DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

Title of the Invention:

A PROCESS FOR PREPARATION OF CARIPRAZINE AND INTERMEDIATES THEREOF

Applicant Name and Address:
Megafine Pharma (P) Ltd
An Indian Company having registered address of
4th Floor, Sethna, 55, Maharshi Karve Road, Marine Lines,
Mumbai – 400 002,
Maharashtra,
India.

The following specification particularly describes the nature of this invention and the manner in which it is to be performed:
FIELD OF THE INVENTION:
The present invention relates to a process for preparation of Cariprazine hydrochloride.

BACKGROUND OF THE INVENTION:
N'-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea (here in “Cariprazine”) also known as Vraylar® is represented by the following structural formula:

Cariprazine, a potent dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors was first disclosed in US7737142 (hereafter US‘142). US’142 disclose two methods for preparation of Cariprazine from compound of formula (7a) (Scheme 1).

The process described in US’142 involves the use of expensive catalyst such as BINAP; aldehyde intermediate of formula (5); and hazardous compound like triphosgene. Further, the starting material is purified using chromatography technique and the estimated overall yield of the two disclosed methods for the preparation of Cariprazine is low (around 41% and 33 %) making the process less favorable at an industrial scale. The process described in US’142 discloses the coupling of amine compound 7(a, trihydrochloride) and N,N-dimethylcarbamoylchloride compound (8) at room temperature for 48 hours in presence of triethylamine as a base for preparation of cariprazine, wherein the obtained yield is low (65%). The reported alternative process discloses the coupling of amine of compound 7(a, trihydrochloride) and triphosgene to form isocynate derivative of compound (7a) which is further reacted with N,N-dimethylamine hydrochloride at room temperature for 20 hours in presence of triethylamine as a base for preparation of cariprazine, wherein the obtained yield is low (52%). The isocynate derivative of compound (7a) formed during the reaction is unstable and thus leads to lower yield.

WO2015056164 (hereafter WO‘164) discusses the preparation of Cariprazine as depicted in schemes 2 and 3.

WO’164 processes describes use of Xantphos ruthenium complex, and involves chromatographic techniques for purification, making the process tedious. Further, the estimated overall yield of the process is very low (around 35% for scheme 2, around 15% for scheme 3).

To overcome the above discussed process hurdles, the present invention, provides a simple, economical and industrially feasible process for preparation of Cariprazine and its acid addition salts thereof.

OBJECTS OF THE PRESENT INVENTION:
The primary object of the present invention is to provide efficient, feasible and industrially viable process for the preparation of Cariprazine and its acid addition salt thereof.

DETAILED DESCRIPTION OF THE INVENTION:
Before the present invention is described, it is to be understood that this invention is not limited to particular methodologies and materials described, as these may vary as per the person skilled in the art. It is also to be understood that the terminology used in the description is for the purpose of describing the particular embodiments only, and is not intended to limit the scope of the present invention.

Before the present invention is described, it is to be understood that unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Further, it is to be understood that the present invention is not limited to the methodologies and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described, as these may vary within the specification indicated. Unless stated to the contrary, any use of the words such as "including," "containing," "comprising," "having”, means "including without limitation" and shall not be construed to limit any general statement that it follows to the specific or similar items or matters immediately following it. Embodiments of the invention are not mutually exclusive, but may be implemented in various combinations. The described embodiments of the invention and the disclosed examples are given for the purpose of illustration rather than limitation of the invention as set forth the appended claims. Further the terms disclosed embodiments are merely exemplary methods of the invention, which may be embodied in various forms.

Before the present invention is described, it is to be understood that in all the aspects described below the stereospecific products are formed either by using the stereospecific starting material as inputs or by using the racemates thereof, wherever applicable.

The term herein “reflux temperature” means the temperature at which the solvent or the solvent system refluxes or boils at atmospheric pressure.

According to one of the embodiment, the present invention provides a process for preparation of Cariprazine hydrochloride, comprising:
a. basifying a compound of formula 13(a) to provide a free base of compound of formula 13 and further protecting the amino group of compound of formula 13 using a suitable amino-protecting agent to provide a compound of formula 17;

b. reducing the compound of formula 17 to provide a compound of formula 18;

c. activating the hydroxyl group of compound of formula 18 using an activating agent in a solvent and in presence of a base to provide a compound of formula 19;

d. reacting the compound of formula 19 with a compound of formula 4(a) in a solvent, in presence of a base to provide a compound of formula 20;

e. deprotecting the amino group of the compound of formula 20 using a suitable acid in a solvent to provide a compound of formula 7;

f. reacting the compound of formula 7 with a compound of formula 21 in a solvent and in presence of a base to provide a cariprazine free base;

g. treating the cariprazine free base obtained in step (f) with acetic acid to obtain cariprazine acetate salt, and converting the cariprazine acetate salt to cariprazine hydrochloride using dilute hydrochloric acid.

