Claims:1. A process for preparation of cariprazine hydrochloride, comprising the steps of:
a) reactinga compound of formula-II salt,

Formula-II
with benzyl chloroformate in presence of suitable base and solvent to get CBZ protected compound of formula-II

Formula-II (CBZ)
b) reductionof Formula-II (CBZ), with suitable reducing agent and solvent to get compound of formula-III

Formula-III
c) activationof compound of formula-III with methane sulfonyl chloride and base to get compound of formula-IV

Formula-IV
d) optionally, isolated compound of formula-IV, treated with 1-(2,3-dichlorophenyl)piperazine hydrochloride in presence of suitable solvent and base to get compound of formula-V

Formula-V
e) deprotectionof compound of Formula-V,without use of hydrogen and under solvent free conditions to get compound of formula-VI

Formula-VI
f) treatingcompound of formula-VI with N,N-dimethylcarbamic chloride to get cariprazine free base with substantially free of desmethyl impurity.

g) treatingstep-(f) with hydrochloric acid with suitable solvent or mixture of solvent to get ICH complied cariprazine hydrochloride.

2. The process according to claim 1, wherein, the solvent used in step(a) to (g) 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; water; or mixtures thereof, excluding acetic acid or formic acid.

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 metalbicarbonates; alkali metal hydroxides; metal hydrides, metal alkoxides;metal amides or liquor ammonia; or organic bases selected fromprimary amines; secondary amines; tertiary amines, N,N-dimethylaniline, N,N-diisopropyl ethyl amine, trimethyl amine, pyridine, lutidine,pyrimidine, and N,N-dimethylethyl amine or mixtures thereof.

4. The process according to claim 1, wherein, the reducing agent used instep (b) is selected from NaBH4, LiAlH4, LiBH4, vitride, DIBAL, sodium cyanoborohydride, sodium triacetoxyborohydride;

5. The process according to claim-4, NaBH4 in the presence of Lewis acids BH3.THF, BH3-SMe2 (Borane-dimethyl sulfide), I2, ZnCl2, CaCl2 (or) NaBH4 in the presence of Lithium salts, LiCl, LiBr with alcohols like methanol, ethanol, isopropanol; more preferably NaBH4withmethanol.
6. The process according to claim 1, wherein deprotection in step-(e) is selected from strong mineral acids like HCl, HBr and organic acids like Methansulfonic acid, triflouroacitic acid.morepreferablyorganic acids.

7. The process according to claim-1, free base of compound of formula-VI, comprising the steps of:
a) reactinga compound of formula-II salt,

Formula-II
with benzyl chloroformate in presence of suitable base and solvent to get CBZ protected compound of formula-II

Formula-II (CBZ)
b) reductionof Formula-II (CBZ), with sodium borohydride with alcoholin presence of suitablesolvent to get compound of formula-III

Formula-III
c) activationof compound of formula-III with methanesulfonyl chloride and base to get compound of formula-IV

Formula-IV
d) Optionally, isolated compound of formula-IV, treated with 1-(2,3-dichlorophenyl)piperazine hydrochloride in presence of suitable solvent and base to get compound of formula-V

Formula-V
e) deprotection of compound of Formula-V with methanesulfonic acid to get compound of formula-VIas a free basewith compound of formula VIA and VIB as an impurities.

Formula-VI

Formula-VIA Formula-VIB

8. The process according to claim-7, one or more steps are performed without isolation of intermediates.

9. The process according to claim-1, Cariprazine hydrochloride of formula-1, comprises the steps
(f) treatingcompound of formula-VI with N,N-dimethylcarbamic chloride in presence of base and suitable solvents or its mixture to get substantially free of below mentioned impurities

(g) treatingstep-(f) with hydrochloric acid with suitable solvent or mixture of solvent to get ICH complied cariprazine hydrochloride.

