FIELD OF INVENTION The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of highly pure Amisulpride.
BACKGROUND OF THE INVENTION U.S Patent No. 4,401,822 discloses a variety of benzamide derivatives, specifically Amisulpride, chemically named as 4-amino-N-[(l-ethylpyrrolidin-2-yI)methyl]-5-ethylsulfonyl-2-methoxy-benzamide, pharmaceutically acceptable salts thereof, processes for their preparation, pharmaceutical compositions and method of use thereof. Amisulpride is represented, by the following structural formula I:
Amisulpride is an atypical antipsychotic used to treat psychosis in schizophrenia and episodes of mania in bipolar disorder and is sold under the trade names Amazeo, Amipride, Amival, Solian, Soltus, Sulpitac, Sulprix, and Socian in various countries like India, Australia, Brazil, Russia, Ireland, United Kingdom and South Africa.
Various processes for the preparation of Amisulpride, its intermediates and pharmaceutically acceptable salts are disclosed in U.S. Patent No. US 4,401,822 A, U.S. Patent application No. US 2013/0096319A1, CN 103819383 A, CN 102838520 A, CN 102807516 A, andCN 101628886 B.
As per the process described in U.S. Patent No. 4,401,822 (hereinafter referred to as US'822 patent), Amisulpride is prepared by the oxidation of 2-methoxy-4-amino-5-ethyl-thio benzoic acid using acetic acid and hydrogen peroxide to obtain 2-methoxy-4-amino-5-ethyl-sulfonyl benzoic acid which is further coupled with l-ethyl-2-amino methyl pyrrolidine, in acetone in the presence of ethyl chloroformate and triethylamine and purified in acetone to get a

yield of 57%. The oxidation step requires a very long duration and the yields are comparatively low.
However, the process described in the US'822 patent suffers from the disadvantages such
as longer reaction times, low yields and purity.
Therefore, a need still remains for an industrially feasible process for the preparation of
Amisulpride with high purity and yield.
SUMMARY OF THE INVENTION It has been found that Amisulpride can be obtained with high purity and high yields by D carrying out the coupling reaction of 4-Amino-5-ethylsulfonyl-2-methoxybenzoic acid with 1-ethyl-2-aminomethyl-pyrrolidine in a chlorinated solvent, followed by purification in an alcohol solvent.
The purification process disclosed herein produces Amisulpride with a purity of greater than about 99.7%, specifically greater than about 99.8%, and most specifically greater than about 5 99.9% as measured by HPLC.
In one aspect, provided herein is a process for the preparation of Amisulpride by reacting 4-Amino-5-ethylsulfonyl-2-methoxybenzoic acid with I-ethyl-2-aminomethyl-pyrrolidine in a chlorinated solvent. The chlorinated solvent used is selected from the group consisting of dichloromethane, chloroform, chlorobenzene, 1,2-dichloroethene, • 1,1,2-trichloroethene and D mixtures thereof. A most specific chlorinated solvent is selected from the group consisting of chloroform, dichloromethane, and mixtures thereof.
In another aspect, provided herein is a purification process for the preparation of highly pure Amisulpride in an alcohol solvent. The alcohol solvent used is selected from the group consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butyl alcohol and mixtures 5 thereof. A most specific alcohol solvent is isopropyl alcohol.
DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided an improved process for the preparation of Amisulpride of formula I: 3

or a pharmaceutically acceptable salt thereof, comprising reacting 4-Amino-5-ethylsuIfonyl-2-methoxybenzoic acid of formula II:
or a salt thereof, with I-ethyI-2-aminomethyl-pyrrolidine of formula III:
or a salt thereof, in presence of a base and an alkyl chloroformate in a chlorinated solvent to produce Amisulpride of formula I or a pharmaceutical ly acceptable salt thereof, and optionally purifying the Amisulpride using an alcohol solvent to obtain highly pure Amisulpride.
In one embodiment, the chlorinated solvent used in the coupling reaction is selected from the group consisting of dichloromethane, chloroform, 1,2-dichIoroethene, 1,1,2-trichIoroethene, chlorobenzene, and mixtures thereof. A most.specific solvent is chloroform, dichloromethane, or a mixture thereof-
In another embodiment, the base used in the coupling reaction is selected from the group consisting of triethylamine, N,N-dirnethylamine, N,N-diisopropylethyIamine, pyridine, N-methylmorpholine, dimethylaminopyridine, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like. A most preferred base is triethylamine.

