DESC:FORM 2

THE PATENTS ACT 1970
(SECTION 39 OF 1970)

&

THE PATENT RULES, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

IMPROVED PROCESS FOR THE PREPARATION OF CARIPRAZINE INTERMEDIATE OR ITS SALTS AND USE THEREOF

We, NIFTY LABS PVT LTD.,
a company incorporated under the companies act, 1956 having address at F. No: 203, Satya Sai Residency, Plot No. 7-1-54/1, Beside MCH Park, Dharam Karan Road, Ameerpet, Hyderabad- 500016, Telangana State, INDIA
.

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of cariprazine intermediate or its salts.

The present invention specifically relates to an improved process for the preparation of 2-((1R, 4R)-4-aminocyclohexyl) acetate derivatives of the Formula (I)

Formula (I)
or its salts, wherein R represents C1-C6 alkyl group and X is halogen.

The present invention more specifically relates to an improved process for the preparation of alkyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrohalide.

The present invention more specifically relates to an improved process for the preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride.

The present invention also relates to a purification method for ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride.

The present invention also relates to a process for the preparation of Cariprazine of the Formula (II)

Formula (II)
or it’s salts using compounds of Formula (I).

BACKGROUND OF THE INVENTION
The ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate and its derivatives are excellent starting materials for the synthesis of active pharmaceutical agents. Therefore it is important to provide an economical process by which the ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate and its derivatives can be prepared easy-to-make manner in the required drug-purity and with good yields. For the synthesis of active pharmaceutical agents only the optical (stereomerically) pure trans isomer form may be applicable.

CN 106543017 B patent claims a process for preparing 4-amino-cyclohexanoic acid hydrochloride by hydrogenation of 4-nitrophenylacetic acid as shown below:

KR 10-0641825 B1 issued to Kolon Corporation claims a process for the preparation of biphenyl-4-phenyl acetic acid as shown below:

This patent specifically discloses process for the preparation of 2-(4-aminophenyl)
acetic acid shown in below scheme:

US 4,719,203 A patent specifically discloses process for the preparation of p-aminophenyl acetic acid shown in below scheme:

US 7,858,630 B2 patent discloses a process for the preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride shown in below scheme:

US 8,802,888 B2 discloses a process for p-aminophenyl acetic acid as shown in the scheme given below:

The process disclosed in this patent specifically relates to a in situ process starting from
2-(4-nitrophenyl) acetic acid to ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride. Further, the process involve use of protic solvent (water). This patent does not enable a process wherein intermediates formed in each stage are isolated and use of aprotic solvent.

Journal of Medicinal Chemistry 1998, Vol 41, page 760-771 discloses process for the preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride shown in below scheme:

In the above mentioned journal, ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride is obtained from 4-nitrophenyl acetic acid by hydrogenation. The hydrogenation of a sodium salt is carried out at first in an aqueous medium in the presence of Raney-Ni catalyst at 49°C and under 130 psi at pressures, then further at 130°C and under 172 at pressures. The 4-amino-cyclohexyl-acetic acid obtained consists of about 81% of trans and 19% of cis isomers. Isolation of the required trans isomer is difficult to manage, as the mixture of the isolated trans and cis 4-amino-cyclohexyl acetic acid is dissolved in ethanol and saturated with anhydrous hydrochloric acid gas and heated to reflux. After cooling the mixture is filtered, the filtrate obtained is concentrated and the trans product is precipitated by ether.

Journal of Medicinal Chemistry 2013, Vol. 56, Issue 22, page 9199-9221 discloses process for the preparation of ethyl 2-(trans-4-aminocyclohexyl) acetate shown in below scheme:

Ethyl 2-(trans-4-aminocyclohexyl) acetate was synthesized by hydrogenation of 4-nitrophenyl acetic acid in a parr shaker for 3 days at 60 psi, followed by ethyl ester
formation in presence of concentrated hydrochloric acid and ethanol. The trans stereoisomer was isolated as the hydrochloride salt by fractional crystallization from diethyl ether and acetonitrile

Journal of Medicinal Chemistry 2015, Vol 58, issue13, page 5287-5307 discloses a process for the preparation of ethyl 2-(trans-4-aminocyclohexyl) acetate shown in below scheme:

