THE PATENT ACT, 1970
(39 OF 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"PROCESS FOR THE PREPARATION OF TRANS-4-AMINOCYCLOHEXYLACETIC ACID DERIVATIVES"
2. APPLICANT
a. NAME: INDOCO REMEDIES LIMITED
b. NATIONALITY: INDIAN
c. ADDRESS: Indoco House,166 C.S.T. Road, Santacruz East,
Mumbai - 400 098, Maharashtra, India

TITLE: Process for the preparation of trans-4-aminocyclohexyl acetic acid derivatives.
FIELD OF INVENTION:
The present invention relates to a process for the preparation of ethyl trans-2-(4-aminocyclohexyl)acetate and its salt.
BACKGROUND AND PRIOR ART:
The compound ethyl trans-2-(4-aminocyclohexyl)acetate and its salt are an important starting materials for the synthesis of active pharmaceutical ingredient which has partial agonist activity at dopamine D1, D2 and D3 receptors. The 1,4-disubstituted cyclohexyl ring exists in cis and trans isomers. It is found that the trans isomers of 1,4-disubstituted cyclohexyl ring show greater affinity to Dl, D2 and D3 receptors than the corresponding cis isomer. Therefore it is important to provide an economical process by which the compound ethyl trans-2-(4-aminocyclohexyl)acetate and its salt of Formula I can be prepared with good yields.

US 8802888 B2 discloses a process for the preparation of trans-4-aminocyclohexylacetic acid ethyl ester HC1. The process disclosed involves two step hydrogenation of 4-nitrophenylacetic acid, wherein the reaction is carried out in presence of catalyst Pd/C and water as solvent. After completion of the reaction, catalyst is filtered and solvent is distilled out at 80°C under vacuum to get the residual mass. Further to the residual mass obtained, ethyl alcohol is added and distilled under vacuum at 80°C to get the compound 4-aminocxyclohexylacetic acid. The esterification reaction of the acid is carried out using hydrochloric ethanol at reflux. After the reaction the solvent is concentrated

under vacuum. Additional ethyl alcohol is added and distilled out the solvent completely at 80°C. The product trans-4-aminocyclohexylacetic acid ethyl ester hydrochloride is isolated using solvent acetonitrile.
The drawback in the process is the multiple time solvent addition and distillation, which is time consuming and difficult to implement at industrial scale. The process involves the use of ethyl alcohol, which is a controlled substance and requires strict vigil at the time of use on large scale.
Izvesztiya Akademii Nauk SSSR, Seriya Khimicheskaya, (10), 2374-2379 (Russian) 1980, discloses a process for the preparation of cis and trans isomers of 4-aminocyclohexylacetic acid and their derivatives. Accordingly, cis and trans isomers of 4-aminocyclohexylacetic acid are obtained starting from 4-nitrophenylacetic acid sodium salt by a hydrogenation reaction at 130°C and 150 atm pressures in the presence of Raney-Nickel catalyst. The product 4-aminocyclohexylacetic acid obtained are isolated in the form of hydrogen chloride salts.
According to Wustrow et al (Journal of Medicinal Chemistry, 1998, vol. 41, No. 5, 768), trans-aminocyclohexylacetic acid ethyl ester hydrochloride salt is obtained from 4-nitrophenylacetic acid by hydrogenation followed by esterification. The hydrogenation of sodium salt of 4-nitrophenylacetic acid is carried out at first in an aqueous medium in the presence of Raney-Nickel catalyst at 49°C under 130 atm pressures, then further at 130°C under 172 atm pressures. The product formed is mixture of cis and trans isomers of 4-aminocyclohexylacetic acid. Isolation of the required trans isomer from the mixture is difficult, so the mixture of the isolated trans and cis 4-amino-cyclohexyl acetic acid is dissolved in ethanol, saturated with anhydrous hydrochloric acid gas and heated to reflux. After cooling the mixture is filtered, the filtrate obtained is concentrated to get the residual mass. The product trans-4-aminocyclohexylacetic acid ethyl ester hydrochloride is isolated by using 1:1 mixture of ethanol and ether solvent.

