DESC:FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Cariprazine or its pharmaceutically acceptable salts.
BACKGROUND OF THE INVENTION
Cariprazine is an atypical antipsychotic drug and is a potent dopamine D3/D2 receptor partial agonist with preferential binding to D3 receptors. The structural formula of Cariprazine is:

US7737142 discloses the compound 3-((1R,4R)-4-(2-(4-(2,3-dichlorophenyl) piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea and pharmacologically acceptable salts thereof with a process for preparation as depicted in scheme 1.

Scheme 1
The process of scheme 1 discloses synthesis of intermediate (6) wherein intermediate (4) is reacted with intermediate (5) in the presence of sodium triacetoxy borohydride for 12 hours. Intermediate (6) is further treated with acid to obtain intermediate (7).
The intermediate (7) as depicted in Scheme-1 (“Route-A”) is treated with N,N- dimethylcarbamoyl chloride (8) in the presence of triethylamine at ambient temperature for 48 hours to produce Cariprazine with 65% yield. In “Route-B” the intermediate (7) is treated with triphosgene and dimethyl amine hydrochloride in dry dichloromethane in the presence of triethylamine at ambient temperature for 20 hours to produce Cariprazine with 52% yield.
Routes A & B require long reaction time of 20 hours & 48 hours respectively. Further, the intermediate trans-tert-butyl (4- (2-oxoethyl) cyclohexyl) ammonium format (5) is expensive.
CN104496854 discloses a route for the preparation of Cariprazine hydrochloride. Scheme 2 is depicted below:

Scheme 2
Scheme 2 requires long reaction time of 18 hours. Further, the intermediate sodium triacetoxyborohydride and intermediate (14) are expensive.

WO2015056164A1 discloses two methods (Scheme 3 and Scheme 4) for the preparation of Cariprazine depicted below:

Scheme 3

Scheme 4
The process of Scheme 3 discloses synthesis of Cariprazine from intermediate (16) & (4) in the presence of Ruthenium complex and Xantphos ligand with 35% yield.
Scheme 3 requires long reaction time of 12 hours. Further, expensive reagents such as ruthenium complex and Xantphos ligand are used. In addition to these drawbacks, this process involves chromatographic techniques for purification which is tedious.

The process of scheme 4 discloses synthesis of Cariprazine from intermediate (17) & (4) in the presence of Ruthenium complex and Xantphos ligand followed by deprotection with trifluoroacetic acid to obtain intermediate (7). Intermediate (7) on reaction with carbonyldimidazole (CDI) followed by reaction with dimethyl amine for 20 hours to obtain Cariprazine.

The drawbacks of the Scheme 4 are that in the condensation step of intermediate (4) & intermediate (14) and final step i.e. reaction with dimethyl amine, the reaction times are 12 hours & 20 hours respectively. Expensive reagents such as ruthenium complex and Xantphos ligand are used. Further, highly unstable intermediate (19) is formed even in the presence of trace amount of moisture during the reaction of intermediate (7) with carbonyldimidazole (CDI).

US 8569496 discloses a route for the preparation of Intermediate 7 and scheme 5 is depicted below:

Scheme 5
The drawback of scheme 5 is that the reaction time is 16 hours for condensation of intermediate (4) and intermediate (14). US’496 uses alkyl mesylates and tosylates which are genotoxic and hence not desirable.
IN 201621039002 / IN 201721035910 discloses a process for the preparation of intermediate (20) wherein intermediate (4) is reacted with intermediate (19) in the presence of base as per Scheme 6 depicted below:

Scheme 6
Scheme 6 requires reaction temperature in the range of 60-65 °C and expensive solvents for the reaction and hence not desirable.
Yadav et al in Synth Commun. 2003; 33: 2483–2486 and Tetrahedron Lett. 1998; 39: 3259–3262 have reported zinc mediated alkylation of cyclic secondary amines and/or amino group protection in relatively expensive THF solvent.
Aim of the present invention is to provide a cost-effective industrial process for the preparation of Cariprazine or its pharmaceutically acceptable salts.
OBJECT OF THE INVENTION
The main objective of the present invention is to provide a cost-effective industrial process for the preparation of Cariprazine or its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION
The present invention provides a process (scheme 7) for the preparation of Cariprazine (I) or its pharmaceutically acceptable salts comprising:
a) reacting a compound of formula (IV) with a compound of formula (V) in the presence of zinc and acid in a solvent to obtain a compound of formula (III);
b) treating the compound of formula (III) with acid to obtain a compound of formula (II);
c) reacting the compound of formula (II) with a compound of formula (VI) in the presence of zinc and acid in a solvent to obtain Cariprazine (I);
d) optionally converting the Cariprazine compound of formula (I) into its pharmaceutically acceptable salts.