The common disadvantages of the above known procedures are e.g. that the processes can be carried out only at very high temperatures and pressures in the presence of the very pyrophoric Raney-Ni catalyst therefore the industrial procedures are uneconomical and dangerous and require extra equipment and extreme conditions. Further disadvantage is that a sodium salt is hydrogenated therefore the working-up and recovering steps are difficult to manage. Namely, ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride is produced in anhydrous conditions in ethanol, saturated with hydrochloric acid in addition the reaction mixture is heated to reflux and the product is precipitated with ether. The procedure is disadvantageous from environmental point of view due to use of the very corrosive hydrochloric acid and inflammable ether.

Our aim was to provide a safe and easy-to-handle process for the preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride or well isolable derivatives thereof in industrial scale by which the product can be prepared via simple reaction steps and besides that said steps require neither solvents that are highly flammable and/or corrosive nor extra equipment. Further, the intermediates are isolated at each stage which provides the ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride in pure form.

Accordingly, there is a need for a process for ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride at relatively high yields and high purity while not using hazardous materials.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of cariprazine intermediate or its salts.

In another objective of the present invention is to provide an improved process for the preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate or its salts.

In another objective of the present invention is to provide an improved process for preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrohalide.

In another objective of the present invention is to provide an improved process for preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride.

In another objective of the present invention is to provide a purification process for the preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride which is commercially feasible / industrially scalable.

It is therefore an object of the present invention to provide a simple, economical and commercially feasible process for the synthesis of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride with a high yield and high purity.

SUMMARY OF THE INVENTION
In an aspect, the present invention is to provide an improved process for the preparation of cariprazine intermediate or its salts.

In another aspect, the present invention is to provide an improved process for the preparation of 2-((1R, 4R)-4-aminocyclohexyl) acetate derivatives of the Formula (I)

Formula (I)
or its salts, wherein R represents C1-C6 alkyl group and X is halogen.

In another aspect, present invention is to provide an improved process for preparation of alkyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrohalide.

In another aspect, the present invention is to provide an improved a process for preparation of 2-((1R, 4R)-4-aminocyclohexyl) acetate derivative of Formula (I)

Formula (I)
as hydrohalide salt, wherein process comprising the steps of:
a. hydrogenating 4-nitrophenyl acetic acid of the Formula (III)

Formula (III)
in an aprotic solvent at a temperature between 20-45°C in presence of Pd/C,
b. isolating the formed 2-(4-aminophenyl)acetic acid of the Formula (IV),

Formula (V)
c. hydrogenating the obtained 4-aminophenyl acetic acid and isolating 4-aminocyclohexyl acetic acid of the Formula (IV),

Formula (V)
d. esterifying the 4-aminocyclohexyl acetic acid obtained in step (c) in a solvent, and
e. isolating alkyl 2-((1R, 4R)-4-aminocyclohexyl) acetate as hydrohalide salt of Formula (I).

In yet another aspect, the present invention provides ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride obtained in a purity equal to or in excess of 98 %.

In yet another aspect, the present invention provides purification of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride by using an organic solvent; wherein the purification process is carried out by:
a. diluting crude compound in an alcoholic solvent,
b. addition of triethyl orthoformate,
c. removing alcoholic solvent and adding nitrile solvent
d. hearing the reaction mass to a temperature of 70 to 90°C, and
e. cooling the reaction mass to obtain pure product.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved process for the preparation of 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride derivatives of Formula (I).

The term alkyl as used herein includes methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, t-butyl and the like.

The inventors of the present application have surprisingly found that when 4-nitrophenyl acetic acid is hydrogenated in aprotic solvent in presence of Pd/C. The reaction proceeded very quickly in comparison to what was reported in the prior art. The inventors of the patent application have surprisingly found that by using aprotic solvent at low temperature, the reaction was complete in an hour as compared to time taken reported in prior-art. The reason being 4-nitrophenyl acetic acid and hydrogen solubility is less in water compared with an aprotic solvent like acetone, acetonitrile, N,N-dimethyl formamide (DMF), N,N-Dimethyl acetamide (DMA), and Tetrahydrofuran (THF).