The disadvantages of the above known procedures are that the process is carried out at very high temperatures and pressures. Further disadvantage is the isolation of the product from ether, which is highly flammable solvent. Use of high temperature and pressure for the reaction and solvent ether for isolation of the product makes the process unsafe to be used on industrial scale.
There is always a need to develop a safe and cost effective process for the preparation of ethyl trans-2-(4-aminocyclohexyl)acetate and its salt, by using economical reagents and safe solvents, which makes the process industrially viable and overcomes the problems associated with the processes known in the art. The present invention therefore seeks to address these issues.
Our aim is to provide a safe and easy-to-handle process for the preparation of ethyl trans-2-(4-aminocyclohexyl)acetate and its salt on industrial scale by which the product can be prepared via simple reaction steps and require solvents and reagents that are not flammable and economical and commercially available. Thus it becomes an objective of the present invention is to prepare ethyl trans-2-(4-aminocyclohexyl)acetate, the compound of Formula I or its salt with an industrially viable and cost effective process.
SUMMARRY OF THE INVENTION:
Accordingly, the present invention provides a process for preparing ethyl trans-2-(4-aminocyclohexyl)acetate, the compound of Formula I or its salt using readily available, cost effective, and industrially safe reagents and solvents.
According to primary object of the present invention, there is provided a cost effective and industrially safe process for the preparation of ethyl trans-2-(4-aminocyclohexyl)acetate, the compound of Formula I or its salt;


which comprises the steps of
i. hydrogenating the compound 2-(4-nitrophenyl)acetic acid of Formula II in
presence of catalyst and reacting with di-tert-butyl dicarbonate in presence
of base to isolate the compound 2-(4-((tert~
butoxycarbonyl)amino)cyclohexyl)acetic acid of Formula III;

ii. reacting the compound of Formula III with ethyl halide in presence of base and a solvent to isolate the compound ethyl 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)acetate of Formula IV;

iii. converting the compound of Formula IV to get crude ethyl trans-2-(4-aminocyclohexyl)acetate, compound of Formula I or its salt; and
iv. crystallising the crude compound of Formula I to isolate pure ethyl trans-2-(4-aminocyclohexyl)acetate, the compound of Formula I or its salt.
DETAILED DESCRITION OF THE INVENTION:
The present invention relates to a process for preparing ethyl trans-2-{4-aminocyclohexyl)acetate, the compound of Formula I or its salt.


In an aspect, the present invention provides a process for the preparation of ethyl trans-2-(4-aminocyclohexyl)acetate, the compound of Formula I or its salt, which comprises the steps of;
i. hydrogenating the compound 2-(4-nitrophenyl)acetic acid of Formula II in
presence of catalyst and reacting with di-tert-butyl dicarbonate in presence
of base to isolate the compound 2-(4-((tert-
butoxycarbonyl)amino)cyclohexyl)acetic acid of Formula III;

ii. reacting the compound of Formula III with ethyl halide in presence of base and a solvent to isolate the compound ethyl 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)acetate of Formula IV;

iii. converting the compound of Formula IV to get crude ethyl trans-2-(4-aminocyclohexyl)acetate, compound of Formula I or its salt; and
iv. crystallising the crude compound of Formula I to isolate pure ethyl trans-2-(4-aminocyclohexyl)acetate, the compound of Formula I or its salt.

In an embodiment of the present invention, the catalyst used for hydrogenation reaction in step (i) is selected from the group of Raney-Nickel, palladium on carbon (Pd/C) and platinum on carbon (Pt/C). The most preferred catalyst used for the hydrogenation is palladium on carbon (Pd/C).
In an embodiment of the present invention, the hydrogenation reaction in step (i) is carried out under hydrogen pressure of 1 bar to 4 bar and at the temperature in the range of 40°C to 55°C.
In an embodiment of the present invention, the reaction of step (i) is carried in presence of solvent selected from the group consisting of methanol, n-propanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, methyl vinyl ketone, methyl ethyl ketone, acetone and water or mixture thereof. The preferred solvent for the reaction is methanol, isopropanol, acetone and water or mixture thereof, wherein the preferred solvent for the reaction is acetone and water and mixture thereof.
In an embodiment of the present invention, the base used in step (i) is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, N,N-diisopropylethylamine, triethylamine. The preferred base used for the reaction is potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide and sodium hydroxide, wherein the most preferred base used is potassium carbonate.
In an embodiment of the present invention, the ethyl halide used in step (ii) is selected from the group of compounds ethyl iodide, ethyl bromide and ethyl chloride. The preferred ethyl halide used for the reaction is ethyl bromide.
In an embodiment of the present invention, the base used in step (ii) is selected from the group of compounds potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, N,N-diisopropylethylamine and triethylamine.