The acetate salt of cariprazine obtained in step (g) may be optionally isolated from the reaction mass.

The compounds of formulae (19), (20), (7) and (1) may be in its hydrate, solvate, or anhydrous form and may be isolated from the reaction mass.

The compounds of formulae (17), (18), (19), (20), (7) and (1) can be optionally isolated from the reaction mass and purified by involving at least one of the following methods like solvent extraction, crystallization, or distillation methods.
The compound of formulae (13a) is basified to provide compound of formula (13) in a solvent in the presence of a base.

The solvent used for the basification is selected from the group consisting of alkyl acetate selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, pentane; aromatic hydrocarbons selected from toluene, xylene, naphthalene; halogenated hydrocarbons selected from dichloromethane, chloroform, ethylene dichloride, chlorobenzene; dialkylformamides selected from dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, diisopropyl ether, diethyl ether and dimethyl ether, methyl butyl ether, dimethoxy ethane; cyclic ethers selected from tetrahydrofuran, 1,4-dioxane; substituted cyclic ethers selected from 2-methyl tetrahydrofuran, 4-methyl tetrahydropyran; alcohols selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, ethylene glycol, diethylene glycol; esters; ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides selected from ?,?-dimethyl acetamide; nitriles selected from acetonitrile, and propionitrile; ionic liquids; hexamethylphosphorous triamide; hexamethylphosphoramide; water; or mixtures thereof. Preferably, the solvent used for the basification is ether, water. More preferably, the solvent used is dimethoxy ethane, water or mixtures thereof.

Steps (a), (b), (c), (d), (e) (f), and (g) of the embodiment is carried out at a temperature of 25°C to reflux temperature of the solvent.
The base used for basifying step (a) is selected from inorganic bases selected from alkali metal carbonates selected from potassium carbonate, sodium carbonate, and cesium carbonate; alkali metal bicarbonates selected from sodium bicarbonate, and potassium bicarbonate; alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, barium hydroxide, and lithium hydroxide; metal hydrides, metal alkoxides selected from sodium methoxide, sodium ethoxide, and potassium tert butoxide; metal amides or liquor ammonia; and organic bases selected from primary amines selected from methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, and 2-amino ethanol; secondary amines selected from ?,?-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, and pyrrole methylethanolamine; tertiary amines like triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine, pyridine, lutidine, pyrimidine, and ?,?-dimethylethyl amine or mixtures thereof. Preferably, base is selected from alkali metal bicarbonates. More preferably, the basic compound for basifying is selected sodium bicarbonate.

The amino group of the compound of formula (13) obtained is further protected insitu using amino-protecting agents to provide a compound of formula (17).

The reaction of protecting the amino group of compound of formula (13) is carried out in a solvent, in the presence of a base, an amino protecting agent and optionally in presence of a phase transfer catalyst.

The solvent used for the amino protection of the compound of formula (13) is selected from the group consisting of alkyl acetate selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, pentane; aromatic hydrocarbons selected from toluene, xylene, naphthalene; halogenated hydrocarbons selected from are dichloromethane, chloroform, ethylene dichloride, chlorobenzene; dialkylformamides selected from dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, diisopropyl ether, diethyl ether and dimethyl ether, methyl butyl ether, dimethoxy ethane; cyclic ethers selected from tetrahydrofuran, 1,4-dioxane; substituted cyclic ethers selected from 2-methyl tetrahydrofuran, 4-methyl tetrahydropyran; alcohols selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, ethylene glycol, diethylene glycol; esters; ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides selected from ?,?-dimethyl acetamide; nitriles selected from acetonitrile, and propionitrile; ionic liquids; hexamethylphosphorous triamide; hexamethylphosphoramide; water; or mixtures thereof. Preferably, the solvent used for the in-situ amino protection of the compound of formula (13) is ethers and water. More preferably, the solvent used is dimethoxy ethane and water or mixtures thereof.

The “phase transfer catalyst” used for the amino protection of compound of formula (13) is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide. Preferably, the phase transfer catalyst used in step (a) tetra butyl ammonium bromide (TBAB).

The amino-protecting agent used for preparation of compound of formula (17) is selected from, but not limited to di-tert-butyl dicarbonate (DIBOC), benzyl chloro formate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, alkyl or aryl sulfonyl halides or anhydrides such as mesyl halides, mesyl anhydride, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, and trifluoroacetyl chloride. Preferably, the amino-protecting agent used for preparation of compound of formula (17) is di-tert-butyl dicarbonate (DIBOC).

The reduction of the compound of formula (17) to obtain compound of formula (18) is carried out in a solvent and using a reducing agent.