The conversion of 4-nitrophenyl acetic acid to 2-(4-aminophenyl) acetic acid is isolated in the present process unlike in most of the prior-arts isolation of this intermediate does not take place. The inventors have found that by isolating the 2-(4-aminophenyl) acetic acid they were able to eliminate the traces of 4-nitrophenyl acetic acid since this nitro compound is a potential genotoxic impurity. The inventors aimed to control the genotoxic impurities as low as possible at upstream processes in comparison to the reported methods. By isolating, the 2-(4-aminophenyl) acetic acid the inventors have found that the carryover risk of genotoxic impurities was eliminated.

The obtained 2-(4-aminophenyl) acetic acid is further subjected to hydrogenation in Pd/C at to give 2-(4-aminocyclohexyl) acetic acid. This 2-(4-aminocyclohexyl) acetic acid is esterified in an esterifying alcohol, thionyl chloride and oxalyl chloride. However, in this stage the inventors have used azeotropic distillation with toluene to remove the residual water that accelerated the completion of the esterification to the maximum extent. The inventors employed azeotropic distillation with an aromatic hydrocarbon solvent because it was observed through a number of experiments that higher level of water content results in incomplete reaction resulting in increase of unreacted compounds as impurities. The inventors have observed that there is greater than 10 % of previous stage unreacted compounds. This ultimately leads to low purity and low yield of the final intermediate i.e. trans-4-aminocyclohexyl ethyl acetate hydrochloride.

Besides the inventors have surprisingly found that when the cis/trans mixture of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride salt prepared according to the invention the trans product can be isolated in extremely high purity and good yield.

The inventors have unexpectedly found that by selecting the above mentioned experimental conditions they were able to separate the mixture of cis/trans ethyl ester hydrochloric acids into corresponding cis/trans products with good trans yield.

The aprotic solvents employed are acetone, acetonitrile, DMF, DMA, DMSO, and THF.

The aromatic hydrocarbon solvents employed aretoluene, xylene, phenol,styrene, diethylbenzene, ethylbenzene etc.

Halide group as used in the present invention is bromo, chloro, fluoro or iodo group.

The main advantages of the present invention is isolation of all intermediate compounds of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride. This is achieved by using a mixture of solvents which are hitherto unreported in prior-art. The obtained solid was further purified in aromatic hydrocarbon solvents to yield highly pure ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride.

By the present improvisation of the process conditions and purification methods the inventors of the present application were able to prepare the trans-4-aminocyclohexyl ethyl acetate hydrochloride wherein the proportion of trans isomer increased substantially to more than 90 % with no other by products. This was achieved by the careful selection of reactions conditions, solvent choice and isolating the intermediary compounds.

The present invention is further illustrated by the following examples which are provided merely to be exemplary of the inventions and is not intended to limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

EXAMPLES
Example-1: Synthesis of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride:

Stage1: Preparation of 2-(4-aminophenyl)acetic acid in DMF:
In a 2.0 L Autoclave was charged with 800 mL of N,N-Dimethyl formamide (DMF) and 200 gm of 2-(4-nitrophenyl)acetic acid at 25-30°C under nitrogen atmosphere, followed by addition of 80 gm of 5% Pd/C and rinsed with additional N, N-Dimethyl formamide (DMF). After charging the catalyst, the vessel was pressurized with 5-7 kg of hydrogen gas and hydrogenation reaction was carried out at a temperature between 25-30°C until the hydrogen uptake is slowed. After completion of reduction, nitrogen was purged and the catalyst was filtered under pressurized nitrogen. The catalyst bed was washed with additional N, N-Dimethyl formamide (DMF). The combined filtrate was distilled out at below 75°C under reduced pressure. 1000 mL of water was added to the residue below 75°C and stirred the resulting solution for 30 minutes. The reaction mixture was cooled to 25-30°C, and the reaction stirred for 30 minutes at 25-30°C. The solid thus obtained was filtered, washed with water to give the 2-(4-aminophenyl) acetic acid (Yield: 150 gm, 90%).