The preferred base used for the reaction is potassium carbonate, sodium carbonate, cesium carbonate, wherein the most preferred base used is potassium carbonate.
In an embodiment of the present invention, the reaction of step (ii) optionally the base used in combination of catalyst selected from potassium iodide and sodium iodide.
In an embodiment of the present invention, the solvent used in step (ii) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, methyl ethyl ketone, acetone, acetonitrile and N~methyl-2-pyrrolidone or mixture thereof. The preferred solvent used is N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and N-methyl-2-pyrrolidone, wherein the most preferred solvent used for the reaction is N,N-dimethylformamide.
In an embodiment of the present invention, the reaction of step (ii) is carried out at a temperature in the range of 25°C to 35°C.
In an embodiment of the present invention, the deprotection of the compound ethyl 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)acetate of Formula IV in step (iii) is carried out in presence of solvent selected from the group consisting of N,N-dimethylformamide, ethyl acetate, acetone, acetonitrile, isopropanol, n-propanol, 1,4-dioxane and tetrahydrofuran or mixture thereof
In an embodiment of the present invention, The preferred solvent used for the deprotection reaction is N,N-dimethylformamide, ethyl acetate, acetone and acetonitrile, wherein the most preferred solvent used is acetonitrile.
In an embodiment of the present invention, the deprotection of the compound ethyl 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)acetate of Formula IV in step (iii) is carried out using acid selected from gaseous hydrochloric acid or aqueous hydrochloric acid.
In an embodiment of the present invention, the deprotection of the compound of Formula IV is carried out in the solvent at a temperature in the range of 20°C to

30°C. The reaction completion is monitored on TLC. After the complete reaction the solvent is concentrated to get the crude compound of Formula I or its salt.
In an embodiment of the present invention, the crude compound obtained above is recrystallised using solvent to isolate the pure compound ethyl trans-2-(4-aminocyclohexyl)acetate, the compound of Formula I or its salt. The solvent used for the recrystallisation of the compound of Formula I or its salt is selected from the group consisting of acetonitrile, acetone, isopropanol, n-propanol, 1,4-dioxane and tetrahydrofuran or mixture thereof The preferred solvent is acetonitrile, acetone and isopropanol, wherein the most preferred solvent used for recrystallisation is acetonitrile.
In an embodiment of the present invention, the recrystallisation of the compound of Formula I or its salt is carried out by heating the reaction mass at a temperature in the range of 50°C to 60°C and finally cooling to 15°C to 20°C.
In an embodiment of the present invention, the compound of Formula I obtained from the present invention is ethyl trans-2-(4-aminocyclohexyl)acetate hydrochloride.
The advantage of the presnt invention over the prior arts is that, the process avoids the multiple time distillation of solvents including water which is tedious and time consuming and isolates the compound by simple filtration. The process of the present invention does not involve the use of ethyl alcohol which is controlled substance and requires strict vigil at the time of use on large scale. Further the present inventions also avoids use of high temperature and pressure for the reaction and the isolation of the product using solvent ether which is highly flammable solvent, and unsafe to be used on industrial scale.
The following examples, which fully illustrate the practice of the preferred embodiments of the present invention, are intended to be for illustrative purpose only, and should not be considered to be limiting to the scope of the present invention.

EXAMPLES:
Example 1: Preparation of 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)-
acetic acid: *
In an autoclave, charged 2-(4-nitrophenyI)acetic acid (1000 g) and 10% Pd/C (moist) (120 g) in water at 25°C to 30°C. Closed the autoclave and flushed with nitrogen. Started purging hydrogen gas and carried out hydrogenation maintaining pressure at 1 bar and temperature at40°C for 24 hours. Raised the temperature of the autoclave to 56°C and continued hydrogenation maintaining pressure of 4 bar and reaction temperature at 54°C to 56°C for48 to 50 hours till no consumption of hydrogen gas was observed. Cooled the reaction and flushed the reaction mass with nitrogen and filtered the catalyst over celite bed. The aqueous filtrate was taken in round-bottomed flask, charged potassium carbonate (860 g, 6.23 mol) in single lot under stirring for 30 minutes. Slowly charged di-tert-butyl dicarbonate (1420 g, 6.51 mol) and maintained the reaction mass under stirring for 16 to 20 hours at 25°C to 30°C. Slowly 15% Hydrochloric acid was added to bring the pH of the reaction mass between 3 to 4. The solid separated was filtered and washed with water. Dried the solid mass at 55°C to 60°C till constant weight to get 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)acetic acid. Yield = 615 g.
Example 2: Preparation of ethyl 2-(4-((tert-butoxycarbonyl)amino)-cyclohexyl) acetate:
In a round bottomed flask, charged 2-(4-((tert-
butoxycarbonyl)amino)cyclohexyl)acetic acid (200 g, 0.78 mol), potassium carbonate (214.8 g, 1.55 mol) and potassium iodide (2.0 g,) into N,N-dimethylformamide (1000 ml) at 25°C to 30°C and stirred for 30 minutes. Charged ethyl bromide (388.86 g, 3.12 mol) slowly in one lot and maintained under stirring for 16 to 24 hours at temperature 25°C to 30°C. The reaction mass was quenched with water (2000 ml), stirred and extracted with ethyl acetate twice (1600 ml). The combined organic layer was washed with water (1000 ml) and