In another embodiment, the alkyl chloroformate used in the reaction is selected from the group consisting of methyl chloroformate, ethyl chloroformate, benzyl chloroformate, tertiary-butyl chloroformate, isobutyl chloroformate and the like. A most preferred alkylchloroformate is ethyl chloroformate.
In another embodiment, the reaction is carried out at a temperature of about -5°C to about 15°C, specifically at a temperature of about 0°C to about 10°C and most specifically at a temperature of about 5°C to about 10°C. The reaction time may vary between about 1 hour to about 5 hours, and specifically about 1 hour to about 1 hour 30 minutes. Further, the reaction mass is maintained at a temperature of about 20°C to about 40°C, more specifically at a temperature of about 25°C to about 30°C.
The reaction mass containing the crude Amisulpride of formula I obtained in the coupling reaction may be subjected to usual work up such as a washing, an extraction, an evaporation, a pH adjustment etc., followed by isolation and/or recrystallization from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
In one embodiment, the reaction mass containing the crude Amisulpride of formula I is extracted with aqueous hydrochloric acid, followed by layer separation and further extraction of • the chloroform layer with aqueous hydrochloric acid.
In another embodiment, the aqueous layer containing the crude Amisulpride is further subjected to carbon treatment, followed by filtration through hyflow, washing with DM water to get a clear aqueous layer. The carbon treatment is carried out by the methods known in the art, for example by stirring the solution with finely powdered carbon at room temperature for at least 5 minutes, and filtering the resulting mixture through charcoal bed to obtain a filtrate containing Amisulpride by removing charcoal. Specifically, finely powdered carbon is a special carbon or . an activated carbon.
In another embodiment, the aqueous layer obtained is subjected to pH adjustment with aqueous sodium hydroxide solution to get a precipitate of crude Amisulpride. The pH of the aqueous layer is adjusted at about 9.0 to 12.0 and more specifically at about 11.0 to 11.5. The reaction mass obtained is stirred for a period of about 1 hour to about 5 hours, and more specifically for a about period of 2 hours to about 3 hours.

In another embodiment, the crude Amisulpride of formula I obtained in the above
coupling reaction is further purified by using an alcohol solvent as per the methods described
herein below. '
According to another aspect, there is provided a process for the purification of crude Amisulpride comprising:
a) providing a solution of crude Amisulpride in an alcohol solvent;
b) subjecting the solution obtained in step-(a) to carbon treatment to obtain a clear solution; ,
c) cooling the solution obtained in step-(b) to cause crystallization; and
d) recovering the highly pure Amisulpride of formula I obtained in step-(c).
In one embodiment, the solvent used in step-(a) is selected from the group consisting of
methanol, ethanol, n-propanol, isopropyl alcohol, n-butyl alcohol and mixtures thereof. A most specific solvent is isopropyl alcohol.
Usually, the amount of isopropyl alcohol employed in step-(a) is about 2 volumes to about 10 volumes, specifically about 2.5 volumes to about 7 volumes,, with respect to the quantity of crude Amisulpride used.
Step-(a) of providing a solution of crude Amisulpride includes dissolving or extracting Amisulpride in an alcohol solvent used in step-(a), or obtaining an existing solution from a previous processing step.
Unless otherwise specified, the impure or crude Amisulpride used in step-(a) above as starting material can be obtained, for example, by the process described in the U.S..Patent No. 4,401,822 patent or by the process described herein above.
In another embodiment, the crude Amisulpride is dissolved or extracted in the alcohol solvent used in step-(a) at a temperature at about 40°C to 70°C, more specifically at a temperature at about 45°C to 65°C to get a clear solution.
The carbon treatment in step-(b) is carried out by the methods as described hereinabove.
The clear solution (filtrate) obtained after carbon treatment is subjected to cooling in step-(c) to a temperature at about -5°C to 10°C and more specifically at about 0°C to 5°C. The resulting mass is stirred for a period of about 1 hour to about 5 hours, more specifically for a period of about 1 hour to about 3 hours.

The process of recovering pure Amisulpride of formula I in step-(d) is carried out by the methods such as filtration, filtration under vacuum, decantation, centrifugation or a combination thereof.
Unless otherwise specified, the Amisulpride of formula I obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.
In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures such as about 35°C to about 90°C, and specifically at about 50°C to about 85°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1* to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed dryer, spin flash dryer, flash dryer, and the like.
The highly pure Amisulpride obtained by the processes disclosed herein has a.purity greater than about 99.7%, specifically greater than about 99.8%, and most specifically greater than about 99.9% as measured by HPLC. For example, the purity of the highly pure Amisulpride obtained by the process disclosed herein is about 99.8% to about 99.99% as measured by HPLC.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES Example 1 Preparation of crude Amisulpride
4-Amino-5-ethylsulphonyl-2-methoxybenzoic acid (125 g) and chloroform (900 ml) were taken into a clean reaction flask at a temperature of 25°C-35°C and the contents were stirred for 30 minutes at the same temperature to form a clear solution. To the resulting solution, triethylamine

