PROCESS FOR THE PREPARATION OF ITOPRIDE, ITS SALTS AND INTERMEDIATES THEREOF

FIELD OF THE INVENTION

The present patent application relates to an improved process for the preparation of Itopride HC1 and its intermediates. Specifically, it relates to the preparation of 4-((3,4-dimethoxybenzamido)methyl)phenyl methanesulfonate thereof, which is used as an intermediate in the preparation of Itopride HC1.

BACKGROUND OF THE INVENTION

Itopride HC1 is chemically described as N-(4-(2-(dimethylamino) ethoxy)benzyl)-3,4-dimethoxybenzamide hydrochloride and is structurally represented by Formula I.
Itopride HC1 is a digestive tract motility activator, useful in the treatment of non-ulcer dyspepsia symptom of digestive system such as gastric discomfort and the like. Itopride HC1 is sold under the brand name "Ganaton" having dosage of 50 mg.

European patent EP 306827 first disclosed the process for the preparation of Itopride, its pharmaceutically acceptable salts and pharmaceutically acceptable compositions thereof. This process includes 4-hydroxy benzaldehyde with 2-dimethylamino ethyl chloride in presence of weak inorganic base to give 4-(2-dimetylamino ethoxy) benzaldehyde, followed by the reaction with hydroxylamine HC1 to obtain 4-(2-dimetylamino ethoxy) benzaldoxime, which is
subsequently reduced with raney nickel to get 4-(2-dimetylamino ethoxy) benzyl amine, which was treated with veratric acid chloride in presence of tertiary amine to get Itopride.

In International PCT application no WO 2007/074386 disclosed new intermediate N-(4-hydroxy benzyl)-3,4-dimethoxy benzamide by catalytic hydrogenation of p-hydroxy benzaldehyde with raney nickel in presence of methanolic ammonia solution and further reacting the obtained product with 3,4-dimethoxy benzoyl chloride in presence of calcium chloride.

Preparation of Itopride HC1 was disclosed in patents and patent applications JP 20044231527, JP 2004231526 and DE 10235312. All these patents disclosed the 4-(2-(dimethylamino)ethoxy)benzylamine used as an intermediate for the synthesis of Itopride HC1.

Prior art process involved in the reaction of 4-(2-dimetylamino ethoxy) benzyl amine with 3,4-dimethoxy benzoyl chloride in presence of hazardous solvents such as SOC12, which is not an eco friendly process making the process not suitable for commercial manufacturing. This problem has been overcome in this application by new process and new chemicals. All of the processes hither to known appear to use expensive, hazardous solvents or reagents, resulting lower yields, making the process not suitable for commercial manufacturing.
Therefore there is a need for a process or to prepare new intermediates which are advantageous in preventing hazardous raw materials and solvents, so as to increase the yields and purity of the Itopride and its pharmaceutically acceptable salts and intermediates.

SUMMARY OF THE INVENTION

The present patent application relates to a process for the preparation of Itopride, its salts and intermediates thereof.

In one aspect the present application provides a process for the preparation of Itopride and its salts of formula I, comprising the steps of:

a) reacting 4-hydroxy benzaldehyde of formula II with methane sulfonyl halide to give 4-formylphenyl methanesulfonate of formula III,

b) reacting the obtained product of step a) of formula III for catalytic hydrogenation with Raney nickel in presence of methanolic ammonia to give 4-(aminomethyl)phenyl methanesulfonate of formula IV,

c) reacting the obtained product of stage b) of formula IV, with 3,4-dimethoxy benzoic acid of formula V to get 4-((3,4-dimethoxy benzamido) methyl)phenyl methanesulfonate of formula VI,

d) reacting the obtained product of stage c) of formula VI with N,N-dimethyl amino ethyl halides or N,N-dimethyl amino ethanol of formula VII to obtain Itopride and finally converting the Itopride into its acid addition salts thereof.