The solvent used for reducing compound of formula (17) is selected from the group consisting of alkyl acetate selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, pentane; aromatic hydrocarbons selected from toluene, xylene, naphthalene; halogenated hydrocarbons selected from dichloromethane, chloroform, ethylene dichloride, chlorobenzene; dialkylformamides selected from dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, diisopropyl ether, diethyl ether and dimethyl ether, methyl butyl ether, dimethoxy ethane; cyclic ethers selected from tetrahydrofuran, 1,4-dioxane; substituted cyclic ethers selected from 2-methyl tetrahydrofuran, 4-methyl tetrahydropyran; alcohols selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, ethylene glycol, diethylene glycol; esters; ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides selected from ?,?-dimethyl acetamide; nitriles selected from acetonitrile, and propionitrile; ionic liquids; hexamethylphosphorous triamide; hexamethylphosphoramide; water; or mixtures thereof.

Preferably, the solvent used for reducing compound of formula (17) is cyclic ethers. More preferably, the solvent used is tetrahydrofuran.

The reduction of compound of formula (17) to obtain compound of formula (18) is carried out using reducing agent selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, Fe/CaCl2, FeSO4, Fe powder, Raney Nickel, Pd/C, NaBH4, Potassium Borohydride, SnCl2.2H2O, Zn dust, Sodium Borohydride with Pd/C, thiophenol + trifluoroacetic acid, sodium sulphite, sodium hyposulphite, Na2S, NaBH4, NaBH4/BF3-diethyl ether, NiCl2.6H2O, LiBH4; LiAlH4. The reduction of the compound of formula (17) can be carried out using reducing agent and suitably, in the presence of Lewis acid; or hydrogen gas or hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid and hydrazinium monoformate.

Preferably, the reduction of compound of formula (17) to obtain compound of formula (18) is carried out using potassium borohydride in presence of Lewis acid selected from lithium chloride, AlCl3, or BF3 etherate.

The solvent used in steps (c), (d), (e), and (f) may be either same or different and is selected from the group consisting of alkyl acetate selected from ethyl acetate, isopropyl acetate; aliphatic hydrocarbons selected from cyclohexane, n-hexane, n-heptane, pentane; aromatic hydrocarbons selected from toluene, xylene, naphthalene; halogenated hydrocarbons selected from are dichloromethane, chloroform, ethylene dichloride, chlorobenzene; dialkylformamides selected from dimethyl formamide; ethers such as but limited to methyl tertiary butyl ether, diisopropyl ether, diethyl ether and dimethyl ether, methyl butyl ether, dimethoxy ethane; cyclic ethers selected from tetrahydrofuran, 1,4-dioxane; substituted cyclic ethers selected from 2-methyl tetrahydrofuran, 4-methyl tetrahydropyran; alcohols selected from methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, n-pentanol, ethylene glycol, diethylene glycol; esters; ketones selected from acetone, methyl ethyl ketone, methyl isobutyl ketone; dialkylsulfoxides such as but limited to dimethyl sulfoxide; dialkylacetamides selected from ?,?-dimethyl acetamide; nitriles selected from acetonitrile, and propionitrile; ionic liquids; hexamethylphosphorous triamide; hexamethylphosphoramide; water; or mixtures thereof.

Preferably, the solvent used in step (c) is halogenated hydrocarbons. More preferably, the solvent used is dichloromethane.

Preferably, the solvent used in step (d) is nitriles, water or mixtures thereof. More preferably, the solvent used is acetonitrile, water or mixture thereof.

Preferably, the solvent used in step (e) is water.

Preferably, the solvent used in step (f) is dialkylsulfoxides. More preferably, the solvent used is dimethyl sulfoxide.

The base used in steps (c), (d), and (f) may be either same or different and is selected from inorganic bases selected from alkali metal carbonates selected from potassium carbonate, sodium carbonate, and cesium carbonate; alkali metal bicarbonates selected from sodium bicarbonate, and potassium bicarbonate; alkali metal hydroxides selected from sodium hydroxide, potassium hydroxide, barium hydroxide , and lithium hydroxide; metal hydrides, metal alkoxides selected from sodium methoxide, sodium ethoxide, and potassium tert butoxide; metal amides or liquor ammonia; and organic bases such as but not limited primary amines selected from methylamine, ethanolamine aniline, propyl amine, 2-propyl amine, butyl amine, and 2-amino ethanol; secondary amines selected from ?,?-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, and pyrrole methylethanolamine; tertiary amines like triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine, pyridine, lutidine, pyrimidine, and ?,?-dimethylethyl amine or mixtures thereof. Preferably, the base used in steps (c) and (f) is tertiary amines. More preferably, the base used is triethylamine. Preferably, the base used in step (d) is alkali metal carbonates. More preferably, the base used is potassium carbonate.
Deprotection of compound of formula (20) is carried out using an acid as a deprotecting agent, wherein the acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, and methane sulfonic acid. Preferably, deprotection of compound of formula (20) is carried out using the hydrochloric acid. Subsequently, aqueous ammonia is added to reaction mass of step (e) to obtain free base of compound of formula (7)

