2-(4-((tert-butoxy carbonyl) amino) cyclohexylidene) acetate (8) using a suitable hydrogenating source in presence of suitable catalyst to yield ethyl 2-(4-((tert-butoxy carbonyl) amino) cyclohexyl) acetate (7).
In yet another embodiment, the hydrogenating source used in step b) may be selected from the group comprising of hydrogen gas, ammonium formate, ammonium acetate, hydrazine, cyclohexadiene or the like. The catalyst used was selected from a group comprising of Raney nickel, platinum oxide, platinum on activated carbon, palladium hydroxide, palladium on barium sulfate, palladium on activated carbon, and palladium

carbonate or the like. More preferably combination of ammonium formate and palladium on activated carbon was used in the present invention.
In some embodiment, step c) proceeds with the deprotection of the amino protecting group of intermediate (7) using a suitable deprotecting agent subsequently treating with suitable carbamoyl halide reagent in presence of base in an aprotic solvent to form ethyl 2-(4-(3,3-dimethylureido) cyclohexyl) acetate (6). Deprotection of amine protecting group of intermediate (7) in step c) may be carried out by treating intermediate (7) with organic or inorganic acids. The organic acid may be selected form the group consisting of carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoro methane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-toluenesulphonic acid. The inorganic acid may be selected from the group consisting of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate. More preferably trifluoroacetic acid may be used in the present invention.
In another embodiment, the suitable reagent for amide formation in step c) may be selected from a group comprising of diethylcarbamoyl chloride, N-methylcarbamoyl chloride, dimethylcarbamoyl chloride, diphenylcarbamoyl chloride or the like, preferably dimethylcarbamoyl chloride was used in the present invention. The said reaction is carried out at a temperature from about -10 °C to 60 °C, preferably about 5 °C to 35 °C.
In some embodiment, step d) involves hydrolysis of ethyl 2-(4-(3,3-dimethyl ureido) cyclohexyl) acetate (6) using suitable base in an aprotic solvent. It further involves the - resolution of mixture of isomers formed to a pure isomer of 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) acetic acid (5) using a suitable protic solvent.

The protic solvent used in step d) was preferably methanol, the purity of trans isomer of intermediate (5) is more than 99.0% and is advantageous over prior arts as it is applicable at industrial scale.
In some embodiment, step e) involves reduction of intermediate (5) using a suitable reducing agent with an additive in an aprotic solvent to form 3-((trans)-4-(2-hydroxyethyl) cyclohexyl)-l,l-dimethyl urea (4). The use of sodium borohydride with boron trifluoride etherate for the conversion of 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) acetic acid (5) to hydroxy intermediate 3-((trans)-4-(2-hydroxyethyl) cyclohexyl)-l,l-dimethylurea (4) takes an advantage of ameliorating diester impurity ethyl 2-((lR,4R)-4-(ethoxycarbonylamino) cyclohexyl) acetate (12) as reported in article Synthesis 2016, 48, A-G, which forms another part of the embodiment.
Synthesis 2016, 48, A-G, disclosed the synthesis of 3-((lR,4R)-4-(2-hydroxyethyl) cyclohexyl)- 1,1-dimethylureaintermediate (4) from 2-((lR,4R)-4-(3,3-dimethylureido) cyclohexyl) acetic acid intermediate (5) through ethyl 2-((lR,4R)-4-(3,3-dimethyl ureido) cyclohexyl) acetate intermediate (5a) as depicted in scheme-3. The ester intermediate (5a) undergo reaction with ethanol in presence of sulphuric acid yields diester impurity ethyl 2-((lR,4R)-4-(ethoxycarbonylamino) cyclohexyl) acetate (12).