In second aspect of the present application relates to the process for the preparation of Itopride and its salts of formula I, comprising the reaction of 2-(4-(aminomethyl)phenoxy)-N,N-dimethylethanamine of formula VIII with 3,4-dimethoxy benzoic acid of formula V to obtain Itopride and finally converting into its acid addition salts thereof.

In the final aspect of the present application relates to the process for the preparation of 4-(aminomethyl)phenyl methanesulfonate of formula V, starting with 4-hydroxy benzaldehyde of formula III without isolation of 4-formylphenyl methanesulfonate of formula IV.

DETAILED DESCRIPTION OF THE INVENTION

The present patent application relates to a process for the preparation of Itopride, its salts and intermediates thereof.

In one aspect the present application provides a process for the preparation of Itopride and its salts of formula I, comprising the steps of:

a) reacting 4-hydroxy benzaldehyde of formula II with methane sulfonyl halide to give 4-formylphenyl methanesulfonate of formula III,

b) reacting the obtained product of step a) of formula HI for catalytic hydrogenation with Raney nickel in presence of methanolic ammonia to give 4-(aminomethyl)phenyl methanesulfonate of formula IV,

c) reacting the obtained product of stage b) of formula IV, with 3,4-dimethoxy benzoic acid of formula V to get 4-((3,4-dimethoxy benzamido) methyljphenyl methanesulfonate of formula VI,

d) reacting the obtained product of stage c) of formula VI with N,N-dimethyl amino ethyl halides or N,N-dimethyl amino ethanol of formula VII to obtain Itopride and finally converting the Itopride into its acid addition salts thereof.

Step a) involves the reaction of 4-hydroxy benzaldehyde of formula II with methane sulfonyl halide to give 4-formylphenyl methanesulfonate of formula III.

Methane sulfonyl halide that may be used in the process of step a) includes methane sulfonyl chloride, methane sulfonyl bromide and methane sulfonyl iodide; preferably methane sulfonyl chloride.

Suitably the mole ratio of methane sulfonyl halide to 4-hydroxy benzaldehyde can range from 1 mole to 3 moles; preferably 1 mole to 1.2 moles.

Suitably the reaction process of step a) is carried out in the presence of acid scavenger such as triethylamine, diisopropylamine, diisopropylethylamine and the like.

Suitable solvents that can be used include but are not limited to; alkyl chlorides solvents such as dichloromethane and dichloroethane, and the like;

Suitable temperatures for conducting the reaction can range from about 0-10°C; preferably at 0-5°C. The reaction can be conducted till the completion of the reaction. Typically the reaction time varies from about 1 hour to 10 hours or about 3-5 hours.

After completion of the reaction, the reaction mixture was heated to 25-35°C and may be quenched with water, layers are separated. The organic layer containing the product may be separated, washed with water in order to remove excess acid scavengers and preceded to next step directly or it can be distilled to obtain the product as residue.

Suitable solvent that may be useful for isolating the product includes esters such as ethyl acetate, n-propylacetate, isopropyl acetate and the like; preferably ethylacetate.
The product obtained may be further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 70° C with or without vacuum. The drying can be carried out for any desired time periods to achieve the desired product purity, times from about 1 to 20 hours frequently being appropriate

Step b) involves reacting the obtained product of step a) of formula III for catalytic hydrogenation with Raney nickel in presence of methanolic ammonia to give 4-(aminomethyl)phenyl methanesulfonate of formula IV.

Suitably the reaction is carried in presence of methanolic ammonia solution. The concentration of methanolic ammonia solution can range from about 12-18%; preferably 15%. Suitably the reaction can be carried out while passing hydrogen gas till the completion of the reaction.
Suitable temperature for conducting the reaction can range from about 20°C-60°C, most preferably at 35°C-40°C. The reaction can be continued till the completion of the reaction. Typically the reaction time varies from about 10 hours to 15 hours or about 10-12 hours.