The activating reagent used in step (c) the present invention is that reagent which converts hydroxyl functionality into a good leaving group and selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl bromide, phosphorous tribromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p- toluenesulfonyl chloride, p-halobenzene sulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, halomethyl methyl ether (MOM), t-butyl chloride, t-butyl bromide, benzyl bromide, benzyl acetate, benzyl ethers, benzyl benzoate, benzyl chloride, p-methoxybenzyl chloride, halotrimethylsilanes, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triisopropylsilyl chloride, triphenylmethyl chloride, acyl chloride, acetic anhydride, t-butylacetyl chloride, t-butylacetic anhydride, alkyl halides and the like.
Preferably, the activating reagent used in step (c) is p-toluenesulfonyl chloride.

The compounds of formulae (17), (18), (19), (20), (7) and Cariprazine is isolated from the reaction mass and purified by involving at least one of the following methods like solvent extraction, filtration, precipitation, column chromatographic purifications or distillation methods.
According to the present invention, isolation followed by purification of compound of the formula (20) from reaction mass of step (d) comprises the steps of:
i. cooling, filtering the reaction mass of step (d) to obtain solid and further slurrying the obtained solid with water, optionally drying the solid; and
ii. purifying the obtained solid in nitrile solvent to obtain pure compound of formula (20).
Preferably, the solvent used in step (ii) is nitrile. More preferably, the solvent used is acetonitrile.

According to the present invention, isolation followed by purification of compound of the formula (7) from reaction mass of step (e) comprises the steps of:
i. cooling the reaction mass of step (e) to room temperature;
ii. basifying the reaction mass to a pH of 7 to 10;
iii. filtering the reaction mass of step (ii) to obtain solid; and
iv. washing the obtained solid with water, and drying the solid to obtain pure compound of formula (7).

According to the present invention, isolation followed by purification of compound of the formula (1) from reaction mass of step (f) comprises the steps of:
i. quenching the reaction mass of step (f) with water;
ii. treating the reaction mass of step (i) with organic solvent;
iii. separating the organic layer and concentrating the organic layer to obtain residue; and
iv. purifying the residue obtained in step (iii) by solvent crystallization or column chromatography technique.

Preferably, the organic solvent used in step (ii) is alkyl acetate. More preferably, the solvent used is ethyl acetate.

Preferably the solvent used for purification either by solvent crystallization or column chromatography is selected from halogenated hydrocarbons; alcohols; esters; ketones; nitriles; water or mixtures thereof.

Cariprazine (I) prepared by the process of the present invention has purity not less than 99.5% by HPLC.

Cariprazine prepared according to the process of the present invention has less than about 0.2% of CIMP-1 impurity, has less than about 0.2% of CIMP-2 impurity, has less than about 0.2% of CIMP-3 impurity, has less than about 0.2% of CIMP-4 impurity, has less than about 0.2% of CIMP-5 impurity, has less than about 0.2% of CIMP-6 impurity, has less than about 0.2% of CIMP-7 impurity, has less than about 0.2% of CIMP-8 impurity, has less than about 0.2% of CIMP-9 impurity, has less than about 0.2% of CIMP-10 impurity, has less than about 0.2% of CIMP-11 impurity.

BEST MODE OR EXAMPLES FOR WORKING OF THE INVENTION
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
Example 1: Preparation of Trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino]-cyclohexyl]-acetic acid ethyl ester:

Purified water (3.0 L) and trans-(4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (1.0 Kg) were charged in the reactor and stirred to obtain clear solution. Obtained solution was basified using aqueous ammonia (1.10 L). Trans-(4-amino-cyclohexyl)-acetic acid ethyl ester was extracted with dichloromethane (5.0 L X 2). Combined organic layer was concentrated under vacuum at below 45°C to obtain the Trans-(4-amino-cyclohexyl)-acetic acid ethyl ester (0.851 Kg).
THF (4.45 L), TBAB (0.008 Kg) and trans-(4-amino-cyclohexyl)-acetic acid ethyl ester (0.851 Kg) were charged in the reactor. Aqueous solution of sodium bicarbonate 7% w/v (6.0 L) was added to the reaction mixture followed by addition of solution of di(tert-butyl) dicarbonate (1.05 Kg) over 45 min at ambient temperature. Reaction mixture was stirred for 60 min at ambient temperature. After completion of the reaction, phases were separated and aqueous layer was washed with dichloromethane (5.67 L). The combined organic layer was washed with purified water (5.67 L) and concentrated under vacuum at below 45°C to obtained the white color residue of trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-acetic acid ethyl ester. (Purity: 98.65%; Yield: 95.0 %)