A suitable reducing agent may be selected from the group comprising of sodium borohydride, lithium borohydride, diisobutylaluminium hydride, sodium triacetoxy brohydride, A suitable additive used in step e) may be selected from the group comprising of boron trifluoride etherate, borane etherate, aluminium trichloride, titanium isopropoxide, tin chloride, cerium (III) chloride, calcium chloride, zinc chloride, copper (II) sulfate, zirconium (IV) chloride, borane dimethyl sulphide, sulfuric acid, catechol, trifluoroacetic acid, 3,4,5-trifluorophenylboronic acid or the like. Preferably sodium borohydride and boron trifluoride etherate was used in the present invention.
In some embodiment, step f) involves protection of the hydroxyl group of intermediate (4) to form 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) ethyl 4-mefhyl benzenesulfonate (3) using suitable protecting agent and a base in an aprotic solvent.
Primary hydroxyl group of the intermediate (4) can be protected as corresponding ethers, silyl ethers, esters, carbamates or the like. Suitable protecting agent to form ethers and silyl ether fuctionality may be selected from the group comprising of tosyl chloride, mesyl chloride, benzyl chloride, tetrahydropyrene, methoxymethyl chloride, trimethylsilyl chloride or the like; suitable protecting agent to form esters functionality may be selected from the group comprising of acetyl chloride, benzyl chloride, N,N-

dimethylacetamide or the like; suitable protecting agent to form carbamate fuctionality may be selected from the group comprising of diethylcarbamoyl chloride, N-methylcarbamoyl chloride, dimethylcarbamoyl chloride, diphenylcarbamoyl chloride or the like. Preferably, tosyl chloride was used in the present invention.
In some embodiment, step g) involves the coupling of intermediate (3) with l-(2,3-dichlorophenyl) piperazine hydrochloride (10) in presence of a suitable base in an aprotic solvent to form 3-((trans)-4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclohexyl)-1,1 -dimethylurea (2). The said reaction may be carried out at a temperature of about 20 °C to about 60 °C, more preferably at 30 °C - 50 °C.
In another embodiment, step g) discloses a process for the preparation 3-((trans)-4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl) ethyl) cyclohexyl)-1,1-dimethylurea (2). The present inventors surprisingly found that effect of temperature of the reaction on the impurity formation. The optimum temperature to control the dimer impurity (11) is in the range of 40 to 55 °C, more preferably the optimum temperature range is 43 to 48 °C. The dimer impurity level in the Cariprazine is less than 0.2% (w/w), more preferably less than 0.15% (w/w) and still more preferably less than 0.1% (w/w). Prior arts do not disclose any information about this impurity.

In some embodiment, step h) proceeds with formation of acid additional salt of Cariprazine (1) by reacting Cariprazine free base (2) with suitable acid in protic solvent.
Suitable acid used in step h) for the preparation of salt of Cariprazine may be selected from the group comprising of organic and inorganic acids. The organic acids may be selected from trifluoroacetic acid, trifluoro methane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid, p-touenesulphonic acid or the like. The inorganic acid may be selected from a group comprising of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid or the like. Preferably hydrochloric acid was used for the preparation of hydrochloride salt of Cariprazine (1) in the present invention.
In another embodiment the present invention provides alternative process for the preparation of Cariprazine hydrochloride (1), which proceeds by reacting intermediate (3) with l-(2,3-dichlorophenyl) piperazine hydrochloride (10) in presence of a suitable base in an aprotic solvent and further treating with hydrochloric acid source to yield Cariprazine hydrochloride (1)
In some embodiment, the suitable hydrochloride source used may be selected from a group comprising of ammonium chloride, hydrochloric acid, ethyl acetate hydrochloride or the like, preferably hydrochloric acid was used in the present invention.
In some embodiment, the suitable protic solvent used in step a), step b), step c), step d), step e), step f), step g), and step h), may be selected from a group comprising of water, methanol, ethanol, isopropyl alcohol (IPA), n-propanol, n-butanol, or the like, preferably water, methanol, ethanol, isopropyl alcohol and n-butanol were used in the present invention.
In some embodiment, the suitable aprotic solvents used in step a), step b), step c), step d), step e), step f), step g) and step i) may be selected from a group comprising of acetone, acetonitrile, 1,4-dioxane, diethyl ether, dichloromethane, ethyl acetate, N, N-