After completion of the reaction, the reaction mixture may be filtered and solvent was distilled out completely under vacuum to obtain the organic product. The organic product was extracted into suitable solvent and washed with water in order to remove impurity traces and preceded to acid addition salt formation or it can be distilled to obtain the product as residue.

Suitable solvent that may be useful for extracting the product includes alkyl chlorides such as ethylene dichloride or dichloromethane; and alcohols such as C1-C5 alcohols, preferably methanol, ethanol, isopropanol and t-butanol.
Suitable solvent that may be useful for isolating the product includes alcohols such as C1-C5 alcohols, preferably methanol, ethanol, isopropanol and t-butanol.

The organic product obtained can be optionally converted into free base or acid addition salt thereof. The organic layer can be reacted directly with acid to form acid addition salt.
In a specific embodiment, the residue obtained in step b) can be directly converted into its acid addition salt thereof. The residue is dissolved in a suitable solvent selected form water and C1-C5 alcohols and reacted with acid to form acid addition salt.

Suitable acids for acid addition salt formation include hydrobromic acid and hydrochloric acid. Preferable acid is Hydrochloric acid.

Step c) reacting the obtained product of stage b) of formula IV with 3,4-dimethoxy benzoic acid of formula V to get 4-((3,4-dimethoxy benzamido) methyl)phenyl methanesulfonate of formula VI.

Suitably the obtained product of stage b) can be in the form of free base or acid addition salt thereof. If the obtained product is in the form of acid addition salt it can be converted into its free base by suitable methods or adjusting the pH to basic with suitable bases well known to those skilled in art.

Suitably the mole ratio of 3,4-dimethoxy benzoic acid with respect to the obtained product of stage b) can range from about 1 mole to 3 moles; preferably 1 to 1.2 moles.

Suitably the reaction may be carried in the presence of or in the absence of coupling reagents; preferably in the presence of coupling reagents.

Suitable coupling reagents for conducting the reaction may be selected from HOBT (hydroxy benzotriazole) and DCC (dicyclohexyl carbodiimide) or both. The mole ratio of the coupling reagents with respect to the obtained product of stage b) can range from about 1 mole to 2 moles; preferably at 1.2 moles.

In one embodiment 3,4-dimethoxy benzoic acid of formula V was treated with HOBT (hydroxy benzotriazole ) in presence of chloro organic solvents. To this solution add DCC (dicyclohexyl carbodiimide) dissolved in chloro organic solvents for 15-30 minutes.

Suitable solvent for conducting the reaction may be selected form chloro organic solvents such as dichloromethane, dichloroethane and the like. The quantity of solvent used for providing solution depends on the solvent and the temperature opted for the process
Suitably the temperature for conducting the reaction can range from about 25-40°C; preferably at 25-30°C. Suitably the time taken for completion of the reaction can range from about 1-4 hours; preferably at 1-2 hours.

After completion of the reaction; the solution was cooled to 0-5°C; stirred about 45 min; then filtered the solid and washed with dichloromethane. The solvent of the filtrate was removed completely under vacuum to obtain the crude.

The above crude was dissolved in dichloromethane and added base (selected from sodium carbonate or potassium carbonate) to the crude. To this solution add the solution of 4-(aminomethyl)phenyl methanesulfonate of formula IV obtained in stage b dissolved in dichloromethane for about 15-40 minutes.

The quantity of solvent used for providing solution depends on the solvent and the temperature opted for the process
Suitably the temperature for conducting the reaction can range from about 25-40°C; preferably at 25-30°C. Suitably the time taken for completion of the reaction can range from about 1-4 hours; preferably at 1-2 hours.
After completion of the reaction, the precipitated HOBT (hydroxy benzotriazole) was filtered, washed with dichloromethane and the solvent was distilled out completely under vacuum to obtain crude.

The above solid was taken in IPA and heated to reflux, 12 N HC1 was added slowly and cooled to 0-5°C. The precipitated solid was filtered and washed with IPA. The wet material was charged with IPA and adjusted the pH to 10-12 with caustic lye and water, the solid material was filtered and washed with water and dried under vacuum.