wherein X is halogen selected from Cl, Br and I.
Scheme 7

DETAILED DESCRIPTION OF INVENTION
It has surprisingly been found that the reaction time for the condensation of intermediate IV and intermediate V and the acylation reaction of intermediate II with dimethylcarbamic chloride is significantly reduced when the reaction is carried out in the presence of zinc and acid in a solvent. The acid is selected from acetic acid, oxalic acid, citric acid, ascorbic acid, benzoic acid, ammonium chloride, sulphurous acid, phosphoric acid.

The present invention provides a process for the preparation of Cariprazine (I) or its pharmaceutically acceptable salts,

comprising:
a) reacting a compound of formula (IV) with a compound of formula (V) in the presence of zinc and acid in a solvent to obtain a compound of formula (III);

wherein X is halogen selected from Cl, Br, I and F

b) treating the compound of formula (III) with acid to obtain a compound of formula (II);

c) reacting the compound of formula (II) with a compound of formula (VI) in the presence of zinc and acid in a solvent to obtain Cariprazine (I);

d) optionally converting the Cariprazine compound of formula (I) into its pharmaceutically acceptable salts.

The step (a) & (c) of the aforesaid process can be carried out in presence of zinc and acid in a solvent.
The acid used in step (a) & (c) is selected from acetic acid, oxalic acid, citric acid, ascorbic acid, benzoic acid, ammonium chloride, sulphurous acid and phosphoric acid.

The solvents of the step (a) & (c) are selected from halogenated hydrocarbons, nitriles, amides, ethers, aliphatic hydrocarbon, aromatic hydrocarbon and water. The halogenated hydrocarbons are selected from methylene chloride, ethylene chloride, chloroform and mixtures thereof. The nitriles are selected from acetonitrile, propionitrile, benzonitrile and mixtures thereof. The amides are selected from dimethyl formamide, dimethyl acetamide, N-methyl pyrrolidinone and mixtures thereof. The ethers are selected from tetrahydrofuran, dimethyl ether, di-isopropyl ether, methyl tertiary butyl ether, 1,4-dioxane and mixtures thereof. The aliphatic hydrocarbons are selected from cyclohexane, n-hexane, n-heptane, pentane and mixtures thereof. The aromatic hydrocarbons are selected from benzene, toluene, xylene, naphthalene and mixtures thereof.

The reaction of step (a) & (c) are carried out at 10°C - 50°C for 30 mins to 6 hours.
The step (b) of the aforesaid process is carried out in presence of acid and an organic solvent.

Acid used in step (b) is selected from acetic acid, trifluroacetic acid and hydrochloric acid.
Cariprazine is optionally converted into its pharmaceutically acceptable salts by any method known in the art.
The invention is exemplified with non-limiting examples.
Example(s):

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

1 g (3.26 mmol) of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino] cyclohexyl]-ethyl bromide and 0.754 g (3.26 mmol) 1-(2, 3-dichlorophenyl) piperzine was added to a stirred solution of 2.13 g (3.26 mmol) Zinc, 0.195 g (3.26 mmol) ACOH and 10 ml toluene. The reaction mixture was stirred for 40 - 60 min at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with ethyl acetate (10 mL*3 times). The combined organic layer was washed with saturated sodium bicarbonate and brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (90 % yield).

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

1 g (3.26 mmol) of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino] cyclohexyl]-ethyl bromide and 0.754 g (3.26 mmol) 1-(2, 3-dichlorophenyl) piperzine was added to a stirred solution of 2.13 g (3.26 mmol) Zinc, 0.195 g (3.26 mmol) ACOH and 10 ml DCM. The reaction mixture was stirred for 1.2 h at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with DCM (10 mL*3 times). The combined organic layer was washed with saturated sodium bicarbonate and brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (85 % yield).