dimethylformamide, methyl tertiary butyl ether, hexane, cyclohexane, toulene, tetrahydrofuran or the like, preferably tetrahydrofuran, ethyl acetate, dichloromethane, , n-hexane , acetonitrile, toulene were used in the present invention.
The suitable bases used in the present invention of steps a), step c), step d), step e), step f) and step g) may be selected from a group comprising of inorganic and organic bases. The inorganic base were used in the present invention was selected from the group comprising of alkoxides of alkali and alkaline metals such as potassium tertiary butoxide, potassium ethoxide, potassium isopropoxide, potassium tertiary amyloxide, sodium methoxide, sodium isopropoxide, lithium tertiary butoxide, magnesium isopropoxide, calcium isopropoxide or the like; hydroxides of alkali and alkaline metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide or the like; carbonates of alkali and alkaline metals such as sodium carbonate, potassium carbonate, magnesium carbonate or the like; and bicarbonates of alkali and alkaline metals such as sodium bicarbonate, potassium bicarbonate or the like.
Suitable organic base used in the present invention may be selected from the group comprising of triethyl amine, diisopropylethylamine, diethyl amine, isopropyl amine, morpholine, N-methyl morpholine, pyridine, ammonia, 1,8-diazabicyclo [5.4.0] undec-7-ene, 1,4-diazabicyclo [2.2.2] octane or the like. Preferably potassium tertiary butoxide, sodium hydroxide, sodium carbonate, potassium carbonate and triethyl amine were used in the present invention.
Cariprazine hydrochloride (1) obtained by the above process may be having purity greater than 99.0% by HPLC. The dimer impurity (11) level in the Cariprazine hydrochloride is less than 0.2% (w/w), more preferably less than 0.15% (w/w) and still more preferably less than 0.1% (w/w). Prior arts do not disclose any information about this impurity.

Another embodiment of the invention is to provide Cariprazine hydrochloride (1) with heavy metals less than 20 ppm. In another embodiment the combination of lead and arsenic is less than 2ppm.
In another embodiment the present invention provides Cariprazine hydrochloride (1) having chloride content less than 8.0, preferably less than 7.0% (w/w) by HPLC.
Another embodiment of the present invention is to provide process for the preparation of solid form of Cariprazine hydrochloride (1) comprising:
I. providing a mixture of Cariprazine hydrochloride (1) in a suitable protic
solvent; II. stirring the reaction mixture at 25-30 °C; and III. isolating solid Cariprazine hydrochloride (1).
The suitable protic solvent used may be selected from the group comprising of alcohols, and water. The alcohols may be selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol or the like. More preferably isopropanol was used in the present invention.
The following examples further illustrate the present invention, but should not be construed in anyway, as to limit its scope.
EXAMPLES
EXAMPLE-1: Preparation of ethyl 2-(4-((tert-butoxycarbonyl) amino)
cyclohexylidene) acetate (8)
125.5g of triethylphosphonoacetate was added to 78.55g potassium tert-butoxide in 1000 mL of tetrahydrofuran at 0-5 °C for 1.5hrs. To the above reaction mass, a solution of lOOg of tert-butyl 4-oxocyclohexylcarbamate (9) dissolved in 800mL of tetrahydrofuran was added at 0-5 °C for 2hrs. The temperature of the reaction mass was raised to 25-30 °C and stirred for 6-8hrs. Upon completion of reaction, the reaction mixture was diluted with water at 15-20 °C and the tetrahydrofuran was distilled off

below 60 °C. The solid so obtained was cooled to 25-30 °C and 100 mL of water and 1.5L of ethyl acetate were added. The aqueous layer was separated and washed with 500 mL of ethyl acetate. The combined organic layers were collected, distilled below 60 °C and the solid dried under hot-air oven at 35-40 °C to obtain ethyl 2-(4-((tert-butoxycarbonyl) amino) cyclohexylidene) acetate (8). Yield: 71.2%, Purity: 95.0%
EXAMPLE-2: Preparation of ethyl 2-(4-((tert-butoxycarbonyI) amino) cyclohexyl) acetate (7)
lOOg of ethyl 2-(4-((tert-butoxycarbonyl) amino) cyclohexylidene) acetate (8) was dissolved in a mixture of 600mL of ethanol and 50mL of water at 25-30 °C. 32.7 g of Palladium on carbon and aqueous ammonium formate solution were added to the reaction mass and heated to 45-50 °C for 2-3hrs. After completion of reaction, the reaction mass was filtered and washed with lOOmL of water and lOOmL of ethanol. The mother liquor solution was concentrated below 60 °C and cooled to 25-30 9C. The solid so obtained was dissolved in 200mL of water and 700mL of ethyl acetate and the phases were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with water, dried over sodium sulphate and concentrated under vacuum below 50 °C to yield ethyl 2-(4-((tert-butoxycarbonyl) amino) cyclohexyl) acetate (7). Yield: 95.2%, Purity: 95.0%
EXAMPLE-3: Preparation of Ethyl 2-(4-(3,3-dimethyl ureido) cyclohexyl) acetate
(6)
lOOg of ethyl 2-(4-((tert-butoxycarbonyl) amino) cyclohexyl) acetate (7) was dissolved in 1000 mL of dichloromethane and 166 mL of trifluoracetic acid was added slowly to the reaction mass. The reaction mass was heated at 40-45 °C for 2-3hrs and then cooled to 30 °C. The solvent was distilled off and co-distilled with toluene below 65 °C. The crude so obtained was cooled to 0-5 °C and dissolved in lOOOmL of dichloromethane. 30% sodium hydroxide was further added to the reaction mass and stirred for 30 min at