The obtained product of stage c) can be used in the preparation of Itopride, its salts and the like: the crude obtained or the filtrate obtained in stage c) can be used directly used in the preparation of pharmaceutical compositions including Itopride, its salts and the like.

In step d) reacting the obtained product of stage c) of formula VI with N,N-dimethyl amino ethyl halides or N,N-dimethyl amino ethanol of formula VII to obtain Itopride and finally converting the Itopride into its acid addition salts thereof.

N,N-dimethyl amino ethyl halides are selected from N,N-dimethyl amino ethyl chloride, N,N-dimethyl amino ethyl bromide, N,N-dimethyl amino ethyl iodide and the like; preferably N,N-dimethyl amino ethyl chloride.

N,N-dimethyl amino ethyl halides or N,N-dimethyl amino ethanol can be in the form of free base or in the form of acid addition salt thereof; preferable acid addition salt is hydrochloride salt. If it is in the form of acid addition salt it is converted into free base and proceeded for the reaction.

Suitably the mole ration of N,N-dimethyl amino ethyl halides to 4-((3,4-dimethoxy benzamido) methyl)phenyl methanesulfonate of formula VI can range from 1 mole to 3 moles; preferably 1 mole to 1.5 moles

Suitable solvent for conducting the reaction can be selected from the dimethylformamide, dimethylacetamide and formamide; preferably dimethylformamide.

Suitable base for conducting the reaction can be selected form alkali metal hydroxides and carbonates such as sodium carbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; preferably in potassium hydroxide. Suitably the mole ratio of base to the 4-((3,4-dimethoxy benzamido) methyl)phenyl methanesulfonate of formula VI can range form about 1-3 moles; preferably at 1.2 moles.
Suitably the reaction may be optionally conducted in the presence or in the absence of phase transfer catalyst. Suitable phase transfer catalyst includes but are not limited to tetra butyl ammonium bromide (TBAB), methyltrioctylammonium chloride, potassium bromide, and the like. Tetra butyl ammonium bromide is preferred.

Suitable temperature for conducting the reaction can range form about 60-90°C; most preferably at 80°C. Suitably the time taken for the completion of the reaction can range from 3-8 hours; preferably at 4 hours or till the completion of the reaction.

After completion of the reaction; the reaction mixture was cooled and filtered. The solvent was distilled off completely under vacuum and the reaction mixture was quenched in water and extracted into suitable solvent at suitable pH. Separate the layers, the aqueous layer was basified with 10% potassium, carbonate. The reaction mass was filtered and the wet cake was washed with water and dried to get Itopride.
Suitable solvent for extracting the product includes esters such as ethyl acetate, n-propylacetate, isopropyl acetate and the like; preferably ethylacetate

The product obtained in stage d) can be converted into its acid addition salts thereof by dissolving the product obtained in stage d) in a suitable solvent selected form water and C1-C5 alcohols and reacted with acid addition salt.
Suitable solvents for conducting the reaction can be selected form water and C1-C5 alcohols such as methanol, ethanol, isopropanol, t-butanol or mixtures thereof.

Suitable acid addition salts can be selected form Hydrochloric acid, Hydrobromic acid, organic acids such as mandelic acid and oxalic acid. Preferable acid was hydrochloric acid.
In a specific embodiment, the residue obtained in step d) can be directly converted into its acid addition salt thereof. The residue is dissolved in a suitable solvent selected form water and C1-C5 alcohols and reacted with acid addition salt to form Itopride acid addition salt thereof.

In second aspect of the present application relates to the process for the preparation of Itopride and its salts of formula I comprising the reaction of 2-(4-(aminomethyl)phenoxy)-N,N-dimethylethanamine of formula VIII with 3,4-dimethoxy benzoic acid of formula V to obtain Itopride and finally converting into its acid addition salts thereof.