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

1 g (3.26 mmol) of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino] cyclohexyl]-ethyl bromide and 0.754 g (3.26 mmol) 1-(2, 3-dichlorophenyl) piperzine was added to a stirred solution of 2.13 g (3.26 mmol) Zinc, 0.195 g (3.26 mmol) ACOH and 10 ml water. The reaction mixture was stirred for 2 h at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with DCM (10 mL*3 times). The combined organic layer was washed with saturated sodium bicarbonate and brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (80 % yield).

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

1 g (3.26 mmol) of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino] cyclohexyl]-ethyl bromide and 0.754 g (3.26 mmol) 1-(2, 3-dichlorophenyl) piperzine was added to a stirred solution of 2.13 g (3.26 mmol) Zinc, 0.17 g (3.26 mmol) ammonium chloride and 10 ml water. The reaction mixture was stirred for 1.5 h at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with DCM (10 mL*3 times). The combined organic layer was washed with saturated sodium bicarbonate and brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (75 % yield).

Example 5: Preparation of trans n-tert-butoxycarbonyl-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexylamine

1 g (3.26 mmol) of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino] cyclohexyl]-ethyl bromide and 0.754 g (3.26 mmol) 1-(2, 3-dichlorophenyl) piperzine was added to a stirred solution of 2.13 g (3.26 mmol) Zinc, 0.195 g (3.26 mmol) ACOH and 10 ml THF. The reaction mixture was stirred for 40 min at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with ethyl acetate (10 mL*3 times). The combined organic layer was washed with saturated sodium bicarbonate and brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (95 % yield).

Example 6: Preparation of trans n-tert-butoxycarbonyl-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl]-cyclohexylamine

1 g (3.26 mmol) of trans-2-[1-[4-(n-tert-butoxycarbonyl)-amino] cyclohexyl]-ethyl bromide was added to a stirred solution of 0.754 g (3.26 mmol) 1-(2, 3-dichlorophenyl) piperzine, 2.13 g (3.26 mmol) Zinc, and 10 ml THF. The reaction mixture was stirred for 50 min at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with ethyl acetate (10 mL*3 times). The combined organic layer was washed with sodium bicarbonate and saturated brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (82 % yield).

Example 7: Preparation of Trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexylamine

TFA (20ml) was added to a stirred solution of 2 g (4.3 mmol) trans n-tert-butoxycarbonyl-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl] cyclohexylamine in DCM. The reaction mixture was stirred at RT for 2 h to complete conversion of starting material, which is monitored by TLC. After completion of reaction, evaporate the reaction mixture and co-distillate using toluene. Residue was diluted with n-hexane, cool at 0°C for 1 hour and filtered to afford Trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexylamine in good yield (1.47 g 94% yield).

Example 8: Preparation of Cariprazine

1 g (3.26 mmol) of Trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexyl amine and 0.30 g (2.8 mmol) dimethylcarbamic chloride was added to a stirred solution of 0.180 g (2.8 mmol) Zinc, 0.15 g (2.8 mmol) ammonium chloride and 10 ml water. The reaction mixture was stirred for 2 h at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with DCM (10 mL*3 times). The combined organic layer was washed with saturated brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (74 % yield).

Example 9: Preparation of cariprazine

1 g (3.26 mmol) of Trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexyl amine and 0.30 g (2.8 mmol) dimethylcarbamic chloride was added to a stirred solution of 0.180 g (2.8 mmol) Zinc, 0.16 g (2.8 mmol) ACOH and 10 ml toluene. The reaction mixture was stirred for 1.5 h at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with DCM (10 mL*3 times). The combined organic layer was washed with sodium bicarbonate and saturated brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (71 % yield).

Example 10: Preparation of Cariprazine

1 g (3.26 mmol) of Trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexyl amine and 0.30 g (2.8 mmol) dimethylcarbamic chloride was added to a stirred solution of 0.180 g (2.8 mmol) Zinc, 0.16 g (2.8 mmol) ACOH and 10 ml DCM. The reaction mixture was stirred for 1.5 h at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with DCM (10 mL*3 times). The combined organic layer was washed with sodium bicarbonate and saturated brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (70 % yield).