0-5 °C. To this reaction solution 67.8g of N, N-dimethyl carbamoyl chloride was added for lhr and maintained for 2hrs. The temperature of the reaction mass was raised to 25-30 °C. Upon completion of reaction, the phases were separated, and the aqueous layer was extracted with dichloromethane. The organic layers were combined and washed with 20% sodium chloride solution. The dichloromethane was removed by distillation under vacuum and the concentrate was co-distilled with 200mL of tetrahydrofuran below 50 °C to furnish ethyl 2-(4-(3,3-dimethyl ureido) cyclohexyl) acetate (6). Yield :83.6%, Purity: 95.0%.
EXAMPLE-4: Preparation of 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) acetic acid (5)
lOOg of ethyl 2-(4-(3,3-dimethyl ureido) cyclohexyl) acetate (6) was dissolved in a mixture of lOOOmL tetrahydrofuran and sodium hydroxide solution (39 g in 250 ml water). The reaction mass was heated to 60-65 °C for 9-10 hrs. On completion of reaction, the solvent was distilled off below 60 °C. The reaction mass was cooled to 25-30 °C and diluted with 300mL of water and 300mL of dichloromethane. The aqueous layer was separated and washed with 300mL of dichloromethane and layers separated. The pH of aqueous layer was adjusted to 1-2 with 50% hydrochloric acid. The solid formed was filtered and washed with 200 raL of water. The wet reaction mass was mixed with 500mL of water, stirred for 10 -15 minutes and filtered. The solid obtained was washed with water and dried at 50-55 °C to obtain 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) acetic acid (5). Yield: 78.6%. Purification of 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) acetic acid (5) 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) acetic acid (5) was mixed with 15 volumes of methanol and heated to 60-65 °C until clear solution observed. The clear solution was cooled to 25-30 °C, maintained for 2hrs and further continued stirring for 3hrs at 0-5 °C. The solid so formed was filtered, washed with chilled methanol and dried in hot air oven at 50-55 °C to obtain pure 2-((trans)-4-(3,3-dimethylureido) cyclohexyl)

acetic acid (5).Yield %: 40 g, Purity %: 99. 85 (Cis isomer content NMT-0.15%) by HPLC.
EXAMPLE-5: Preparation of 3-((trans)-4-(2-hydroxyethyI) cyclohexyI)-l,l-dimethylurea (4)
lOOg of 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) acetic acid (5) and 35g sodium borohydride were added portion wise to a mixture of boron trifluoride etherate (300mL) and tetrahydrofuran (2000mL) which was cooled to 0-5 °C for 1-2 hrs. The temperature of the reaction mixture was raised to 25-30 °C and maintained for lhr. Upon completion of reaction, the reaction mixture was diluted with water (300mL) at 0-5 °C. The temperature of the reaction mixture was raised to 25-30 °C and the solvent was distilled off. 200mL of 50% hydrochloric acid was added to the concentrate and maintained for l-2hr. The pH was adjusted to 14 by adding 50% sodium hydroxide (500mL). 1500mL of dichloromethane was added to the reaction mass and the phases were separated. The aqueous layer was extracted with dichloromethane and the organic layers were combined and washed with water and 20% sodium chloride solution. The organic layer was dried over sodium sulphate and concentrated under vacuum to afford 3-((trans)-4-(2-hydroxyethyl) cyclohexyl)-1,1-dimethyl urea (4).
Alternative process for the purification of 3-((trans)-4-(2-hydroxyethyl) cyclohexyi)-l,l-dimethylurea (4)
3-((trans)-4-(2-hydroxyethyl) cyclohexyl)- 1,1-dimethylurea (4) so obtained was added to 250mL of n-hexane was added and stirred for lhr. The solid mass formed was filtered and washed with n-hexane and dried hot air oven at 50-55 °C. Further the obtained intermediate (4) so obtained was added to dichloromethane (5 volumes) and n-hexane (75 volumes) and stirred for 4hrs. The solid formed was filtered and washed with n-hexane (1 volumes) and dried to obtain pure 3-((trans)-4-(2-hydroxyethyl) cyclohexyl)-1,1-dimethylurea (4). Yield: 74.6%, Purity: 99.0%.