(50 g) was added. The resulting mass was cooled to 0-5°C and ethyl chloroform ate (46 g) was added slowly and maintained for 30 minutes to 1 hour at the same temperature. 1-Ethyl-2-amino methyl-pyrrolidine (79 g) was added to the reaction mass slowly at a temperature of 0°C to 10°C and maintained for 1 hour to 1 hour 30 minutes at the same temperature. The temperature of reaction mass was raised to 25°C-35°C and maintained for 1 hour at the same temperature. After completion of reaction, aqueous hydrochloric acid was added and the reaction mass was extracted into aqueous layer. The layers were separated and the chloroform layer was further extracted twice with aqueous hydrochloric acid. The combined chloroform layers were sent for recovery. The aqueous layer was heated to 50°C-55°C to remove traces of chloroform. The reaction mass was cooled to 25°C-30°C. Carbon (10 g) and hyflow (25 g) were added to the reaction mass and stirred for 15 minutes. The reaction mass was filtered and further washed with DM water (100 ml). The pH of the reaction mass was adjusted to 11-11.5 with dilute sodium hydroxide solution at 25°C-30°C and stirred for a period of 2 hours to 3 hours at the same temperature. The resulting mass was filtered and washed with DM water (600 ml) to produce 160 g of crude Amisulpride.
Example 2
Purification of crude Amisulpride
Isopropyl alcohol (480 ml) and crude Amisulpride (160 g, obtained in example 1) were taken into a clear reaction flask at 25°C-35°C and heated to a temperature of about 55°C to 60°C. The reaction mass was stirred to get a clear solution. To the resulting solution, carbon (10 g) was added and the mixture was stirred for 10-15 minutes. The resulting mixture was filtered through carbon bed and washed with isopropyl alcohol (65 ml). The filtrate was cooled to 25°C-30°C and further cooled to 0°C-5°C. The reaction mass was maintained ati0°C-5°C for 1 hour to 1 hour 30 minutes at the same temperature. The resulting mass was filtered, washed with isopropyl alcohol and then dried the material at 50°C-55°C for 2 hours to 3 hours to produce 142.5 g of pure Amisulpride (HPLC purity 99.9%).

We Claim:
1. A process for the preparation of Amisulpride of formula I:
or a pharmaceutical I y acceptable salt thereof, comprising reacting 4-Amino-5-ethylsulfonyl-2-methoxybenzoic acid of formula II:
or a salt thereof, with l-ethyl-2-aminomethyl-pyrrolidine of formula III:
or a salt thereof, in presence of a base and an alkyl chloroformate in a chlorinated solvent
to produce Amisulpride of formula 1 or a pharmaceutical^ acceptable salt thereof, and
optionally purifying the Amisulpride using an alcohol solvent to obtain highly pure
Amisulpride. '
The process of claim I, wherein the chlorinated solvent used in the reaction is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethene, 1,1,2-trichloroethene, chlorobenzene, and mixtures thereof; wherein the base is selected from the group consisting of triethylamine, N,N-dimethylamine, N,N-diisopropylethylamine, pyridine, N-methylmorpholine, dimethylaminopyridine, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide; and wherein the alkyl chloroformate

is selected from the group consisting of methyl chloroformate, ethyl chloroformate, benzyl
chloroformate, tertiary-butyl chloroformate and isobutyl chloroformate.
The process of claim 2, wherein the chlorinated solvent used in the reaction is chloroform;
wherein the base used in the reaction is triethylamine; and wherein the alkyl chloroformate
used in the reaction is triethyl chloroformate.
A process for the purification of crude Amisulpride comprising:
a) providing a solution of Amisulpride in an alcohol solvent;
b) subjecting the solution obtained in step-(a) to carbon treatment to obtain'a clear solution;
c) cooling the solution obtained in step-(b) to cause crystallization; and
d) recovering the highly pure Amisulpride obtained in step-(c).
The process of claim 4, wherein the solvent used in step-(a) is selected from the group
consisting of methanol, ethanol, n-propanol, isopropyl alcohol, n-butyl alcohol and mixtures
thereof.
The process of claim 5, wherein the solvent used in step-(a) is isopropyl alcohol.
The process of claim 4, wherein the process of recovering pure Amisulpride in step-(d) is
carried out by filtration, filtration under vacuum, decantation, centrifugation or a
combination thereof.