10. The process according to claim-9, suitable solvent is alcohol, cyclic ether or mixture thereof; more preferably methanol, tetrahydrofuran or mixture thereof.
, Description:FIELD OF INVENTION
The present invention relates to an improved process for the preparation of Cariprazine hydrochloride with substantially free impurities.

BACKGROUND OF THE INVENTION
Cariprazine is a novel atypical antipsychotic, an orally active and potent dopamine D2 and D3 receptor partial agonist with preferential binding to D3 receptors and partial agonist at serotonin 5-HT1A receptors.

The chemical name of Cariprazine is trans-N-{4-[2-[4-(2,3-Dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N’,N’-dimethylurea corresponding to the molecular formula C21H32Cl2N4O. It has a relative molecular mass of 427.41 g/mol and the following structure

Formula-I

The synthesis of the Cariprazineand its derivatives are first disclosed in International patent application WO 2005012266A1 (herein after WO’266), in which two methods has reported for the synthesis of Cariprazineor itsderivatives. The processes for the preparation of Cariprazine as mentioned in WO’266 are depicted inscheme-1.

Scheme-1

As inWO’266 trans-(4-aminocyclohexyl)acetaldehyde and 1-(2,3-dichlorophenyl)piperazine hydrochloride are the key intermediates for the preparation of Cariprazine. In which expensive and hazardous regents like BINAP, Pd2(dba)3were reported for the preparation of 1-(2,3-dichlorophenyl)Piperazine hydrochloride.

To address the abovedeficiency, many other process related publications WO 2010/070368, WO 2010/070369, WO 2010/070370, WO 2010/070371, WO 2011/073705, WO 2015/056164, WO 2017/096997, WO 2018/007986, WO 2019/016828, WO 2019/106490, WO 2020/042876, WO 2020/056929, IN 201721035910, IN 201621039002, CN 103073524, CN 104496854, CN 106543039, CN 106699689, CN 108586389, CN110317182 came up, to solve one or more problems associated with WO’266.

Some of the prior art processes involves the multiple purifications to get the pure form of desired product. Speciallyto qualify the API with ICH standards,final stage involves the multiple purifications, which effects the yield and time cycle of reaction to get the desired product.

Thus, still there is a need to develop an improved process for the preparation of Cariprazine, which provides ICH qualified high pure cariprazine in a simple and cost efficient manner.
OBJECTIVE OF THE INVENTION
The main object of the present invention is to provide an industrially viable process for the preparation ofCariprazinehydrochloride of Formula-I.

Another object of the present invention is to provide a substantially free of desmethyl impurity of Cariprazine hydrochloride of Formula-I.

Desmethyl impurity

SUMMARY OF THE INVENTION
Thepresent invention is to provide an industrially viable process for the preparation of Cariprazine hydrochloride of Formula-I, comprising the steps of
a) reactinga compound of formula-II or its salts,

Formula-II
withbenzyl chloroformate in presence of suitable base and solvent to get CBZ protected compound of formula-II

Formula-II (CBZ)
b) reductionof Formula-II (CBZ), with suitable reducing agent and solvent to get compound of formula-III

Formula-III
c) activation of compound of formula-III with methane sulfonyl chloride and base to get compound of formula-IV

Formula-IV
d) optionally, isolated compound of formula-IV, treated with 1-(2,3-dichlorophenyl)piperazine hydrochloride in presence of suitable solvent and base to getcompound of formula-V

Formula-V

e) deprotectionof compound of formula-V,without use of hydrogen and under solvent free conditions to get compound of formula-VI

Formula-VI

f) treatingcompound of formula-VI with N,N-dimethylcarbamic chloride to get cariprazine free base with substantially free of desmethyl impurity.

g) treatingstep-(f) with hydrochloric acid with suitable solvent or mixture of solvent to get ICH complied cariprazine hydrochloride.

Formula-I

DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process wherein Cariprazine Hydrochloride of formula I is obtained as depicted in scheme III,

Scheme-III
In other embodiment of the invention, one or more chemical conversions are performed without isolating of intermediates.