Example 2: Preparation of Trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino]-cyclohexyl]-acetic acid ethyl ester.
Purified water (20.0 L), sodium bicarbonate (0.810 Kg) and trans-(4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (1.0 Kg) were charged in the reactor and stir for 30 min at ambient temperature. THF (5.5 L), TBAB (0.008 Kg) were charged into the reaction mixture then the solution of di (tert-butyl) dicarbonate (1.05 Kg) was added over 45 min at ambient temperature. Reaction mixture was stirred for 60 min at ambient temperature. After completion of the reaction, phases were separated and aqueous layer was washed with dichloromethane (5.67 L). The combined organic layer was washed with purified water (5.67 L) and concentrated under vacuum at below 45°C to obtained the white color residue of trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-acetic acid ethyl ester. (Purity: 98.35%; Yield: 97.0 %)

Example 3: Preparation of Trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino]-cyclohexyl]-acetic acid ethyl ester:

Purified water (12.0 L) and sodium bicarbonate (0.79 Kg) were charged to the reactor and stirred to obtain clear solution. To the obtained solution was added trans-(4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (1.0 Kg) and stirred for 15 min. To the solution was added dimethoxy ethane (7.0 L) and TBAB (20.0 gm) and stirred for 15 min. Di(tert-butyl) dicarbonate (1.05 Kg) was added over 45 min to the reaction mixture at ambient temperature and was stirred for 60 min. After completion of the reaction, reaction mixture was chilled to 2 to 5°C and stirred for 3-4 hours and filtered.
Wet product was slurried in water (7 L), filtered and dried at 50-55°C for 4-6 hours to obtain trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-acetic acid ethyl ester. (Purity: 98.65%; Yield: 87.0%)

Example 4: Preparation of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino] cyclohexyl]-ethanol:

THF (9.0 L) and trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-acetic acid ethyl ester (1.0 Kg) were charged into the reactor and stirred to obtain solution. To the obtained solution was added lithium chloride (0.37 Kg) and stirred for 30 min at ambient temperature. Potassium borohydride (0.48 Kg) was added in portions to the reaction mixture. The reaction mixture was then stirred for 26-30 hrs at ambient temperature. After completion of the reaction, reaction mixture was quenched with 0.5N HCl solution. pH of the reaction mixture was adjusted between 3 to 4 and stirred for 15-30 min at ambient temperature. Reaction mixture was basified using aqueous ammonia solution and pH of the reaction mixture was adjusted 8 to 9. Desired product was extracted with dichloromethane (5.00 L X 2). Combined organic layer was washed with purified water (5.67 L) and 10.0% brine solution (5.67L). Organic layer was concentrated under vacuum at below 45°C to obtain the white color residue of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethanol. (Purity: 99.0%; Yield: 95.0 %)

Example 5: Preparation of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino] cyclohexyl]-ethanol:

THF (9.0 L) and trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-acetic acid ethyl ester (1.0 Kg) were charged into the reactor and stirred to obtain solution. To the obtained solution was added lithium chloride (0.37 Kg) and stirred for 30 min at ambient temperature. Potassium borohydride (0.48 Kg) was added in portions to the reaction mixture. The reaction mixture was then stirred at 40-45°C for 12-14 hrs at ambient temperature. After completion of the reaction, reaction mixture was quenched with 0.5N HCl solution. pH of the reaction mixture was adjusted between 3 to 4 and stirred for 15-30 min at ambient temperature. Reaction mixture was basified using aqueous ammonia solution and pH of the reaction mixture was adjusted to 8 to 9. Desired product was extracted with dichloromethane (5.00 L X 2). Combined dichloromethane (MDC) layer was washed with purified water (5.67 L) and 10.0% brine solution (5.67L). MDC layer was concentrated under vacuum at below 45°C to obtained the white color residue of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethanol. (Purity: 99.0%; Yield: 98.0 %)

Example 6: Preparation of Trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethyl p-toluene sulfonate

MDC (9.0 L) and trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethanol (1.0 Kg) were charged into the reactor and stirred to obtain solution. To the obtained solution was added triethyl amine (1.24 Kg) and p-toluene sulfonyl chloride (1.33 Kg). Reaction mixture was stirred for 10-12 hr. at ambient temperature. After completion of the reaction, reaction was quenched with purified water (9.0 L). Organic layer was separated and washed with 5.0% aqueous sodium carbonate solution (5.0 L X 3) and 10% brine solution (5.0 L). Organic layer was concentrated under vacuum at below 45°C to obtain crude residue of trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethyl p-toluene sulfonate. To the crude product was charged dimethoxy ethane (3.0 L) and purified water (6.0 L) and suspension was stirred for 45-60 min at ambient temperature, filter and dried to obtained pure trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethyl p-toluene sulfonate. (Purity: 98.50%; Yield: 88.0 %)

Example 7: Preparation of Trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethyl p-toluene sulfonate