Suitably the mole ratio of 3,4-dimethoxy benzoic acid with respect to 2-(4-(aminomethyl)phenoxy)-N,N-dimethylethanamine of formula VIII) can range from about 1 mole to 3 moles; preferably 1 to 1.2 moles.

Suitably the reaction may be carried in the presence of or in the absence of coupling reagents; preferably in the presence of coupling reagents. Suitable coupling reagents for conducting the reaction may be HOBT (hydroxy benzotriazole) and DCC (dicyclohexyl carbodiimide). The mole ratio of the coupling reagents with respect 2-(4-(aminomethyl)phenoxy)-N,N-dimethylethanamine of formula VIII can range from about 1 mole to 2 moles; preferably at 1.2 moles.

In one embodiment 3,4-dimethoxy benzoic acid of formula V was treated with HOBT (hydroxy benzotriazole ) in presence of chloro organic solvents. To this solution add DCC (dicyclohexyl carbodiimide) dissolved in chloro organic solvents for 15-30 minutes.

Suitable solvent for conducting the reaction may be selected form chloro organic solvents such as dichloromethane, dichloroethane and the like. The quantity of solvent used for providing solution depends on the solvent and the temperature opted for the process
Suitably the temperature for conducting the reaction can range from about 25-40°C; preferably at 25-30°C. Suitably the time taken for completion of the reaction can range from about 1-4 hours; preferably at 1-2 hours.
After completion of the reaction; the solution was cooled to 0-5°C; stirred about 45 min; then filtered the solid and washed with dichloromethane. The solvent of the filtrate was removed completely under vacuum to obtain the crude.

The above crude was dissolved in dichloromethane and added base (selected from sodium carbonate and potassium carbonate) to the crude. To this solution add the solution of 2-(4-(aminomethyl)phenoxy)-N,N-dimethylethanamine of formula VIII dissolved in dichloromethane for about 15-40 minutes.

The quantity of solvent used for providing solution depends on the solvent and the temperature opted for the process
Suitably the temperature for conducting the reaction can range from about 25-40°C; preferably at 25-30°C. Suitably the time taken for completion of the reaction can range from about 1-4 hours; preferably at 1-2 hours.
After completion of the reaction, the precipitated HOBT (hydroxy benzotriazole) was filtered, washed with dichloromethane and the solvent was distilled out completely under vacuum to obtain crude.

The above solid was taken in IPA and heated to reflux, 12 N HC1 was added slowly and cooled to 0-5°C. The precipitated solid was filtered and washed with IPA. The wet material was charged with IPA and adjusted the pH to 10-12 with caustic lye and water, the solid material was filtered and washed with water and dried under vacuum to obtain Itopride.

The Itopride obtained can be converted into its acid addition salts thereof by dissolving the product in a suitable solvent selected form water and C1-C5 alcohols and reacted with acid addition salt.

Suitable solvents for conducting the reaction can be selected form water and C1-C5 alcohols such as methanol, ethanol, isopropanol, t-butanol or mixtures thereof.

Suitable acid addition salts can be selected form Hydrochloric acid, Hydrobromic acid, organic acids such as mandelic acid and oxalic acid. Preferable acid was hydrochloric acid.
In a specific embodiment, the residue obtained in step d) can be directly converted into its acid addition salt thereof. The residue was dissolved in a suitable solvent selected form water and C1-C5 alcohols and reacted with acid addition salt to form Itopride acid addition salt.

In the final aspect of the present application relates to the process for the preparation of 4-(aminomethyl)phenyl methanesulfonate of formula V, starting with 4-hydroxy benzaldehyde of formula III without isolation of 4-formylphenyl methanesulfonate of formula IV.

The reaction of 4-hydroxy benzaldehyde of formula III with methane sulfonyl halide was similar to that of as described in the step a) of the first aspect of the invention. After completion of the reaction, the organic layer obtained from the workup may be directly preceded for the next step without isolation of 4-formylphenyl methanesulfonate of formula IV as described in the step b) of the first aspect of the invention.