In another embodiment of the invention, one or more steps are performed using single solvent.

In yet another embodiment, impurities of the present invention including process impurities are controlled to complies with ICH limit.

Substantially free of Desmethyl impurity in the process is less than 0.1%; more preferably 0.05%. Suitable solvent used to get ICH complied cariprazine hydrochloride with substantially free of desmethyl impurity is alcohol & ethers or mixture thereof.

Suitable solvent from step-(a) to (g); wherever necessary is selected from but not limited to hydrocarbon solvents, ether solvent, ester solvents, polar aprotic solvents, chloro solvents, ketone solvents, nitrile solvents, alcohol solvents, polar solvent, water or their mixture.

Suitable base from step-(a) to (g); is selected from organic or inorganic bases;Organic base is selected from group but not limited to triethylamine, N,N-diethylisopropylamine, ?,?-diisopropylethylamine (DIPEA), diethylamine, tripropylaminetrioctylamine, pyridine, lutidine, dimethylaminopyridine (DMAP), and dicyclohexylamine. Inorganic bases selected from alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates such as sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium bicarbonate.

Suitable reducing agent in step-(b), is selected form but not limited to NaBH4,LiAlH4, LiBH4, vitride, DIBAL, sodium cyanoborohydride, sodium triacetoxyborohydride; more preferably NaBH4

NaBH4 in the presence of Lewis acids like AlCl3, BF3, ZnCl2, CaCl2, I2 TMS-Cl, BH3, THF BH3-SMe2(or) NaBH4 in the presence of Lithium salts, LiCl and LiBr in THF alone or with combination of alcohol (MeOH, EtOH, iPrOH).

Suitablereducing agent in step-(b) is NaBH4 with alcohols.
Though, the combination of NaBH4 with alcohols was reported for the reduction of ester intermediate incariprazine synthesis, the determination and role of alcohol in activating the NaBH4 towards ester reduction was unexplained. The present invention highlights the activation of NaBH4 by converting it into alkoxyborohydridesin situ by controlled addition of alcohol to the combination of NaBH4 and ester.

Activating reagent of the present invention 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, phalobenzenesulfonyl 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, tbutyldimethylsilyl chloride, t-butyldiphenylsilyl chloride, triisopropylsilylchloride, triphenylmethyl chloride, acyl chloride, acetic anhydride, t-butylacetylchloride, t-butylacetic anhydride, alkyl halides and the like.

Deprotecting agent in step-(e) is selected from strong mineral acids like HCl, HBr and organic acids like Methansulfonic acid, triflouroacitic acid.

In the following examples, the preferred embodiment of the present invention is described only by way of illustrating the processes of the invention. However, these are not intended to limit the scope of the invention in any way.

Example 1 Preparation of ethyl 2-((1r, 4r)-4-(((benzyloxy) carbonyl) amino) cyclohexyl) acetate:
Aqueous solution of potassium carbonate 50% w/v (0.6 L) was charged in the reactor followed by addition of toluene (0.5L) and trans-(4-amino-cyclohexyl)-acetic acid ethyl ester hydrochloride (100 gm) and stirred to obtain clear solution. A solution of benzyl chloroformate (1.2 mole eq.) added into the reaction mass over 30 min and stirred for 10-12 hrs. After completion of the reaction, phases were separated and aqueous layer was washed with toluene (200 ml X 2) The combined organic layer was washed with 10% aqueous ammonia solution followed by purified water and concentrated under vacuum at below 450C to obtained the white color residue of ethyl 2-((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)acetate. (Purity: 98.65%; Yield: 95.0 %).