EXAMPLE-6: Preparation of 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) ethyl 4-methylbenzenesulfonate (3)
lOOg of 3-((trans)-4-(2-hydroxyethyl) cyclohexyl)-1,1-dimethylurea (4) was added to 1000 mL of dichloromethane at 25-30 °C. 94.5 g of triethylamlne was added to the reaction mass at 25-30 °C and cooled to 0-5 °C. Further, 106.5g of/?-toluenesulfonyl chloride was then added to the reaction mass at 0-5 °C and stirred for 3 hrs. The temperature of the reaction mass was raised to 25-30 °C for 7-8hrs. On completion of reaction, 1000 mL of 10% of sodium carbonate solution was added to the reaction mass and separated the phases. The organic layer was washed with IN hydrochloric acid, water and 20% sodium chloride solution and distilled off the organic layer under vacuum followed by co-distillation with n-hexane. To the obtained solid, n-hexane was added and maintained for 30min. The reaction mass was filtered and the solid was washed with n-hexane and dried under vacuum to obtain 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) ethyl 4-methylbenzenesulfonate (3). Yield: 70.5%, Purity: 95.0%
EXAMPLE-7: Preparation of Cariprazine (2)
lOOg of 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) ethyl 4-methylbenzenesulfonate (3) was dissolved in 20 volumes of acetonitrile and stirred for 15 mins. 83.6g of l-(2,3-dichlorophenyl) piperazine hydrochloride (10), 224.5g of potassium carbonate and lOOOmL of water were added to the reaction mass and temperature raised to 45-50 °C for 21hrs. On completion of reaction, the reaction mass was cooled to 25-30 °C and stirred for lhr.The solid formed was washed with a mixture of water and acetonitrile and dried under vacuum below 50 °C to obtain Cariprazine (2). Purification of Cariprazine (2)
The Cariprazine (2) was dissolved in 8 volumes of 10% dichloromethane in n-butanol and heated to 40-50 °C for lhr. The reaction mass was cooled, filtered and washed the solid with 0.5 volumes of acetonitrile at 25-30 °C. The solid so obtained was dried under vacuum to form pure Cariprazine (2). Yield: 45.4%, Purity: 99.5%.

EXAMPLE-8: Preparation of Cariprazine hydrochloride (1)
lOOg of Cariprazine (2) was dissolved in 700mL of methanol and stirred for 10-15 mins at 25-30 °C. 130mL of 15% ethyl acetate hydrochloride was added to the reaction mass to maintain pH of 5.3-5.0. The reaction mixture was stirred for 45 min to lhr at 25-30 °C. The reaction mass was filtered through Hyflo and distilled off to form of Cariprazine hydrochloride (1). Yield: 60%, Purity: 99.89%.
Example-9: Alternative process for preparation of Cariprazine hydrochloride (1)
lOOg of 2-((trans)-4-(3,3-dimethylureido) cyclohexyl) ethyl 4-methylbenzenesulfonate (3) was dissolved in 1800 mL of acetonitrile and stirred for 15 mins. 83.6g of l-(2,3-dichlorophenyl) piperazine hydrochloride (10), 224.5g of potassium carbonate and lOOOmL of water were added to the reaction mass and temperature raised to 43-48 °C. The reaction mixture was maintained for 21hrs at 43-48 °C. The reaction mass was cooled to 25-30 °C and added 130mL of 10% dilute hydrochloric acid. Suspension was stirred for 3-4hrs at 25-30 °C and then cooled to 0-5 °C for 45-60 min. The precipitated product was filtered and washed with a mixture of 300mL of water and lOOmL of acetonitrile and dried at below 60 °C to obtain Cariprazine hydrochloride. Yield: 65%, Purity: 99.85%.
Example-10: Alternative process for the preparation of Cariprazine hydrochloride
(1)
lOOg of Cariprazine (2) was dissolved in 900mL of water and 200 mL of D (-) tartaric acid solution was then added to it at 25-30 °C. 400mL of 1.5N hydrochloric acid solution was further added and stirred for lhr. The reaction mass was then cooled to 0-5 °C and filtered under vacuum. The solid obtained was washed with a mixture of water and dichloromethane and dissolved in methanol. The reaction mass was then filtered through 0.2 mm micron filter. The filtrate was distilled off under vacuum below 45 °C. 50mL of isopropyl alcohol was then added to the residue and distilled off below 45 °C. The residue was then cooled to 25-30 °C and filtered. The solid obtained was washed