In yet another embodiment of the present invention describes the preparation of Itopride hydrochloride from 4-hydroxy benzaldehyde without isolating any of the intermediate. The organic layer of the intermediate may be directly preceded to the next step.

The product obtained in any step of the present invention may be further dried. Drying may be carried out in a tray dryer, vacuum oven, air oven,fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 70° C with or without vacuum. The drying can be carried out for any desired time periods to achieve the desired product purity, times from about 1 to 20 hours frequently being appropriate

The precipitated solid in any of the reaction step of the present application may be isolated by any method including decantation, filtration by gravity or by suction, centrifugation, and the like. Other techniques for separating the solids from the reaction mixtures are also within the scope of this invention. The process may include further drying of the product obtained with or without vacuum and in presence or absence of inert atmosphere.

The process of the present invention is simple and convenient for commercial manufacturing.
Having thus described the invention with reference to particular preferred embodiments and illustrative example, those in the art may appreciate modification to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set for the to aid in understanding the invention but are not intended to, and should not be construed to, limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well know to those of ordinary skilled in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.

EXAMPLES

Example 1: Preparation of 4-formvlphenvl methanesulfonate 4-Hydroxy benzaldehyde (20 gm, 1 moles) was charged in 200 ml of ethylene chloride at 25-35°C. Cool the reaction mixture to 0-5°C and charge TEA (20 gm, 1.2 moles) to the reaction mixture. Add Methane sulfonyl chloride (18 gm, 1 mole) at 0-5°C and maintain for I hour. After completion of the reaction checked by thin layer chromatography (TLC), the reaction mixture was quenched in 200 ml of water. Separate the layers and the organic layer was washed with 2% Soiumhydroxide solution:20ml and dried in Sodiumsulfate:5gmsdistilled out under the vacuum to get 29 gm of the title compound as crude.

Yield: 90%,
Purity:98% HPLC

Example 2: Preparation of 4-(aminomethvl)phenyl methanesulfonate Charge 13-15% methanolic ammonia (200ml) in an autoclave and add 4-formylphenyl methanesulfonate (12.0 gms) followed by raney nickel (2.5 gms). The hydrogenator was evacuated and flushed with nitrogen a few times. The autoclave is pressurized to 5 kg/cm2 with hydrogen and maintained for 12 hours at 25-40°C. The reaction is monitored on TLC and the reaction is continued till the starting material is less than 2%. Hydrogen pressure is released and the catalyst is filtered. Nitrogen gas is purged in the solution for 1 hour till the ammonia gas ceases. The solvent was distilled off uptol/3rd of the total volume under vacuum at 40-45°C. Charge 100 ml of ethylene chloride to the reaction mass and washed with 30 ml of water. Distilled out the solvent completely under vacuum to get 10.2 gm of the residue. Yield: 85%, Purity: 98% HPLC

Example 3: Preparation of 4-((3,4-dimethoxv benzamido) methvUphenvl methane sulfonate
A mixture of 3,4-dimethoxy benzoic acid (19gm,l mol) in dichloromethane (450 ml) and hydroxy benzotriazole( HOBT)(16.9 gm,1.2 mol) was stirred about 10 min. To this solution was added a solution of dicyclohexyl carbodiimide (DCC)(26.4gms,1.2mol) over a period of 15-30 min, and the reaction mixt ure was stirred about 1.5 hours at ambient temperature. After completion of the reaction (checked by thin layer chromatography), the solution was cooled to 0-5°C, stirred about 45 minutes, then the dicyclohexyl urea layer was filtered and washed with dichloromethane and the solvent of the filtrate was removed under vacuum completely. A mixture of the above crude, dichloromethane and potassium carbonate was stirred for 10 min, a solution of 4-(aminomethyl)phenyl methanesulfonate in dichloromethane was added over a period of 15-30 min and the reaction mixture was stirred for 45-60 minutes at ambient temperature. On completion of the reaction (checked by thin layer chromatography) the solution was cooled to 0-5°C and stirred for 45 minutes and precipitated hydroxy benzotriazole was filtered, washed with dichloromethane, and the solvent of the filtrate was removed completely under vacuum. The reaction mixture of the above solid was charged with IPA (3 times of the crude) was heated to reflux and maintained for 30 minutes, cooled to 0-5°C, and stirred for 45 minutes. Finally the precipitated solid was filtered and washed with IPA, the solid material was filtered, washed with water and dried at 50°C under vacuum to constant weight to afford the title compound. Yield:90% Purity:97% HPLC