MDC (9.0 L) and trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethanol (1.0 Kg) were charged into the reactor and stirred to obtain solution. To the obtained solution was added triethyl amine (1.24 Kg) and p-toluene sulfonyl chloride (1.37 Kg) in portions. Reaction mixture was stirred for 10-12 hr. at ambient temperature. After completion of the reaction, reaction was quenched with purified water (7.0 L). Organic layer was separated, washed with 10% brine solution (5.0 L) and concentrated under vacuum at <45°C to obtain residue of trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethyl p-toluene sulfonate (Purity: 86%; PTSA: 8%; Yield: 100.0 %)

Example 8: Preparation of trans n-tert-butoxycarbonyl-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexylamine

Purified water (15.0 L) and trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethyl p-toluene sulfonate (1.0 Kg) were charged into the reactor and stirred for 5-10 min. To the obtained suspension was added potassium carbonate (0.869 Kg) and 1-(2,3-dichlorophenyl) piperazine hydrochloride (4a) (1.00 Kg) and stir for 1-2 hrs at 75-80°C. After completion of reaction, reaction mixture was cooled to 25-30°C and was stirred for 45-60 min filter and dried to obtained crude product. To the obtained crude product was added acetonitrile (4.0 L) and was heated to reflux temperature for 45-60 min and then cooled to 0-5°C. Precipitated product was stirred at 0-5°C for 60 min, filter and dried to obtained pure trans-N-tert-butoxycarbonyl-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexylamine. (Purity: 99.0%; Yield: 90.0 %)
Example 9: Preparation of trans n-tert-butoxycarbonyl-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexylamine

Purified water (8.0 L) and potassium carbonate (0.869 Kg) were charged into the reactor and stirred for 5-10 min. To the obtained solution was added -(2,3-dichlorophenyl) Piperazine (DCPP.HCl, 4a, 1.00 Kg), trans-2-[1-[4-(N-tert-butoxycarbonyl)-amino]-cyclohexyl]-ethyl p-toluene sulfonate (1.0 Kg) and acetonitrile (1.0 L) and stir for 1-2 hrs at 60-65°C. After completion of reaction, reaction mixtures was cooled to 25-30°C and was stirred for 45-60 min, filter and dried to obtained crude product. To the obtained crude product was added acetonitrile (5.6 L) and was heated to reflux temperature for 45-60 min and then cooled to 0-5°C. Precipitated product was stirred at 0-5°C for 60 min, filter and dried to obtained pure trans-N-tert-butoxycarbonyl-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexylamine. (Purity: 99.0%; Yield: 88.0 %)

Example 10: Preparation of Trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexylamine

Purified water (7.0 L) and trans-N-tert-butoxycarbonyl-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexylamine (1.0 Kg) were charged into the reactor. Conc. HCl (1.0 L) was added to the reaction mixture and heated to 80-85°C. Reaction mixture was stirred for 1-2 hrs at 80-85°C. After completion of the reaction, reaction mixture was cooled to 25-30°C and stirred for 45-60 min. pH of reaction mass was adjusted to 8-10 by using aqueous ammonia solution and reaction mixture was stirred for 45-60 min at ambient temperature, filter and dried to obtained trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexylamine as a monohydrate. (Purity: 99.0%; Yield: 95.0 %)

Example 11: Preparation of Cariprazine Base:

To a 500 ml four-necked flask were added dichloromethane (180 ml), 40% sodium hydroxide (40 ml), TBAB (0.54 g) and S-Methyl N,N-Dimethylthiocarbamate (3.13 g). The mixture was stirred at a temperature between 20-25° C. for 30 minutes and then 6.24 g (0.0145 mol) of trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexyl amine was added. With rigorous stirring the reaction mixture was placed in an oil bath preheated to 40-45° C. and heated to boiling temperature under nitrogen for 10 hours. Reaction mixture was cooled to room temperature, the phases were separated and the organic layer was washed with water (80 ml × 3) and then with 10% sodium chloride solution (80 ml). The solvent was distilled out under vacuum and the residue obtained was further dried at maximum 50°C temperature, until its weight was constant to obtain crude Cariprazine base. The obtained crude Cariprazine base was crystallized from ethanol. Obtained purified compound was dissolved in Dichloromethane (50 ml) and washed with 1N HCl (32 ml X 5). Organic layer was distilled under vacuum to obtain residue. To the obtained residue was added water (75 ml) and the obtained suspension was basified with aqueous ammonia till to achieve pH 8 to 9 and stirred for 45-60 min and filtered to obtain pure Cariprazine base. (Purity: 99.87%; Yield: 48%)
Example 12: Preparation of Cariprazine Base.
To a 2.0L four-necked flask were added Dimethyl sulfoxide (DMSO) (350 ml), trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexyl amine (50 g) mixture was stirred till dissolution. S-Methyl N,N-Dimethylthiocarbamate (25 g) and triethylamine (28.4 g) was added to the solution and stirred for 16 hrs at 25-30° C. Reaction mixture was quenched with water (750ml) and cariprazine free base was extracted in ethyl acetate (350ml x 2). Layers were separated and the ethyl acetate layer was concentrated at vacuum at 45° C to obtain residue of crude cariprazine free base, which was purified by column chromatography using MDC and methanol mixture as purification solvent. (Purity: 99.0%; Yield: 58.33%)