with the mixture of 200 mL ethyl acetate and isopropyl alcohol (1:1) and dried under vacuum below 45 °C to yield Cariprazine hydrochloride (1). Yield: 80%; Purity: 99.90%.
Exampl-11: Purification of Cariprazine hydrochloride (1)
The Cariprazine hydrochloride (1) was mixed with 500 mL isopropyl alcohol and stirred for 30-60 min at 40-45 °C. The reaction solvent was distilled off at below 45 °C. The solid so formed was cooled to 25-30 °C and 300mL of isopropyl alcohol was added and maintained for 2-3 hrs. The solid was filtered and washed with isopropyl alcohol and dried under vacuum to obtain Cariprazine hydrochloride (1). Yield: 68%; Purity: 99.95%.

h) converting Cariprazine free base (2) to Cariprazine hydrochloride (1)
2. The process, as claimed in claim 1, wherein the suitable Wittig reagent used in step a) is selected from a group comprising of triethyl phosphonoacetate, trimethyl phosphonoacetate, triphenyl phosphonoacetate, ethyl (triphenylphosphoranylidene)acetate, methyl (triphenylphosphoranylidene) acetate or the like.
3. The process, as claimed in claim 1, wherein the suitable catalyst used in step b) is selected from Raney nickel, platinum oxide, platinum on activated carbon, palladium hydroxide, palladium on barium sulfate, palladium on activated carbon, and palladium carbonate.
4. The process, as claimed in claim 1, wherein the suitable deprotecting agent used in step c) is selected from a group comprising of carboxylic acid or sulphonic acid such as trifluoroacetic acid, trifluoro methane sulphonic acid, methane sulphonic acid, formic acid, tartaric acid and p-toluene sulphonic acid, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid and sodium hydrogen phosphate.
5. The process, as claimed in claim 1, wherein the suitable reagent for amide formation in step c) is selected from a group comprising of diethyl carbamoyl chloride, N-methyl carbamoyl chloride, dimethyl carbamoyl chloride, diphenyl carbamoyl chloride.
6. The process, as claimed in claim 1, wherein the suitable reducing agent used in step e) is sodium borohydride in combination with boron trifluoride etherate.
7. The process, as claimed in claim 1, wherein the hydroxy 1 protecting groups used in step f) is selected from tosyl chloride, mesyl chloride, benzyl

chloride, tetrahydropyrene, methoxymethyl chloride, trimethylsilyl chloride acetyl chloride, benzyl chloride, N,N-dimethylacetamide diethyl carbamoyl chloride, N-methyl carbamoyl chloride, dimethyl carbamoyl chloride, diphenyl carbamoyl chloride.
8. A process for preparing solid form of Cariprazine hydrochloride (1)
characterized by X-ray powder diffraction pattern as shown in figure -1,
comprising:
i. providing a mixture of Cariprazine hydrochloride (1) in a suitable protic solvent selected from the group comprising of methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol; ii. stirring the reaction mixture at 25-30 °C; and iii. isolating solid Cariprazine hydrochloride (1).
9. A process for the purification of Cariprazine hydrochloride, which
comprises:
a) providing a mixture of Cariprazine hydrochloride (1) in a suitable protic solvent;
b) stirring the reaction mixture at 25-30 °C; and
c) isolating solid Cariprazine hydrochloride (1).
10. The process, as claimed in claim 9, wherein the Cariprazine hydrochloride
(1) is having purity greater than 99.0 % by HPLC and one or more of the
following;
a. less than 0.15% of dimer impurity; and
b. combination of lead and arsenic is less than 2ppm.