Example 4: Preparation of Itopride Hydrochloride
Charge Dimethyaminoethanol (6.5 gm, 1.2 mol) in 40 ml of DMF at 25-35°C and stirred for dissolution . Add KOH (4 gms, 1.2 mol) to the reaction mixture, heat to 50°C and maintained for 1 hour. Charge 4-((3,4-dimethoxy benzamido) methyl)phenyl methanesulfonate (20 gm. 1 mole) to the reaction mixture at 50°C and heat the reaction mixture to 80°C and maintained for 4 hours. After completion of the reaction checked by thin layer chromatography, the reaction mixtures was cooled to 25-35°C, add water (4 times) to the reaction mixture and maintained for 1 hour. Filter the reaction mixture and dried to get 19.5 gms of the Itopride.
Charge 19.5 gm of Itopride in 170 ml of IPA at 25-35°C. Heat the reaction mixture to45- 50°C. Adjust the pH of the reaction mixture to 2 with 15% IPA HC1 to the reaction mass and maintain for 1 hour at 45-50°C at pH 2. Cool the reaction mixture to 25-35°C, filtered the reaction mixture and the filtrate was washed with 20 ml IPA and dried to get 20 gms of Itopride hydrochloride. Yield: 93%, Purity: 99% by HPLC.

Example 5: Preparation of Itopride Hydrochloride from 2-(4-(aminomethvl) phenoxy) - N. N-dimethvlethanamine A mixture of 3,4-dimethoxy benzoic acid (19gm,l mol) in dichloromethane (450 ml) and hydroxy benzotriazole( HOBT)(16.9 gm,1.2 mol) was stirred about 10 min. To this solution was added a solution of dicyclohexyl carbodiimide (DCC) over a period of 15-30 min, and the reaction mixture was stirred about 1.5 hours at ambient temperature. After completion of the reaction (checked by thin layer chromatography), the solution was cooled to 0-5°C, stirred about 45 minutes, then the dicyclohexyl urea layer was filtered and washed with dichloromethane and the solvent of the filtrate was removed under vacuum completely. A mixture of the above crude, dichloromethane and potassium carbonate was stirred for 10 min, a solution of 2-(4-(aminomethyl) phenoxy)-N,N-dimethylethanamine in dichloromethane was added over a period of 15-30 min and the reaction mixture was stirred for 45-60 minutes at ambient temperature. On completion of the reaction (checked by thin layer chromatography) the solution was cooled to 0-5°C and stirred for 45 minutes and precipitated hydroxy benzotriazole was filtered, washed with dichloromethane, and the solvent of the filtrate was removed completely under vacuum. The reaction mixture of the above solid was charged with IPA (3 times of the crude) was heated to reflux and maintained for 30 minutes, cooled to 0-5°C, and stirred for 45 minutes. Finally the precipitated solid was filtered and washed with IPA, the solid material was filtered, washed with water and dried at 50°C under vacuum to constant weight to afford the 19.5 gm of Itopride. Charge 19.5 gms of Itopride in 170 ml of IPA at 25-35°C. Heat the reaction mixture to45- 50°C. Adjust the pH of the reaction mixture to 2.0 with 15% IPA HC1 to the reaction mass and maintain for 1 hour at 45-50°C at pH 2.0. Cool the reaction mixture to 25-35°C, filtered the reaction mixture and the filtrate was washed with 20 ml IPA and dried to get 20 gms of Itopride hydrochloride. Yield: 93%, Purity: 99% by HPLC.