Example 13: Preparation of Cariprazine Base.
To a 500 ml four-necked flask were added MDC (180 ml), 40% sodium hydroxide (40 ml), tetra-n-butyl ammonium bromide (0.54 g) and N,N-Dimethylcarbomyl bromide (5.54 g). The mixture was stirred at a temperature between 20-25° C. for 30 minutes and then (6.50 g) of trans 4-{2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl}-cyclohexyl amine was added. With rigorous stirring the reaction mixture was placed in an oil bath preheated to 40-45° C. and heated to boiling temperature under nitrogen for 10 hours. Reaction mixture was cooled to room temperature, the phases were separated and the organic layer is washed with water (80 ml × 3) and then with 10% sodium chloride solution (80 ml). The solvent was distilled out under vacuum and the residue obtained was further dried at maximum 50°C temperature, until its weight was constant to obtain crude Cariprazine base. The obtained crude Cariprazine base was crystallized from ethanol. Obtained purified compound was dissolved in MDC (50 ml) and washed with 1N HCl (32 ml X 5). Organic layer was distilled under vacuum to obtain residue. To the obtained residue was added water (75 ml) and the obtained suspension was basified with aqueous ammonia till to achieve pH 8 to 9 and stirred for 45-60 min and filtered to obtain pure Cariprazine base.

Example 14: Preparation of S-Methyl N,N-Dimethylthiocarbamate:
A 40% aq. soln of dimethyl amine (13.50 g) was added drop wise over 15-20 min to S,S'-Dimethyl dithiocarbonate (12.20 g) under stirring and maintained at 20-25 °C. The reaction mixture was heated to 40 °C and maintained for 3h. The mixture was diluted with dichloromethane (200 mL), organic layer was separated and washed with water (25 ml), and evaporated under reduced pressure to obtain crude S-Methyl N,N-Dimethylthiocarbamate. (Purity: 100.0%; Yield: 99.5%)

Example 15: Preparation of Cariprazine Hydrochloride:

To a 1.0 L four-necked flask was added water (400 ml) and Cariprazine base (40 gm). Obtained suspension was stirred for 5-10 min and to the suspension was added acetic acid (5.7 gm) to obtain Cariprazine acetate salt, which further was stirred for 45-60 min at ambient temperature. To the suspension of Cariprazine acetate was added dilute HCl prepared by using Con. HCl (11.84 ml) and water (80 ml). Suspension was stirred for 3 to 4 hours at ambient temperature and then cooled to 0-5°C for 45-60 min. precipitated product was filtered and dried to obtain Cariprazine HCl (Purity: 99.87%; Yield: 81%)
,CLAIMS:We claim:
1. A process for preparation of cariprazine hydrochloride, said process comprising:
a. basifying a compound of formula 13(a) to provide a free base of compound of formula 13 and further protecting the amino group of compound of formula 13 using a suitable amino-protecting agent to provide a compound of formula 17 in a solvent and in presence of base;

b. reducing the compound of formula 17 to provide a compound of formula 18;

c. activating the hydroxyl group of compound of formula 18 using an activating agent in a solvent and in presence of a base to provide a compound of formula 19;

d. reacting the compound of formula 19 with a compound of formula 4(a) in a solvent and in presence of a base to provide a compound of formula 20;

e. deprotecting the amino group of the compound of formula 20 using a suitable acid in a solvent to provide a compound of formula 7;

f. reacting the compound of formula 7 with a compound of formula 21 in a solvent and in presence of a base to provide a cariprazine free base;

g. treating the cariprazine free base obtained in step (f) with acetic acid to obtain cariprazine acetate salt, and converting the cariprazine acetate salt to cariprazine hydrochloride using dilute hydrochloric acid.

2. The process according to claim 1, wherein, the solvent used in step (a), (b), (c), (d), (e), and (f) may be either same or different and is selected from the group alkyl acetate; aliphatic hydrocarbons; aromatic hydrocarbons; halogenated hydrocarbons; dialkylformamides; ethers; cyclic ethers; substituted cyclic ethers; alcohols; esters; ketones; dialkylsulfoxides; dialkylacetamides; nitriles; ionic liquids; hexamethyl phosphorous triamide; hexamethyl phosphoramide; water; or mixtures thereof.