20% brine (1000 ml), then dried over anhydrous sodium sulphate. Concentrated the solvent under vacuum maintaining temperature below 45°C to get the solid mass of ethyl 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)acetate. Yield = 209.6 g
Example 3: Preparation of ethyl trans-2-(4-aminocyclohexyl)acetate hydrochloride:
In a round bottomed flask, charged acetonitrile (1000 ml) to the solid mass of ethyl 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl)acetate (209 g, 0.73 mol) and stirred al 25nC to 30°C, Purged dry hydrogen chloride gas till the reaction mass attains saturation. Distilled out solvent under vacuum, maintaining the temperature below 45°C to get the residual mass. Charged acetonitrile (600 ml) to the residual mass and raised the temperature to 55°C to 60°C to dissolve the mass and get clear solution. Slowly cooled the solution to 25°C to 30°C and maintained for 2.0 hours. Further cooled to 18°C to 20°C and maintained for about 2.0 hours. Filtered the Solid and washed with cooled acetonitrile (100 ml). Dried the solid at 50°C to 55°C till constant weight to get the compound ethyl trans-2-(4-aminocyclohexyl)acetate hydrochloride. Yield = 41.34 g.

Claims:
1. A process for preparation of ethyl trans-2-(4-aminocyclohexyl)acetate, the compound of Formula I or its salt;

which comprises the steps of;
i. hydrogenating the compound 2-(4-nitrophenyl)acetic acid of Formula II in presence of catalyst and reacting with di-tert-butyl dicarbonate in presence of base to isolate the compound 2-(4-((tert-butoxycarbonyl)amino)cyclohexyl) acetic acid of Formula III;

ii. reacting the compound of Formula III with ethyl halide in presence of base and a solvent to isolate the compound ethyl 2-(4-((tert-butoxycarbonyl)amino) cyclohexyl)acetate of Formula IV;

iii. converting the compound of Formula IV to get crude ethyl trans-2-(4-aminocyclohexyl)acetate, compound of Formula I or its salt; and
iv. crystallising the crude compound of Formula I to isolate pure ethyl trans-2-(4-aminocyclohexyl)acetate, the compound of Formula I or its salt.

2. The process according to claim 1, wherein the catalyst used for hydrogenation in step (i) is selected from the group consisting of Raney-Nickel, palladium on carbon (Pd/C) and platinum on carbon (Pt/C).
3. The process according to claim 1, wherein the reaction of step (i) is carried out in presence of solvent selected from the group consisting of methanol, n-propanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide, methyl vinyl ketone, methyl ethyl ketone, acetone and water or mixture thereof.
4. The process according to claim 1, wherein the base used in the reaction of step (i) is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium hydroxide, sodium hydroxide, lithium hydroxide, N,N-diisopropylethylamine and triethylamine.
5. The process according to claim 1, wherein ethyl halide used in step (ii) is selected from the group consisting of ethyl iodide, ethyl bromide and ethyl chloride.
6. The process according to claim 1, wherein the base used in the reaction of step (ii) is selected from the group consisting of potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, N,N-diisopropylethylamine and triethylamine.
7. The process according to claim 1, wherein the solvent used in the reaction of step (ii) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, methyl ethyl ketone, acetone, acetonitrile and N-methyl-2-pyrrolidone or mixture thereof
8. The process according to claim 1, wherein the reaction of step (iii) is carried out in presence of acid selected from gaseous hydrochloric acid and aqueous hydrochloric acid.
9. The process according to claim 1, wherein the reaction of step (iii) is carried out in presence of solvent selected from the group consisting of N,N-dimethylformamide, ethyl acetate, acetone and acetonitrile or mixture thereof.

10. The process according to claim 1, wherein the crude compound of Formula I or its salt obtained as above in step (iii) is crystallised from the solvent selected from the group consisting of acetonitrile, acetone, n-propanol, isopropanol, 1,4-dioxane and tetrahydrofuran or mixture thereof.