Claims:

1) A process for the preparation of Itopride HC1 comprising;

a) reaction of 4-hydroxy benzaldehyde of formula II with methane sulfonyl halide to give 4-formylphenyl methane sulfonate of formula III,

b) reacting the obtained product of step a) of formula III for catalytic hydrogenation with Raney nickel in presence of methanolic ammonia to give 4-(aminomethyl)phenyl methanesulfonate of formula IV,

c) reacting the obtained product of stage b) of formula IV, with 3,4-dimethoxy benzoic acid of formula V to get 4-((3,4-dimethoxy benzamido) methyl)phenyl methanesulfonate of formula VI in presence of coupling reagent.

d) reacting the obtained product of stage c) of formula VI with N,N-dimethyl amino ethyl halides or N,N-dimethyl amino ethanol of formula VII to obtain Itopride and its acid addition salts thereof.

2) The process of claim 1 step a), where in methane sulfonyl halide is selected from methane sulfonyl chloride, methane sulfonyl bromide and methane sulfonyl iodide.

3) The process of claim 1 step a), wherein the reaction is carried out in the presence of acid scavenger selected from triethylamine, diisopropylamine, diisopropylethylamine

4) The process of claim 1 step a) wherein the solvent for conducting the reaction is selected from dichloromethane and dichloroethane

5) The process of claim 1 step a) wherein the mole ratio of methane sulfonyl halide to 4-hydroxy benzaldehyde can range from 1 mole to 3 moles and temperatures for conducting the reaction can range from about 0-10°C.

6) The process of claim 1 step b) wherein the concentration of methanolic ammonia solution can range from about 12-18%.

7) The process of claim 1 step b) wherein the temperature for conducting the reaction is from 20°C-60°C.

8) The process of claim 1 step c) wherein the coupling reagent for conducting the reaction is HOBT (hydroxy benzotriazole) and DCC (dicyclohexyl carbodiimide).

9) The process of claim 1 step c) wherein the solvent for conducting the reaction is selected from dichloromethane and dichloroethane.

10) The process of claim 1 step c) wherein the temperature for conducting the reaction is from 20°C-40°C.

11) The process of claim 1 step d) wherein N,N-dimethyl amino ethyl halides are selected from N,N-dimethyl amino ethyl chloride, N,N-dimethyl amino ethyl bromide, N,N-dimethyl amino ethyl iodide and N,N-domethylamino ethanol.

12) The process of claim 1 step d) wherein the solvent is selected from the
dimethylforrnamide, dimethylacetamide and formamide.

13) The process of claim 1 step d) wherein phase transfer catalyst is selected
from tetra butyl ammonium bromide (TBAB), methyltrioctylammonium chloride, potassium bromide.

14) A process for the preparation of Itopride and its salts of formula I comprising the reaction of 2-(4-(aminomethyl)phenoxy)-N,N-dimethylethanamine of formula VIII with 3,4-dimethoxy benzoic acid of formula V to obtain Itopride and finally converting into its acid addition salts thereof.

15) The process of claim 14, wherein the the reaction of 2-(4-(aminomethyl)phenoxy)-N,N-dimethylethanamine of formula VIII with 3,4-dimethoxy benzoic acid of formula V is carried out in presence of coupling reagent.

16) The process of claim 15 wherein the coupling reagent is HOBT (hydroxy benzotriazole) and DCC (dicyclohexyl carbodiimide).

17) The process of claim 14, wherein the solvent used for conducting the reaction is selected from dichloromethane and dichloroethane.

18) The process of claim 14 wherein the acid addition salt is selected from HC1 and HBr.

19) The process of claim 14, wherein the mole ratio of 3,4-dimethoxy benzoic acid with respect to 2-(4-(aminomethyl)phenoxy)-N,N-dimethylethanamine of formula VIII) can range from about 1 mole to 3 moles.