3. The process according to claim 1, wherein, the base used in steps (a), (c), (d), and (f) may be either same or different and is an inorganic bases selected from alkali metal carbonates; alkali metal bicarbonates; alkali metal hydroxides; metal hydrides, metal alkoxides; metal amides or liquor ammonia; or organic bases selected from primary amines; secondary amines; tertiary amines, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethyl amine, pyridine, lutidine, pyrimidine, and ?,?-dimethylethyl amine or mixtures thereof.

4. The process according to claim 1, wherein, the “phase transfer catalyst” used step (a) is selected from the group consisting of but not limited to tetra butyl ammonium bromide, tetra propyl ammonium bromide, tributyl benzyl ammonium bromide, tetra octyl ammonium bromide, tetra butyl ammonium iodide, tetra butyl ammonium hydrogen sulfate, benzyl trimethyl ammonium chloride, benzyl triethyl ammonium chloride, tetra butyl ammonium acetate, tetra butyl ammonium iodide, ethyl triphenyl phosphonium bromide, more preferably tetra butyl ammonium bromide or alkali iodides like sodium iodide, potassium iodide and lithium iodide.
5. The process according to claim 1, wherein, the amino-protecting agent used in step (a) is selected from di-tert-butyl dicarbonate (DIBOC), benzyl chloro formate, fluorenylmethyloxy carbonyl chloride (FMOC chloride), acetyl chloride, acetic anhydride, benzoyl halides, benzyl halides, alkyl or aryl sulfonyl halides or anhydrides such as mesyl halides, mesyl anhydride, tosyl halides, tosyl anhydrides, alkyl trifluoroacetates such as methyl trifluoroacetate, ethyl trifluoroacetate, isopropyl trifluoroacetate, vinyl trifluoroacetate, trifluoroacetic acid, and trifluoroacetyl chloride.

6. The process according to claim 1, wherein, the reducing agent used in step (b) is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, Fe/CaCl2, FeSO4, Fe powder, Raney Nickel, Pd/C, NaBH4, Potassium Borohydride, SnCl2.2H2O, Zn dust, Sodium Borohydride with Pd/C, thiophenol + trifluoroacetic acid, sodium sulphite, sodium hyposulphite, Na2S, NaBH4, NaBH4/BF3-diethyl ether, NiCl2.6H2O, LiBH4; LiAlH4; Lewis acid selected from lithium chloride, AlCl3, or BF3 etherate; or hydrogen gas or hydrogen source selected from ammonium formate, hydrazine hydrate, hydrazine glyoxylate, glyoxylic acid and hydrazinium monoformate.

7. The process according to claim 1, wherein, the activating reagent used in step (c) is selected from thionyl chloride, oxalyl chloride, phosphorous trichloride, phosphorous pentachloride, thionyl bromide, phosphorous tribromide, methanesulfonyl chloride, methanesulfonic anhydride, trifluoromethanesulfonyl chloride, trifluoromethanesulfonic anhydride, p- toluenesulfonyl chloride, p-halobenzene sulfonyl chloride, p-nitrobenzenesulfonyl chloride, benzenesulfonyl chloride, halomethyl methyl ether (MOM), t-butyl chloride, t-butyl bromide, benzyl bromide, benzyl acetate, benzyl ethers, benzyl benzoate, benzyl chloride, p-methoxybenzyl chloride, halotrimethylsilanes, t-butyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triisopropylsilyl chloride, triphenylmethyl chloride, acyl chloride, acetic anhydride, t-butylacetyl chloride, t-butylacetic anhydride, alkyl halides.

8. The process according to claim 1, wherein, the acid used for deprotection in step (e) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, trifluoroacetic acid, and methane sulfonic acid.

9. The process as claimed in claim 1, wherein isolation followed by purification of cariprazine base (1) from reaction mass of step (f) comprises the steps of:
i. quenching the reaction mass of step (f) with water;
ii. treating the reaction mass of step (i) with alkyl acetate;
iii. separating the organic layer and concentrating the organic layer to obtain residue; and
iv. purifying the residue obtained in step (iii) by solvent crystallization or column chromatography technique to provide pure cariprazine base (1).

10. The process as claimed in any of the preceding claims wherein the Cariprazine prepared by foregoing process, having less than about 0.2% of CIMP-1 impurity, has less than about 0.2% of CIMP-2 impurity, has less than about 0.2% of CIMP-3 impurity, has less than about 0.2% of CIMP-4 impurity, has less than about 0.2% of CIMP-5 impurity, has less than about 0.2% of CIMP-6 impurity, has less than about 0.2% of CIMP-7 impurity, has less than about 0.2% of CIMP-8 impurity, has less than about 0.2% of CIMP-9 impurity, has less than about 0.2% of CIMP-10 impurity, has less than about 0.2% of CIMP-11 impurity.

11. A compound of formula (21),

Which is used as an intermediate for preparation of cariprazine.