Example 11: Preparation of cariprazine

1 g (3.26 mmol) of Trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexyl amine and 0.30 g (2.8 mmol) dimethylcarbamic chloride was added to a stirred solution of 0.180 g (2.8 mmol) Zinc, 0.16 g (2.8 mmol) ACOH and 10 ml water. The reaction mixture was stirred for 3 h at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with DCM (10 mL*3 times). The combined organic layer was washed with sodium bicarbonate and saturated brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (65 % yield).

Example 12: Preparation of Cariprazine

1 g (3.26 mmol) of Trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexyl amine and 0.30 g (2.8 mmol) dimethylcarbamic chloride was added to a stirred solution of 0.180 g (2.8 mmol) Zinc, 0.16 g (2.8 mmol) ACOH and 10 ml THF. The reaction mixture was stirred for 50 min at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with DCM (10 mL*3 times). The combined organic layer was washed with sodium bicarbonate and saturated brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (80 % yield).

Example 13: Preparation of Cariprazine

1 g (3.26 mmol) of Trans-4-[2-[4-(2,3-dichlorophenyl)-piperazine-1-yl]-ethyl-cyclohexyl amine was added to a stirred solution of 0.30 g (2.8 mmol) dimethylcarbamic chloride 0.180 g (2.8 mmol) Zinc, and 10 ml THF. The reaction mixture was stirred for 3 h at RT to complete conversion of starting material, which is monitored by TLC. After completion of reaction, the reaction mixture was filtered through celite pad and the residue was extracted with DCM (10 mL*3 times). The combined organic layer was washed with sodium bicarbonate and saturated brine solution. The combined organic layer was dried over sodium sulphate and evaporated under vacuum to obtain a pure product (76 % yield).

Example 14: Preparation of Cariprazine hydrochloride

1 g (2.3 mmol) cariprazine was dissolved in (2 ml) methanol, (10 ml) water and was stirred for 20 min at 65°C. To the stirred solution 30% Aq. HCl was added dropwise and stirred for same temperature for 20 min. cooled the reaction to 0°C and stirred for 3 h. filtered the solid and washed with cold water and dried to give cariprazine hydrochloride in good yield (92% yield).
The present invention has surprisingly found that the condensation reaction time between intermediate IV and intermediate V, and the acylation reaction of intermediate II with dimethylcarbamic chloride is significantly reduced to 0.5 hours to 1 hours as compared to prior art processes which take 16 hours - 48 hours.
Further, the present invention achieves this significant reduction in reaction time with the use of readily available and relatively cheaper reagents and solvents as compared to expensive reagents used in the prior art.
,CLAIMS:1. A process for preparation of Cariprazine compound of formula (I) or its pharmaceutically acceptable salts comprising:
e) reacting a compound of formula (IV) with a compound of formula (V) in the presence of zinc and acid in a solvent to obtain a compound of formula (III);
f) treating the compound of formula (III) with acid to obtain a compound of formula (II);
g) reacting the compound of formula (II) with a compound of formula (VI) in the presence of zinc and acid in a solvent to obtain Cariprazine (I);
h) optionally converting the Cariprazine compound of formula (I) into its pharmaceutically acceptable salts.
wherein X is halogen selected from Cl, Br and I.

2. The process as claimed in claim 1, wherein the acid used in steps (a) and (c) is selected from acetic acid, oxalic acid, citric acid, ascorbic acid, benzoic acid, ammonium chloride, sulphurous acid and phosphoric acid.
3. The process as claimed in claim 1, wherein the solvent in steps (a) and (c) is selected from halogenated hydrocarbons, nitriles, amides, ethers, aliphatic hydrocarbon, aromatic hydrocarbon and water.

4. The process as claimed in claim 1, wherein the acid used in step (b) is selected from acetic acid, trifluroacetic acid and hydrochloric acid.

5. A process for the preparation of compound of formula (III) comprising, reacting a compound of formula (IV) with a compound of formula (V) in the presence of zinc and acid in a solvent to obtain a compound of formula (III).

6. A process for the preparation of Cariprazine compound of formula (I) or its pharmaceutically acceptable salt thereof, comprising reacting the compound of formula (II) with a compound of formula (VI) in the presence of zinc and acid in a solvent to obtain Cariprazine (I).

7. The process as claimed in claim 5 and claim 6, wherein acid is acetic acid.

8. The process as claimed in claim 5 and claim 6, the reaction is carried out 10°C - 50°C for 30 mins to 6 hours.