Example 2: Preparation of benzyl ((1r,4r)-4-(2-hydroxyethyl)cyclohexyl)carbamate:
THF (800 ml) and ethyl 2-((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)acetate ( 100 gm) were charged into the reactor and stirred to obtain solution. To the obtained solution was added sodium borohydride (96 gm) and stirred for 30 min at ambient temperature. Methanol (300 ml) was added dropwise into the reaction mixture. The reaction mixture was then stirred at 40-450C 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 8 to 9. Desired product was extracted with dichloromethane (200 ml X 2). Combined organic layer was washed with purified water and 10.0% brine solution. Organic layer was concentrated under vacuum at below 450C to obtain the white color residue of benzyl ((1r,4r)-4-(2-hydroxyethyl)cyclohexyl)carbamate. (Purity: 99.0%; Yield: 92.0 %)

Example 3: Preparation of benzyl ((1r,4r)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclo hexyl)carbamate
MDC (1.0 L) and benzyl ((1r,4r)-4-(2-hydroxyethyl)cyclohexyl)carbamate (100 gm) were charged into the reactor and stirred to obtain solution. To the obtained solution was added triethyl amine (110 gm) and methane sulfonyl chloride (62 gm). Reaction mixture was stirred for 2-3 hr. at ambient temperature. After completion of the reaction, reaction was quenched with purified water (200 ml). 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 450C to obtain crude residue of 2-((1r,4r)-4-(((benzyloxy)carbonyl)amino)cyclohexyl)ethyl methane sulfonate.

To the crude product was charged acetonitrile (1.0 L) and stirred for 5-10 min. To the obtained suspension was added potassium carbonate (100 gm) and 1-(2,3-dichlorophenyl) piperazine hydrochloride (91.64 gm) and stir for 8-10 hrs at 75-800C. After completion of reaction, distilled acetonitrile completely under vacuum below 50 C. Then reaction mixture was cooled to 25-300C, added Ethyl Acetate (200 ml) followed by water (500 ml) and stirred for 45-60 min. Filter and dried to obtained product. (Purity: 99.0%; Yield: 85.0 %)

Example 4: Preparation of (1r,4r)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexanamine
Methane sulfonic acid (200 ml) and benzyl ((1r,4r)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)carbamate (100 gm) were charged into the reactor. Reaction mixture was stirred for 6-8 hr. at ambient temperature. After completion of the reaction, reaction was quenched with purified water (300 ml) at low temperature and pH of the reaction mass was adjusted to basic by Aq. Ammonia solution. Reaction mass was stirred for 2 hr. at ambient temperature. Filter and reslurried the product in 10 % sodium bicarbonate solution followed by methyl tert butyl ether to get pure compound. The material was dried to obtained (1r,4r)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexanamine. (Purity: 99.2%; Yield: 85.0 %)

Example 5: Preparation of 3-((1r,4r)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexyl)-1,1-dimethylurea(Cariprazine Base):
(1r,4r)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexanamine (100 gm), 30% sodium hydrate aqueous solution (650ml) and tetrahydrofuran (600ml), are added in 2L RBF and reaction is stirred at room temperature 20 minutes. N, N- dimethyl methyl acyl chlorides (90.54 g) are added, under nitrogen protection, 8 hours is stirred at room temperature. After completion of the reaction, organic solvent is concentrated out, 500ml water is added. Filtered the product and reslurried the product in water. After ethyl alcohol recrystallization, the material was dried to obtained (1r,4r)-4-(2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl)cyclohexanamine. (Purity: 99.2%; Yield: 80.0 %)

Example 6: Preparation of Cariprazine Hydrochloride:
To a 1.0 L four-necked flask was added water (333 ml), Methanol (500 ml) and Cariprazine base (100 gm). Obtained suspension was stirred for 5-10 min and heated to 65-700C. to the suspension was added dilute HCl prepared by using Con. HCl 36.36gm in water 50 ml. Suspension was stirred for 3 to 4 hours at 65-700C and then distilled the solvent. After distillation, water (500 ml) was added & the product was filtered and dried to obtain Cariprazine Hydrochloride (Purity: 99.87%; Yield: 81%)