Stage1: Preparation of 2-(4-aminophenyl)acetic acid in DMA:
In a 2.0 L Autoclave was charged with 800 mL of N,N-Dimethyl acetamide (DMA) and 200 gm of 2-(4-nitrophenyl)acetic acid at 25-30°C under nitrogen atmosphere, followed by addition of 80 gm of 5% Pd/C and rinsed with additional N, N-Dimethyl acetamide (DMA). After charging the catalyst, the vessel was pressurized with 5-7 kg of hydrogen gas and hydrogenation reaction was carried out at a temperature between 25-30°C until the hydrogen uptake is slowed. After completion of reduction, nitrogen was purged and the catalyst was filtered under pressurized nitrogen. The catalyst bed was washed with additional N, N-Dimethyl acetamide (DMA). The combined filtrate was distilled out at below 75°C under reduced pressure. 1000 mL of water was added to the residue below 75°C and stirred the resulting solution for 30 minutes. The reaction mixture was cooled to 25-30°C, and the reaction stirred for 30 minutes at 25-30°C. The solid thus obtained was filtered, washed with water to give the 2-(4-aminophenyl) acetic acid (Yield: 145 gm, 87%).

Stage1: Preparation of 2-(4-aminophenyl)acetic acid in THF:
In a 2.0 L autoclave was charged with 1000 mL of tetrahydrofuran (THF) and 200 gm of 2-(4-nitrophenyl)acetic acid at 25-30°C under nitrogen atmosphere, followed by addition of 80 gm of 5% Pd/C and rinsed with additional tetrahydrofuran (THF). After charging the catalyst, the vessel was pressurized with 5-7 kg of hydrogen gas and hydrogenation reaction was carried out at a temperature between 25-30°C until the hydrogen uptake is slowed. After completion of reduction, nitrogen was purged and the catalyst was filtered under pressurized nitrogen. The catalyst bed was washed with additional tetrahydrofuran (THF). The combined filtrate was distilled out at below 50°C under reduced pressure. 1000 mL of water was added to the residue below 75°C and stirred the resulting solution for 30 minutes. The reaction mixture was cooled to 25-30°C, and the reaction stirred for 30 minutes at 25-30°C. The solid thus obtained was filtered, washed with water to give the 2-(4-aminophenyl) acetic acid (Yield: 141 gm, 84.6%).

Stage2: Preparation of 2-(4-aminocyclohexyl) acetic acid:
800 mL water was charged of in a 2.0 L autoclave and 200 gm of 2-(4-amniophenyl) acetic acid at 25-30°C, was added followed by 48 gm of 5% Pd/C. The autoclave was pressurized with 5-7 kg of hydrogen gas, and hydrogenation was carried out at a temperature between 75-80°C. After completion of hydrogen uptake, the reaction mass was cooled to a temperature between 25-30°C and nitrogen was purged and the catalyst is filtered, washed with additional water. The combined filtrate was distilled out at below 75°C. The residue obtained was cooled to a temperature below 30°C, and ethanol was added, reaction mass was stirred at 75°C for 30 minutes. The reaction mass was cooled to 0-5°C, followed by filtration of the solid. The solid was washed with ethanol and dried to give the 2-(4-aminocyclohexyl)acetic acid (Yield: 187 gm, 90%)

Stage 3: Preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride:
In to 1000 mL round bottom flask equipped with mechanical stirrer and reflux condenser was charged with 600 ml of toluene and 200 gm 2-(4-aminocyclohexyl)acetic acid was added at 25-30°C. The reaction mass temperature was raised to about 60-65°C, distilled out toluene completely to remove residual water, and ethanol was charged at 25-30°C, under nitrogen atmosphere. The reaction mixture was cooled to 0-5°C and thionyl chloride was added along with catalytic amount of N,N-Dimethyl formamide (DMF). The reaction mass temperature was raised to 80-85°C and the reaction mixture was stirred for 2-3 hours. After completion of reaction, the reaction mixture was distilled to obtain a residue and to this residue was added acetonitrile. The obtained solid was filtered to give ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride which was subjected to purification.

To ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride crude product 400 mL of ethanol was added in a 1000 mL round bottom flask at 25-30°C followed by addition of triethyl orthoformate at 25-30°C. The reaction mixture was stirred at 40-45°C for 4-5 hours. The ethanol was distilled out at 40-45°C to obtain residue. Acetonitrile was added to the residue and the reaction mass temperature was raised to 80-85°C. The reaction mass was cooled to 25-30°C and the solid thus obtained was filtered, washed with water and dried to give pure ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride compound (Yield: 149 gm, 55% ).

Stage 3: Preparation of ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride:
In to 1000 mL round bottom flask equipped with mechanical stirrer and reflux condenser was charged with 600 ml of toluene and 200 gm 2-(4-aminocyclohexyl)acetic acid was added at 25-30°C. The reaction mass temperature was raised to about 60-65°C, distilled out toluene completely to remove residual water, and ethanol was charged at 25-30°C, under nitrogen atmosphere. The reaction mixture was cooled to 0-5°C and oxalyl chloride was added along with catalytic amount of N,N-Dimethyl formamide (DMF). The reaction mass temperature was raised to 80-85°C and the reaction mixture was stirred for 2-3 hours. After completion of reaction, the reaction mixture was distilled to obtain a residue and to this residue was added acetonitrile. The obtained solid was filtered to give ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride which was subjected to purification.

To ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride crude product 400 mL of ethanol was added in a 1000 mL round bottom flask at 25-30°C followed by addition of triethyl orthoformate at 25-30°C. The reaction mixture was stirred at 40-45°C for 4-5 hours. The ethanol was distilled out at 40-45°C to obtain residue. Acetonitrile was added to the residue and the reaction mass temperature was raised to 80-85°C. The reaction mass was cooled to 25-30°C and the solid thus obtained was filtered, washed with water and dried to give pure ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride compound (Yield: 145 gm, 53.5% ).

,CLAIMS:We Claim:
1. An improved process for the preparation of 2-((1R, 4R)-4-aminocyclohexyl) acetate derivatives of the Formula (I)

Formula (I)
or its salts, wherein R represents C1-C6 alkyl group and X is halogen, wherein the process comprising the steps of:
a. hydrogenating 4-nitrophenyl acetic acid of the Formula (III)

Formula (III)
in an aprotic solvent at a temperature between 20-45°C in presence of Pd/C,
b. isolating the formed 2-(4-aminophenyl)acetic acid of the Formula (IV),

Formula (V)
c. hydrogenating the obtained 4-aminophenyl acetic acid and isolating 4-aminocyclohexyl acetic acid of the Formula (IV),

Formula (V)
d. esterifying the 4-aminocyclohexyl acetic acid obtained in step (c) in a solvent, and
e. isolating alkyl 2-((1R, 4R)-4-aminocyclohexyl) acetate as hydrohalide salt of Formula (I) followed by purification.
2. The process as claimed in claim 1, wherein the compound of Formula (I) specifically is ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride.

3. The process as claimed in claim 1, wherein ethyl 2-((1R, 4R)-4-aminocyclohexyl) acetate hydrochloride obtained in a purity equal to or in excess of 98 %.
4. The process as claimed in claim 1, wherein the compound of Formula (I) is purified by using an organic solvent; wherein the purification process is carried out by:
f. diluting crude compound in an alcoholic solvent,
g. addition of triethyl orthoformate,
h. removing alcoholic solvent and adding nitrile solvent,
i. hearing the reaction mass to a temperature of 70 to 90°C, and
j. cooling the reaction mass to obtain pure product.
5. The process as claimed in claim 1, wherein the aprotic solvents employed are selected from acetone, acetonitrile, DMF, DMA, DMSO, and THF.
6. The process as claimed in claim 4, wherein the organic solvent employed are aromatic hydrocarbon solvents selected from toluene, xylene, phenol, styrene, diethylbenzene, ethylbenzene etc.
7. The process for preparing Cariprazine of the Formula (II)

Formula (II)
or its salts comprising the process for preparing compound of Formula (I) as claimed in any of claims 1-6.

Dated this Sixteenth (16th) day of May, 2020

__________________________________
Dr. S. Padmaja
Agent for the Applicant
IN/PA/883